ChemWiki - User contributions [en]

Rep:Mod:knt11Y3S1C

2013-11-26T13:49:13Z

Xc2611: /* Analysis of the properties of the alkene epoxides */

== Y3S1C: Third year Synthesis Laboratory Module 1C ==
Name: Kai Ni Teh 
CID: 00697229 

== Introduction ==
Over the past few decades, the use of computational methods and modelling has become more prevalent in determining the outcome of reactions and the stability and properties of molecules. With this understanding in mind, this computational exercise consists of two parts, the first with the aim to introduce basic computational techniques and the second with the aim to assign stereochemistry of compounds synthesised in a related organic synthesis laboratory session. Instead of UFF, which is a method that can be used across the periodic table of elements but is a simpler model which fixes the hybridisation of each atom, MMFF94s is used.

== Conformational analysis using Molecular Mechanics ==
This part of the exercise compares the energies of related compounds, isomers or atropisomers in some cases, to determine and explain the relative stability of one of the compounds.

=== Cyclopentadiene dimerisation ===

Cyclopentadiene dimerises readily and the two dimers are the exo and endo dimers.

[[File:knt_cp_dimerisation2.jpg|350px|center]] 

The MMFF94s method is run to determine the energies of the exo and endo dimers and the results are shown in Table 1.

{| class="wikitable" border="1" style="margin: 1em auto 1em auto;"
|+
| || align="center" | Compound 1 || align="center" | Compound 2
|-
| Figure || align="center" | [[File:knt_cp_exo.png|200px]] || align="center" | [[File:knt_cp_endo.png|150px]]
|-
| Total bond stretching energy /kcalmol-1 || align="center" | 3.54296 || align="center" | 3.46794
|-
| Total angle bending energy /kcalmol-1 || align="center" | 30.77260 || align="center" | 33.18931
|-
| Total torsional energy /kcalmol-1 || align="center" | -2.73079 || align="center" | -2.94950
|-
| Total van der Waals energy /kcalmol-1 || align="center" | 12.80159 || align="center" | 12.35874
|-
| Total electrostatic energy /kcalmol-1 || align="center" | 13.01368 || align="center" | 14.18456
|-
| Total energy /kcalmol-1 || align="center" | 55.37342 || align="center" | 58.19067
|}
<div style="text-align: center;">Table 1. Energies for exo and endo dimers of cyclopentadiene.</div> 

Cyclopentadiene dimerisation is an example of Diels Alder cycloaddition reaction with π2s + π4s or π4s + π2s components.

Comparing the total energies of the exo and endo dimers, it is clear that the exo dimer is the thermodynamically more stable product given its lower energy. However, it is a well-known fact that Diels Alder cycloaddition reactions usually produce the endo product preferentially. This can be explained by secondary orbital interactions derived from the endo transition state, which is absent in the exo transition state.<ref name="jo00384a016">M. A. Fox, R. Cardona, N. J. Kiwiet, "Steric Effects vs. Secondary Orbital Overlap in Diels-Alder Reactions. MNDO and AM1 Studies.", ''J. Org. Chem.'', '''1987''', ''52'', 1469–1474. {{DOI|10.1021/jo00384a016}}</ref> Hence, the endo dimer is the product under kinetic control and it is formed at a faster rate. This also illustrates the overriding effect of this favourable secondary orbital interactions over the higher angle strain observed in the endo dimer.

=== Hydrogenation of cyclopentadiene ===
Partial hydrogenation of the endo dimer initially produces one of the dihydro derivatives 3 or 4, instead of the tetrahydro derivative which is only formed after prolonged hydrogenation.

[[File:knt_cp2_hydrogenation.jpg|600px|center]] 

The MMFF94s method is run to determine the energies of the dihydro derivatives and the results are shown in Table 2.

{| class="wikitable" border="1" style="margin: 1em auto 1em auto;"
|+
| || align="center" | Compound 3 || align="center" | Compound 4
|-
| Figure || align="center" | [[File:knt_cph_3.png|175px]] || align="center" | [[File:knt_cph_4.png|175px]]
|-
| Total bond stretching energy /kcalmol-1 || align="center" | 3.31222 || align="center" | 2.82313
|-
| Total angle bending energy /kcalmol-1 || align="center" | 31.97095 || align="center" | 24.68535
|-
| Total torsional energy /kcalmol-1 || align="center" | -1.59562 || align="center" | -0.37840
|-
| Total van der Waals energy /kcalmol-1 || align="center" | 13.64004 || align="center" | 10.63730
|-
| Total electrostatic energy /kcalmol-1 || align="center" | 5.11949 || align="center" | 5.14702
|-
| Total energy /kcalmol-1 || align="center" | 50.44570 || align="center" | 41.25749
|}
<div style="text-align: center;">Table 2. Energies for partially hydrogenated dimers of cyclopentadiene.</div> 

With a double bond in the norbornene ring, Compound 3 has a much larger ring strain and this leads to a higher angle bending energy, resulting in a much higher total energy. From the results in Table 2, it is clear that Compound 4 is the thermodynamic product with a much lower energy. {{fontcolor1|black|yellow|Compound 4 also has a lower van der Waals energy, indicating a smaller...}}

In fact, the observation of the preference for partial hydrogenation on the norbornene ring is also supported by Skála et al. It was found that using Pd/C catalyst, the rate of hydrogenation of the alkene in the norbornene ring is much higher than that of the other alkene of the endo dimer even though both hydrogenation processes are exothermic.<ref name="skala">D. Skála , J. Hanika , "Kinetics of dicyclopentadiene hydrogenation using Pd/C catalyst", ''Petroleum and Coal'', '''2003''', ''45'', 105-108. </ref>

=== Atropisomerism in an intermediate related to the synthesis of Taxol ===
Compounds 9 and 10 are intermediates in the synthesis of taxol.

[[File:knt_comps9and10_2.jpg|450px|center]] 

The MMFF94s method is run to determine the energies of these intermediates and the results are shown in Table 3.

{| class="wikitable" border="1" style="margin: 1em auto 1em auto;"
|+
| || Compound 9 || Compound 10
|-
| Figure || align="center" | [[File:knt_atrop_9.png|300px]] || align="center" | [[File:knt_atrop_10.png|300px]]
|-
| Total bond stretching energy /kcalmol-1 || align="center" | 7.71672 || align="center" | 7.60335
|-
| Total angle bending energy /kcalmol-1 || align="center" | 28.39788 || align="center" | 18.82902
|-
| Total torsional energy /kcalmol-1 || align="center" | 0.00414 || align="center" | 0.19294
|-
| Total van der Waals energy /kcalmol-1 || align="center" | 33.30781 || align="center" | 33.27766
|-
| Total electrostatic energy /kcalmol-1 || align="center" | 0.30257 || align="center" | -0.05571
|-
| Total energy /kcalmol-1 || align="center" | 70.55929 || align="center" | 60.55428
|}
<div style="text-align: center;">Table 3. Energies for taxol-related intermediates.</div> 

On standing, the compound apparently isomerises to the alternative carbonyl isomer. This is an example of atropisomerism[5]. Clearly the stereochemistry of carbonyl addition depends on which isomer is the most stable. It is also noted that during subsequent functionalisation of the alkene, this reacted abnormally slowly!

Using MMFF94s force-field to determine the most stable isomer 9 or 10, and to rationalise why the alkene reacts slowly (hint: read the literature on hyperstable alkenes![6]. Pay particular attention to the conformation of the resulting optimised structure, to see if any aspect of this structure could be improved by further minimisations (preceeded if necessary by a manual edit of the structure to move atoms into more correct orientations).

== Spectroscopic Simulation using Quantum Mechanics ==

Sum of electronic and thermal Free Energies= -1651.460773

== Analysis of the properties of the alkene epoxides ==

=== Crystal structure of the pre-catalysts ===

For 21 analyse and discuss the C-O bond lengths for any anomeric centres (i.e. those with O-C-O substructures) using the Mercury program and any other interesting features you might discover.
For 23 analyse and discuss the close approach of the two adjacent t-butyl groups on the rings and any other interesting features you might discover.

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Adduct of Dicyclopentadiene dimerization'''
| '''Exo Adduct of Dicyclopentadiene dimerization'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=19,atomno=1,atomno=2; color green;measure 19 1;measure 19 2;</script>
<uploadedFileContents>knt_comp21.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>Exodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=7,atomno=17; color green;measure 17 7;</script>
<uploadedFileContents>knt_comp23.mol</uploadedFileContents>
</jmolApplet></jmol>
|-
|}

=== NMR spectra of epoxides ===

You can compute the expected 13C and 1H spectra (chemical shifts and coupling constants) of your epoxides to check the integrity of what you have made. The technique for doing this was illustrated for taxol above. This on its own however will not identify the absolute configuration of your product.

=== Assignment of the absolute configuration of the epoxides ===

==== Optical rotation data ====

==== VCD spectra ====

=== Transition state of the reactions ===

==== Investigation of the non-covalent interactions in the active site of the reaction transition state ====

==== Investigation of the Electronic topology (QTAIM) in the active site of the reaction transition state ====

==== Suggestions for new candidates for investigations ====

== Conclusion ==

== References ==
<references/>

Rep:Mod:knt11Y3S1C

2013-11-26T13:48:37Z

Xc2611: /* Analysis of the properties of the alkene epoxides */

== Y3S1C: Third year Synthesis Laboratory Module 1C ==
Name: Kai Ni Teh 
CID: 00697229 

== Introduction ==
Over the past few decades, the use of computational methods and modelling has become more prevalent in determining the outcome of reactions and the stability and properties of molecules. With this understanding in mind, this computational exercise consists of two parts, the first with the aim to introduce basic computational techniques and the second with the aim to assign stereochemistry of compounds synthesised in a related organic synthesis laboratory session. Instead of UFF, which is a method that can be used across the periodic table of elements but is a simpler model which fixes the hybridisation of each atom, MMFF94s is used.

== Conformational analysis using Molecular Mechanics ==
This part of the exercise compares the energies of related compounds, isomers or atropisomers in some cases, to determine and explain the relative stability of one of the compounds.

=== Cyclopentadiene dimerisation ===

Cyclopentadiene dimerises readily and the two dimers are the exo and endo dimers.

[[File:knt_cp_dimerisation2.jpg|350px|center]] 

The MMFF94s method is run to determine the energies of the exo and endo dimers and the results are shown in Table 1.

{| class="wikitable" border="1" style="margin: 1em auto 1em auto;"
|+
| || align="center" | Compound 1 || align="center" | Compound 2
|-
| Figure || align="center" | [[File:knt_cp_exo.png|200px]] || align="center" | [[File:knt_cp_endo.png|150px]]
|-
| Total bond stretching energy /kcalmol-1 || align="center" | 3.54296 || align="center" | 3.46794
|-
| Total angle bending energy /kcalmol-1 || align="center" | 30.77260 || align="center" | 33.18931
|-
| Total torsional energy /kcalmol-1 || align="center" | -2.73079 || align="center" | -2.94950
|-
| Total van der Waals energy /kcalmol-1 || align="center" | 12.80159 || align="center" | 12.35874
|-
| Total electrostatic energy /kcalmol-1 || align="center" | 13.01368 || align="center" | 14.18456
|-
| Total energy /kcalmol-1 || align="center" | 55.37342 || align="center" | 58.19067
|}
<div style="text-align: center;">Table 1. Energies for exo and endo dimers of cyclopentadiene.</div> 

Cyclopentadiene dimerisation is an example of Diels Alder cycloaddition reaction with π2s + π4s or π4s + π2s components.

Comparing the total energies of the exo and endo dimers, it is clear that the exo dimer is the thermodynamically more stable product given its lower energy. However, it is a well-known fact that Diels Alder cycloaddition reactions usually produce the endo product preferentially. This can be explained by secondary orbital interactions derived from the endo transition state, which is absent in the exo transition state.<ref name="jo00384a016">M. A. Fox, R. Cardona, N. J. Kiwiet, "Steric Effects vs. Secondary Orbital Overlap in Diels-Alder Reactions. MNDO and AM1 Studies.", ''J. Org. Chem.'', '''1987''', ''52'', 1469–1474. {{DOI|10.1021/jo00384a016}}</ref> Hence, the endo dimer is the product under kinetic control and it is formed at a faster rate. This also illustrates the overriding effect of this favourable secondary orbital interactions over the higher angle strain observed in the endo dimer.

=== Hydrogenation of cyclopentadiene ===
Partial hydrogenation of the endo dimer initially produces one of the dihydro derivatives 3 or 4, instead of the tetrahydro derivative which is only formed after prolonged hydrogenation.

[[File:knt_cp2_hydrogenation.jpg|600px|center]] 

The MMFF94s method is run to determine the energies of the dihydro derivatives and the results are shown in Table 2.

{| class="wikitable" border="1" style="margin: 1em auto 1em auto;"
|+
| || align="center" | Compound 3 || align="center" | Compound 4
|-
| Figure || align="center" | [[File:knt_cph_3.png|175px]] || align="center" | [[File:knt_cph_4.png|175px]]
|-
| Total bond stretching energy /kcalmol-1 || align="center" | 3.31222 || align="center" | 2.82313
|-
| Total angle bending energy /kcalmol-1 || align="center" | 31.97095 || align="center" | 24.68535
|-
| Total torsional energy /kcalmol-1 || align="center" | -1.59562 || align="center" | -0.37840
|-
| Total van der Waals energy /kcalmol-1 || align="center" | 13.64004 || align="center" | 10.63730
|-
| Total electrostatic energy /kcalmol-1 || align="center" | 5.11949 || align="center" | 5.14702
|-
| Total energy /kcalmol-1 || align="center" | 50.44570 || align="center" | 41.25749
|}
<div style="text-align: center;">Table 2. Energies for partially hydrogenated dimers of cyclopentadiene.</div> 

With a double bond in the norbornene ring, Compound 3 has a much larger ring strain and this leads to a higher angle bending energy, resulting in a much higher total energy. From the results in Table 2, it is clear that Compound 4 is the thermodynamic product with a much lower energy. {{fontcolor1|black|yellow|Compound 4 also has a lower van der Waals energy, indicating a smaller...}}

In fact, the observation of the preference for partial hydrogenation on the norbornene ring is also supported by Skála et al. It was found that using Pd/C catalyst, the rate of hydrogenation of the alkene in the norbornene ring is much higher than that of the other alkene of the endo dimer even though both hydrogenation processes are exothermic.<ref name="skala">D. Skála , J. Hanika , "Kinetics of dicyclopentadiene hydrogenation using Pd/C catalyst", ''Petroleum and Coal'', '''2003''', ''45'', 105-108. </ref>

=== Atropisomerism in an intermediate related to the synthesis of Taxol ===
Compounds 9 and 10 are intermediates in the synthesis of taxol.

[[File:knt_comps9and10_2.jpg|450px|center]] 

The MMFF94s method is run to determine the energies of these intermediates and the results are shown in Table 3.

{| class="wikitable" border="1" style="margin: 1em auto 1em auto;"
|+
| || Compound 9 || Compound 10
|-
| Figure || align="center" | [[File:knt_atrop_9.png|300px]] || align="center" | [[File:knt_atrop_10.png|300px]]
|-
| Total bond stretching energy /kcalmol-1 || align="center" | 7.71672 || align="center" | 7.60335
|-
| Total angle bending energy /kcalmol-1 || align="center" | 28.39788 || align="center" | 18.82902
|-
| Total torsional energy /kcalmol-1 || align="center" | 0.00414 || align="center" | 0.19294
|-
| Total van der Waals energy /kcalmol-1 || align="center" | 33.30781 || align="center" | 33.27766
|-
| Total electrostatic energy /kcalmol-1 || align="center" | 0.30257 || align="center" | -0.05571
|-
| Total energy /kcalmol-1 || align="center" | 70.55929 || align="center" | 60.55428
|}
<div style="text-align: center;">Table 3. Energies for taxol-related intermediates.</div> 

On standing, the compound apparently isomerises to the alternative carbonyl isomer. This is an example of atropisomerism[5]. Clearly the stereochemistry of carbonyl addition depends on which isomer is the most stable. It is also noted that during subsequent functionalisation of the alkene, this reacted abnormally slowly!

Using MMFF94s force-field to determine the most stable isomer 9 or 10, and to rationalise why the alkene reacts slowly (hint: read the literature on hyperstable alkenes![6]. Pay particular attention to the conformation of the resulting optimised structure, to see if any aspect of this structure could be improved by further minimisations (preceeded if necessary by a manual edit of the structure to move atoms into more correct orientations).

== Spectroscopic Simulation using Quantum Mechanics ==

Sum of electronic and thermal Free Energies= -1651.460773

== Analysis of the properties of the alkene epoxides ==

=== Crystal structure of the pre-catalysts ===

For 21 analyse and discuss the C-O bond lengths for any anomeric centres (i.e. those with O-C-O substructures) using the Mercury program and any other interesting features you might discover.
For 23 analyse and discuss the close approach of the two adjacent t-butyl groups on the rings and any other interesting features you might discover.

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Adduct of Dicyclopentadiene dimerization'''
| '''Exo Adduct of Dicyclopentadiene dimerization'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=19,atomno=1,atomno=2; color green;measure 19 1;measure 19 2;</script>
<uploadedFileContents>knt_comp21.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>Exodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=7,atomno=17; color green;measure 17 7;</script>
<uploadedFileContents>XcwExodimer1.mol</uploadedFileContents>
</jmolApplet></jmol>

=== NMR spectra of epoxides ===

You can compute the expected 13C and 1H spectra (chemical shifts and coupling constants) of your epoxides to check the integrity of what you have made. The technique for doing this was illustrated for taxol above. This on its own however will not identify the absolute configuration of your product.

=== Assignment of the absolute configuration of the epoxides ===

==== Optical rotation data ====

==== VCD spectra ====

=== Transition state of the reactions ===

==== Investigation of the non-covalent interactions in the active site of the reaction transition state ====

==== Investigation of the Electronic topology (QTAIM) in the active site of the reaction transition state ====

==== Suggestions for new candidates for investigations ====

== Conclusion ==

== References ==
<references/>

Rep:Mod:Computationalreport1C

2013-11-22T18:06:52Z

Xc2611: /* Bibliography */

= '''Synthesis and Computational Lab: 1C''' =
== '''Part 1: Introduction to Molecular Mechanics''' ==
=== '''Introduction to MMFF94 and MMFF94s''' ===

With the improvement of computational data and computer processing power, the usage of molecular mechanics/dynamics forcefield has become very integrated in predicting properties of chemical molecules. A molecular mechanics/dynamics forcefield should be able to predict characteristics such as molecular geometries, conformational/stereoisomeric energies, vibrational frequencies etc. to a reasonable accuracy as compared to experimental-derived values.

Building on work from Kollman et al. s’ AMBER forcefield and Allinger et al. s’ MM1, MM2, MM3 and MM4, Merck Research Laboratories have managed to optimized and improved the previous computational algorithms and produced MMFF94 (Merck Molecular Force Field 94). One of the most prominent advantages of MMFF94 over other preceeding work is its enhanced prediction accuracy. The reason lies in the fact that MMFF94’s core parameterization utilizes an unprecedently large amount of computational data obtained from ab initio calculations1.

Subsequently after the development of MMFF94, a new “static” variant of the MMFF was introduced i.e. the MMFF94s. Unlike MMFF94 that was developed for the use of molecular dynamics simulations (which can be expensive), MMFF94s was developed with the purpose of energy minimization studies in mind. Although both systems provide identical results for most systems, they differ for amides and unsaturated amines which contain resonance-delocalized trigonal nitrogen atoms2.

In this computational exercise, MMFF94s is used predominantly as oppose to the alternative Universal Force Field (UFF). Although versatile across the entire periodic table, UFF is derived from simple rules and atomic parameters such as fixed hybridization that increases the likelihood of erroneous structural and energetic predictions3.

=== '''Forms of MMFF94s''' ===

Steric energy of a molecule is the energy arise due to its geometry or conformation. Energy minimization of steric energy process ensures that the molecule is in its lowest energy conformation.

MMFF94s assumes that the total steric energy of a molecule can be found by the sum of a few specific interactions in a molecule.

ES = EBS + EAB + E SB + ET + EOOP + EVdW + EEE

'''where the bonded interactions are:'''

ES = Total Steric energy

EBS = Total Bond Stretching energy

EAB = Total Angle Bending energy

ESB = Total Stretch Bending energy

ET = Total Torsional Energy

EOOP = Total Out-Of-Plane Bending energy, and

'''where the non-bonded interactions are:'''

EVdW = Total Van der Waals Energy

EEE = Total Electrostatic Energy

{| border="1" cellspacing="1" cellpadding="10"
|-
| width="300" align="center" | '''Types of Energies'''
! width="600" align="center" | '''Explanation'''
|-
| colspan="2" style="text-align: center;" | '''Bonded Interactions'''
|-
| width="300" align="center" | '''Total Bond Stretching Energy'''
! width="600" align="left" | The total bond stretching energy is related to the vibration energy of the molecules in comparison to the equilibrium bond length. Whenever a bond deviates from the equilibrium bond length, the energy value increases.

MMFF94s uses a quartic function that has the force constant term (relate to bond strength). The quartic function term is superior to the cubic function term (used in MM2) in the sense that it avoid the “cubic stretch catastrophe” where progressive elongation of molecule bond length leads to negative infinity.
|-
| width="300" align="center" | '''Total Angle Bending Energy'''
! width="600" align="left" | Similar to Total Bond Stretching Energy, the total angle bending energy is also related to the vibration energy of the molecules about the equilibrium bond length. However, unlike EBS that measures the bond strength, EAB is associated with the stiffness of the molecules based on the Hookiean potential. Whenever bond angles deviate from the norm during vibration, this energy term increases as well.
|-
| width="300" align="center" | '''Total Stretch-Bending Energy'''
! width="600" align="left" | This energy term takes into account of the energy due to increase in bond length when bond angle between two atoms changes.
|-
| width="300" align="center" | '''Total Torsional Energy'''
! width="600" align="left" | Total torsional energy is the energy required for intermolecular rotation about the bonds. In molecule mechanics, however, this term is often used as a correction that must be added or subtracted to the total energy of the molecule to fit a quantum mechanical calculation about the dihedral angles of bonds.
|-
| width="300" align="center" | '''Total Out-Of-Plane Bending Energy'''
! width="600" align="left" | This energy term refers to the energy needed to deform the dihedral angle (zero degrees) of a planar group of atoms such as carbonyl or amide functional groups.
|-
| colspan="2" style="text-align: center;" | '''Non-Bonded Interactions'''
|-
| width="300" align="center" | '''Total Van der Waals Energy'''
! width="600" align="left" | The total Van der Waals energy term examines the intramolecular interactions such as repulsion or attraction between non-bonded atoms in the molecule. This term is crucial in determining the preferred conformation of the molecule.

MMFF94s employs the novel “Buffered-14-7”. The name is derived from a buffering constant and the 14th and 7th power dependencies of the repulsive and attractive energy in the equation.
|-
| width="300" align="center" | '''Total Electrostatic Energy'''
! width="600" align="left" | The total electrostatic energy functions take into account of the Coulombic potential and partial charge/dipole/atomic point charges interactions within the molecule.
|-

|}

 

== '''Part 2 : Conformational Analysis Using Molecular Mechanics''' ==
=== '''The Hydrogenation of Cyclopentadiene Dimer''' ===

==== '''Endo and exo adduct from the Dimerization of Cyclopentadiene''' ====
Cyclopentadiene will undergo dimerization by Diels-alder reaction to form either an endo or exo adduct.

[[File:XcwDimerization of CP.png|500px|center]]

==== '''Stereoselectivity of Dimerization of Cyclopentadiene''' ====
Although the exo adduct is thermodynamically more stable than the endo adduct, the endo adduct is form preferentially. Using the QST2 method, the transition state of the Diels Alder dimerization was found. It was discovered that due to the secondary orbital interactions in the endo transition state, the endo dimer is formed preferentially (the kinetic product). Hence, it is proven that the Diels Alder dimerization between two cyclopentadiene are kinetically controlled.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Transition State of Dimerization of Cyclopentadiene'''
| '''Imaginary Stretch Frequency (-881.25) of the Endo Transition State (click to animate)'''
| '''Secondary Orbital Interaction (Red overlapping orbitals)'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<uploadedFileContents>EndotsDCPD2.mol
</uploadedFileContents>
</jmolApplet></jmol>
| [[File:Xcwendotsimaginary.gif|300px|center]]
| [[File:XcwSecondary orbital interaction1.jpg|300px|center]]
|-
|}

 

==== '''Asynchronous Bond Formation of Dimerization of Cyclopentadiene''' ====

The initial study of the molecular orbitals of the transition states seemed a bit peculiar. Instead of getting a LUMO with symmetrical orbitals, the calculations showed a HOMO that is asymetric at the carbons where the new sigma bonds will be formed. Running an IRC further, it soon became clear that the asymmetry of the HOMO leads to an asychronous bond formation before leading to the product.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''IRC plot following the Endo Transition State '''
| '''IRC following the Endo Transition State (click to animate)'''
| '''Asymmetry of orbitals at the carbons where the new sigma bonds will be formed'''
|- align="center"
| [[File:XcwendotscyclopentadieneIRC.png|300px|center]]
| [[File:XcwendotsIRC.gif|300px|center]]
| [[File:XcwAsynchronous mo.jpg|300px|center]]
|-
|}

 

==== '''Comparison of Energies between the Endo and Exo adduct of Dicyclopentadiene''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Adduct of Dicyclopentadiene dimerization'''
| '''Exo Adduct of Dicyclopentadiene dimerization'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=19,atomno=1,atomno=2; color green;measure 19 1;measure 19 2;</script>
<uploadedFileContents>XcwEndodimer3.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>Exodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=7,atomno=17; color green;measure 17 7;</script>
<uploadedFileContents>XcwExodimer1.mol</uploadedFileContents>
</jmolApplet></jmol>
|-
|}

 

Using MMFF94s ab initio calculations, the energies for the exo dimer and the endo dimer are derived.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Exodimer'''
| '''55.374'''
| 3.543
| 30.772
| -2.041
| -2.728
| 0.015
| 12.800
| 13.014
|-
| '''Endodimer'''
| '''58.191'''
| 3.468
| 33.187
| -2.082
| -2.950
| 0.023
| 12.360
| 14.186
|-
|}

 

The MMFF94s steric energy (after minimization) for the exo dimer is lower than that of the endo dimer. This is reflected by the large difference for the EEE between the endo dimer and the exo dimer due to unfavourable steric repulsion between the two “arched down” cyclopentene rings.

==== '''Hydrogenation of Dicyclopentadiene''' ====

Hydrogenation of the endo dicyclopentadiene (DCPD) would lead to two potential products: dihydro product 1 and dihydro product 2.

[[File:XcwFormation of Dihydro products.png|500px|center]]

Using MMFF94s, the energy of the two dihydro products are calculated.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Dihydro Product 1'''
| '''50.123'''
| 3.308
| 30.864
| -1.927
| 0.060
| 0.015(2)
| 13.281
| 5.121
|-
| '''Dihydro Product 2'''
| '''41.257'''
| 2.823
| 24.685
| -1.657
| -0.379
| 0.000(2)
| 10.639
| 5.147
|-
| '''Tetrahydro Product'''
| '''39.042'''
| 2.730
| 25.151
| -1.676
| 1.287
| 0.000
| 11.551
| 0.000
|}

 

From the MMFF94s calculation, it can be seen that dihydro product 2 has a lower steric energy than dihydro product 1. Therefore, dihydro product 2 is the thermodynamic product for the hydrogenation of dicylopentadiene. And indeed, this was what was observed by Skala et al.. He observed that the first hydrogenation occur at the norborene part of the molecule (rate of hydrogenation several times faster than that in the cyclopentene ring)6. The first heat of hydrogenation at the norborene is 138.8 kJ/mol while the second hydrogenation at the cyclopentene right is 109.5 kJ/mol6.

From the above results, it is also obvious that tetrahydro product is much more stable than either dihydro product. And yet, studies have shown that the tetrahydro product will only form after prolonged hydrogenation under high temperature. However, subjecting DCPD to high temperature leads to low yield due to cracking of DCPD.

Since thermodynamically it is predicted to form favourably, the fact that it does not could only mean that the hydrogenation of DCPD to tetrahydrodicyclopentadiene (TH-DCPD) is kinetically controlled. Most possibly, the transition state of the hydrogenation of DCPD is highly unstable hence it is unlikely to form.

=== '''Atropisomerism in an Intermediate related to the Synthesis of Taxol''' ===

Atropisomerism is a type of stereoisomerism that is form as a result of hindered rotation about a single bond.

[[File:XcwAtropisomerism example.png|500px|center]]

In the case of the 6,6’-dinitro-2,2’-diphenic acid, rotation about the bonds joining the two substituted phenyl rings would have to overcome large steric interaction between the bulky substituents. The barrier of rotation is high enough for the two conformers to be isolated individually.

In the synthesis of taxol, one of the key intermediates exhibit atropisomerism.

==== '''Atropisomerism in Taxol Synthesis''' ====

For the key intermediate, rotation about the carbon-carbon bonds would lead to two types of atropisomers, each with either the carbonyl group poining upwards or downwards in relative to the bridge.

[[File:XcwIntermediate 9 and Intermediate 10.png|500px|center]]

Once again by using MMFF94s ab initio calculations, the steric energies for the two intermediates are illustrated as below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 9'''
| '''70.571'''
| 7.743
| 28.356
| -0.062
| 0.004
| 0.949
| 33.293
| 0.288
|-
| '''Intermediate 10'''
| '''60.553'''
| 7.599
| 18.838
| -0.139
| 0.199
| 0.844
| 33.269
| -0.056
|-

|}

 

Analyzing the data above, the largest energy difference between Intermediate 9 and Intermediate 10 stems from the EAB which is related to the strain of the ring. Intermediate 9 has an excess of 9.518 kcal/mol EAB as compared to Intermediate 10. This comes as a surprise as intermediate 9 is predicted to be more stable alkene.

The rationale behind the prediction of the stability of intermediate 9 stems from the fact that the through-space distance of the upward-pointing carbonyl oxygen with the carbon-carbon is further than the through space distance between the downward-pointing carbonyl oxygen with the -CH2-CH2- fragment at the norbornene part in intermediate 10.

==== '''Hyperstable Olefins''' ====

Intermediate 9 and Intermediate 10 does not react readily with other reagents during functionalization. This is due to the hyperstability effect found in hyperstable olefins.

Hyperstable olefins are alkenes that contain less strain in the ring (i.e. negative olefin strain values) compared to the parent hydrocarbon. To study this further, further MMFF94s calculation was done to compare Intermediate 10 with the parent hydrocarbon.

[[File:XcwIntermediate10andPH.png|500px|center]]

The energies that we calculated are tabulated as shown below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 10'''
| '''44.878 '''
| 5.211
| 15.488
| -0.267
| -1.655
| 0.998
| 25.014
| 0.088
|-
| '''Parent Hydrocarbon'''
| '''50.564'''
| 4.692
| 21.979
| 0.109
| -0.958
| 0.247
| 24.495
| 0.000
|-

|}

 

Scrutinizing the results, the largest energy difference between intermediate 10 and the parent hydrocarbon stems from the Total Angle Bending Energy, EAB. Since the Total Angle bending energy is related to the angle strain in the molecules, it is apparent that the parent hydrocarbon has more ring strain as compared to the bridgehead olefin.

== '''Part 3 : Spectroscopic Simulation Using Quantum Mechanics''' ==
=== '''Spectroscopy of an Intermediate Related to the Synthesis of Taxol''' ===

Molecule 17 and 18 are derivatives of intermediate 9 and 10. In this exercise, MMFF94s is used to predict the 1H and 13C NMR of molecule 17 and molecule 18.

[[File:XcwIntermediate17&18.png|500px|center]]

==== '''NMR Spectra of Molecule 17''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 17.mol
</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwHNMRMolecule 17 Chair Overall NMR.png|500px|center]]
| [[File:XcwHNMRMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.1825
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| The first three results were fairly straight forward to be deduced and correlate wit experimental data.

The hydrogen atom that is geminally attached to the carbon of the double bonds is the most deshielded due to the ring current anisotropic effect of the ring current

The second most deshielded hydrogen atom is the hydrogen atom on the methyl group on the bridge. The hydrogen atom is pointing directly to the oxygen atom of the carbonyl functional group.

The peaks with an integration height of 4 is assigned to the hydrogen atoms in the 1,3-dithiolane ring fragment.

Subsequent analysis of the 1H NMR became very complicated very quickly for two reasons:

1. Gaussian calculations showed some atoms with an integration height of 3. Comparing their file atom number and checking their chemical environment, it is not possible to find any correlation between them.

2. Some of the peaks in the literature remains unresolved and are given as multiplets or grouped together.

|- align="center"
| 52
| 3.1775
| 1
| '''2.99'''
|- align="center"
| 53,52,50,51
| 3.0867
| 4
| '''3.40-3.10'''
|- align="center"
| 42,43,39
| 2.7445
| 3
| ''' '''
|- align="center"
| 49
| 2.6187
| 1
| ''' '''
|- align="center"
| 34
| 2.4371
| 1
| ''' '''
|- align="center"
| 35
| 2.3782
| 1
| ''' '''
|- align="center"
| 40,37,26
| 2.2730
| 3
| ''' '''
|- align="center"
| 30
| 2.1566
| 1
| ''' '''
|- align="center"
| 36
| 2.1033
| 1
| ''' '''
|- align="center"
| 32,28
| 2.0259
| 2
| ''' '''
|- align="center"
| 25
| 1.8535
| 2
| ''' '''
|- align="center"
| 38,46,27
| 1.5898
| 3
| '''1.25'''
|- align="center"
| 29
| 1.4557
| 1
| ''' '''
|- align="center"
| 31
| 1.0123
| 1
| ''' '''
|- align="center"
| 44,48,45
| 0.9087
| 3
| '''1.10'''
|- align="center"
| 47
| 0.8354
| 1
| ''' '''
|- align="center"
| 33
| 0.5790
| 1
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 17 Chair Overall NMR2.png|500px|center]]
| [[File:XcwMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 216.2725
| 1
| '''218.79'''
| rowspan="10" style="text-align:center;"| [[File:XcwMolecule 17 image for CNMR.jpg|600px|center]]
|- align="center"
| 13
| 144.8626
| 1
| '''144.63'''
|- align="center"
| 14
| 124.7193
| 1
| '''125.33'''
|- align="center"
| 3
| 91.3340
| 1
| '''72.88'''
|- align="center"
| 2
| 60.9568
| 1
| '''56.19'''
|- align="center"
| 1
| 57.0811
| 1
| '''52.52'''
|- align="center"
| 10
| 52.4663
| 1
| '''48.50'''
|- align="center"
| 16
| 51.4857
| 1
| '''46.80'''
|- align="center"
| 9
| 46.9196
| 1
| '''45.76'''
|- align="center"
| 23
| 43.8647
| 1
| '''39.80'''
|- align="center"
| 22
| 41.9450
| 1
| '''38.81'''
| Comments
|- align="center"
| 4
| 41.8724
| 1
| '''35.85'''
| rowspan="9" style="text-align:left;"| The carbon bonded to the oxygen atom is the most deshielded, as is shown in the predicted values and the experimental values. There is a deviation between the values. Quite possibly, this is due to the fact that in reality, the carbonyl functional group is pointing slightly towards the equatorial position rather than a lateral position relative to the ring (as is in the input for Gaussian calculation)

Most of the 1CNMR values that was predicted by Gaussian are all within an acceptable range of deviation. However, there is carbon 3 that has significant deviation between the predicted value and experimental value.

Carbon 3 is the carbon bonded to the two sulphurs in the 1,3-dithiolane ring fragment. Such a huge deviation would possibly mean that the conformer that was given as input to Gaussian differs from the literature.

The above NMR spectra was corrected with a level of theory B3LYP/6-31G(d,p) using TMS as reference and in chloroform.

|- align="center"
| 15
| 35.4348
| 1
| '''32.66'''
|- align="center"
| 11
| 31.1964
| 1
| '''28.79'''
|- align="center"
| 6
| 28.9432
| 1
| '''28.29'''
|- align="center"
| 7
| 28.3640
| 1
| '''26.88'''
|- align="center"
| 12
| 27.3767
| 1
| '''25.66'''
|- align="center"
| 17
| 26.3311
| 1
| '''23.86'''
|- align="center"
| 15
| 24.5483
| 1
| '''20.96'''
|- align="center"
| 18
| 19.7788
| 1
| '''18.71'''
|-
|}
 

==== '''NMR Spectra of Molecule 18''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 18 Boat for Image2.mol</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"-
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 18 Chair Overall NMR.png|500px|center]]
| [[File:Molecule 18 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
|- align="center"
| 41
| 5.2832
| 1
| '''5.21'''
|- align="center"
| 50
| 3.3175
| 1
| rowspan="4" style="text-align:centre;"| '''3.00-2.70'''
|- align="center"
| 52
| 3.2153
| 1
|- align="center"
| 51,53
| 3.1161
| 2
|- align="center"
| 34,43
| 2.8606
| 2
|- align="center"
| 38
| 2.4549
| 1
| ''' '''
|- align="center"
| 42
| 2.3968
| 1
| ''' '''
|- align="center"
| 25,29,26
| 2.2796
| 3
| ''' '''
|- align="center"
| 39
| 2.0844
| 1
| ''' '''
|- align="center"
| 40,36
| 1.9699
| 2
| ''' '''
|- align="center"
| 37,24
| 1.8519
| 2
| ''' '''
|- align="center"
| 31,27
| 1.6780
| 2
| ''' '''
|- align="center"
| 28
| 1.6175
| 1
| ''' '''
|- align="center"
| 46,49
| 1.4979
| 2
| ''' '''
|- align="center"
| 35
| 1.4150
| 1
| ''' '''
|- align="center"
| 32
| 1.3531
| 1
| ''' '''
|- align="center"
| 48
| 1.1606
| 1
| ''' '''
|- align="center"
| 33,30,47
| 1.0653
| 3
| '''1.03'''
|- align="center"
| 44,45
| 0.9643
| 2
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 18 Full Spectra'''
| '''13C NMR Spectra of Molecule 18 Truncated Spectra'''
|- align="center"
| [[File:XcwMolecule 18 Boat Overall NMR.png|500px|center]]
| [[File:XcwMolecule 18 Boat zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
|- align="center"
| 8
| 211.8325
| 1
| '''211.49'''
|- align="center"
| 13
| 148.6673
| 1
| '''148.72'''
|- align="center"
| 14
| 118.8373
| 1
| '''120.90'''
|- align="center"
| 3
| 89.0869
| 1
| '''74.61'''
|- align="center"
| 2
| 67.8886
| 1
| '''60.53'''
|- align="center"
| 1
| 56.1133
| 1
| '''51.30'''
|- align="center"
| 10
| 55.5998
| 1
| '''50.94'''
|- align="center"
| 16
| 50.1124
| 1
| '''45.53'''
|- align="center"
| 22
| 48.2030
| 1
| '''43.28'''
|- align="center"
| 23
| 44.2222
| 1
| '''40.82'''
|- align="center"
| 4
| 42.0354
| 1
| '''38.73'''
|- align="center"
| 9
| 37.5865
| 1
| '''36.78'''
|- align="center"
| 6
| 35.3106
| 1
| '''35.47'''
|- align="center"
| 15
| 31.0459
| 1
| '''30.84'''
|- align="center"
| 7
| 28.8476
| 1
| '''30.00'''
|- align="center"
| 12
| 28.6623
| 1
| '''25.56'''
|- align="center"
| 17
| 25.7393
| 1
| '''25.35'''
|- align="center"
| 11
| 25.2603
| 1
| '''22.21'''
|- align="center"
| 18
| 23.3944
| 1
| '''21.39'''
|- align="center"
| 5
| 21.0478
| 1
| '''19.83'''
|-
|}
 

== '''Part 4 : Analysis of the Properties of the Synthesized Alkene Epoxides''' ==
=== '''The two catalytics systems''' ===

Assymmetric epoxidation of prochiral alkenes may lead to product with different stereochemical outcome as illustrated as below. To solve this problem, different types of asymmetric epoxidation catalyst have been synthesized. In this study, we shall be focusing on Shi asymmetric fructose catalyst as well as Jacobsen asymmetric catalyst.

[[File:Asymmetric catalyst.png|400px|center]]

==== ''' The Shi Asymmetric Fructose Catalyst''' ====

Molecule 21 is the stable precursor of molecule 22, the active catalyst. Molecule 21 can be converted to molecule 22 by using either persulfuric acid or potassium peroxymonosulphate.

[[File:Molecule 21 to 23.png|400px|center]]

The transition state of the Shi epoxidation was a subject of debate for a few moments. However, recent studies have led to the conclusion that the spiro transition state is more favored than the planar transition state. The spiro transition state is the transition that has its dioxirane perpendicularly bisecting the alkene double bond. This is thought to be more favourable due to interactions between the lone pairs of the oxygen with the LUMO of the alkene.

[[File:Spiro and planar ts.png|500px|center]]

==== ''' The Jacobsen Asymmetric Catalyst''' ====

Molecule 23 is the stable precursor of molecule 24, the active catalyst. Molecule 23 can be converted to molecule 24 by using sodium perchlorate.

[[File:Salen, 23 and 24.png|400px|center]]

Jacobsen catalyst is biphasic. The first phase involves the transfer of oxygen to molecule 23. Sodium perchlorate oxidizes Mn(III) to Mn(V).

In the second step, Jacobsen catalyst acts via a radical mechanism. It is thought to be so because epoxidation of trans-alkene by Jacobsen catalyst yield cis-alkene as well. A radical mechanism will lead to the lost of stereochemical information of the molecule.

=== ''' Crystal structure of the two catalyst''' ===
==== '''Molecule 21''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 21'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 21 strucutre.png|600px|center]]'''
|-
| style="text-align:center;" width="150" | ''' Bond '''
| style="text-align:center;" width="150"| ''' Bond Lenghts (Angstrom)'''
| style="text-align:center;" | ''' Evaluation'''
|-
| style="text-align:center;"| ''' O1-C1 '''
| style="text-align:center;"| ''' 1.400'''
| rowspan="10" style="text-align:left;"| [[File:Molecule 21 2.png|300px|center]]

The normal bond length of an C-O bond is 1.430 angstrom.

The most interesting aspect here is O4 and O2. The lone pair of O4 is antiperplanar to the sigma* orbital of the carbonyl group while the lone pair of O2 is anti periplanar to the carbonyl pi* orbital. Donation of electron can occur because of the correct symmetry. Due to the mixing of the orbitals, the C2-O2 and C4-O4 has been conferred with a certain degree of double bond character.

However, due to the lone pair on oxygen being now donated to the carbonyl antibonding orbitals, the O2 and O4 is slightly “electron deficient” and electron density will be pulled away from O2 and O4. That would explain why the bond length increase for O2-C7 and O4-C10. Increase in bond length is an indicator of the weakening of the bond.
|-
| style="text-align:center;"|'''O1-C7'''
| style="text-align:center;"|'''1.413'''
|-
| style="text-align:center;"|'''O2-C7'''
| style="text-align:center;"|'''1.441'''
|-
| style="text-align:center;"|'''O2-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O4-C4'''
| style="text-align:center;"|'''1.396'''
|-
| style="text-align:center;"|'''O4-C10'''
| style="text-align:center;"|'''1.439'''
|-
| style="text-align:center;"|'''O5-C10'''
| style="text-align:center;"|'''1.409'''
|-
| style="text-align:center;"|'''O5-C5'''
| style="text-align:center;"|'''1.416'''
|-
| style="text-align:center;"|'''O6-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O6-C6'''
| style="text-align:center;"|'''1.420'''
|-
|}
 

==== '''Molecule 23''' ====

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 23'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 23 struc.png|600px|center]]'''
|-
| The most outstanding feature from this molecule is the fact that is adopt a puckered form of the square base pyramidal form. This is no surprise that the molecule is almost planar due to the electron delocalization around each side of the salen ligand.

The tery-butyl hydrogen are oriented closely to one another. Non-covalent interaction studies indicated that repulsion would occur for H---H bond length that are less than 2.1 angstrom while favourable interaction may be dominant with bond length above 2.4 angstrom. It was discovered that all 4 hydrogens have bond length more than 2.4 angstrom hence there should not be any significant repulsion between them. Instead, certain amount of attractive force will ensue and that contributes to the overall stability of the molecule

|-
|}
 

=== ''' The calculated NMR properties of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | '''
Shift (ppm) Degeneracy
7.4891704929 4.0000
7.2988172444 1.0000
3.6627082199 1.0000
3.1170156088 1.0000
2.5382383043 1.0000 '''
| width="100" | '''
Shift (ppm) Degeneracy
7.4892967873 4.0000
7.2987138125 1.0000
3.6632689921 1.0000
3.1151709109 1.0000
2.5339209685 1.0000

'''
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Styrene R HNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Styrene S HNMR.png|400px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | '''
Shift (ppm) Degeneracy
135.1098747604 1.0000
124.1186533632 1.0000
123.4150641684 1.0000
122.9584694331 2.0000
118.2653162569 1.0000
54.0265785300 1.0000
53.4853575062 1.0000 '''
| width="100" | '''
Shift (ppm) Degeneracy
135.1323742030 1.0000
124.1343038829 1.0000
123.4137039868 1.0000
122.9558208084 2.0000
118.2690258882 1.0000
54.0599580762 1.0000
53.4684920923 1.0000
'''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | ''' [[File:Styrene R CNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Styrene S CNMR.png|400px|center|]]'''
|-
| width="100" | ''' '''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | ''' Shift (ppm) Degeneracy
7.5705724829 2.0000
7.4791732656 8.0000
3.5390102503 2.0000
| width="100" | ''' Shift (ppm) Degeneracy
7.5705651164 2.0000
7.4791779628 8.0000
3.5374502607 2.0000
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Stilbene RR HNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|400px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | ''' Shift (ppm) Degeneracy
134.0942417727 2.0000
124.2206838184 2.0000
123.5192390024 2.0000
123.2125901307 2.0000
123.0785800542 2.0000
118.2583039589 2.0000
66.4212770637 2.0000 '''
| width="100" | ''' Shift (ppm) Degeneracy
134.0899175142 2.0000
124.2224499528 2.0000
123.5180152862 2.0000
123.2113538650 2.0000
123.0745448885 2.0000
118.2635789492 2.0000
66.4249347217 2.0000 '''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | ''' [[File:Stilbene RR CNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|400px|center|]]'''
|-
|}

 

=== ''' Assigning the absolute configuration of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''Predicted ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg'''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg '''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental conditions'''
| width="100" | '''1.00g/100ml, chloroform, 21 degree Celcisus, 589 nm wavelength '''
| width="100" | '''1.02g/100ml (99% ee), chloroform, 25 degree Celsius, 589 nm wavelength '''
| width="100" | '''1.01g/100ml, ethanol, 22 degree Celsius, 589 nm wavelength '''
| width="100" | '''0.6g/100ml, ethanol, 20 degree Celsius, 589 nm wavelength '''
|- align="left"
| width="100" | ''' Predicted VCD Spectrum'''
| width="100" | '''[[File:Styrene R VCD.png|200px|center|]] '''
| width="100" | '''[[File:Styrene S VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene RR VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene SS VCD.png|200px|center|]]'''
|-
|}

 

All the assignments given in the literature reports are correct although the predicted value differs slightly with the experimental values

=== ''' Analysis of the Transition State for Reactions''' ===
==== '''Predicting Enantiomeric Excess based on Transition State energies''' ====

One of the energy output from Gaussian calculation is the “sum of electronic and thermal free energies”. This is Gibbs Free Energy at 298.15K and 1 atm.

Using this term and invoking a variant of the Curtin-Hammett Principle, it is possible to calculate a predicted enantiomeric excess of one enantiomer over the other.

[[File:Ee and transition state energy.png|800px|center]]

Using the derivations from above and equation (4), we analyze the enantiomeric excess of beta-methyl styrene and the results are tabulated as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1343.022970'''
| width="100" | '''-1343.017942'''
| width="150" | '''-0.005028'''
| width="150" | '''4.88E-03'''
| width="150" | '''99.03'''
|- align="center"
| width="100" | '''-1343.019233'''
| width="100" | '''-1343.015603'''
| width="150" | '''-0.003630'''
| width="150" | '''2.14E-02'''
| width="150" | '''95.80'''
|- align="center"
| width="100" | '''-1343.029272'''
| width="100" | '''-1343.023766'''
| width="150" | '''-0.005506'''
| width="150" | '''2.94E-03'''
| width="150" | '''99.41'''
|- align="center"
| width="100" | '''-1343.032443'''
| width="100" | '''-1343.024742'''
| width="150" | '''-0.007701'''
| width="150" | '''2.88E-04'''
| width="150" | '''99.94'''
|-
|}

 

The above hartree units are converted to J/mol for calculation of K where 1 hartress = 4.3597E-18

Studying all the free energies of the (R,R) series and compare them with the (S,S) series, it comes as no surprise that (R,R) product is favoured over (S,S) product as (R,R) is more stable. Indeed, this corresponds with the literature value reporting 92% ee of (R,R) products over that of (S,S).

==== '''Analysis of the Transition State of Epoxidation''' ====
==== '''Shi Fructose Catalyst''' ====
For this section, I will be analyzing the the transition state of 1) styrene and 2) trans-stilbene with the Shi fructose catalyst.

===== '''(R) and (S)-styrene transition state''' =====
The transition state for the formation of (R)-styrene oxide and (S)-styrene oxide are given as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R)-styrene oxide'''
| width="150" | '''(S)-styrene oxide'''
|- align="center"
| width="150" | ''' Structure of Catalyst '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide R.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide S ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| [[File:Steric shi fructose R.png|450px|center]]
| [[File:Steric shi fructose S.png|450px|center]]
|-
|}

 

In the transition state for (R)-styrene, it was discovered that the Re face is reacting with the oxygen of the dioxirane. The phenyl ring is oriented endo with respect to the fructose catalyst. However, the (S)-styrene is reacting at the Si face and the phenyl ring is oriented exo relative to the catalyst.

The approach taken by (R)-styrene and (S)-styrene are restricted to only one due to steric interactions. Therefore, the epoxidation of both styrenes by the Shi catalyst will be stereospecific and retains all the stereochemical information of the reactant. However, whether or not (R)-styrene oxide or (S)-styrene oxide is form is dependent on the relative energies of the transition state. The more stable the transition state, the more likely the product of the transition state will be formed.

So in order to examine this, an example of transition state of both styrenes with Shi catalyst are obtained and analyzed.
 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1303.736813'''
| width="100" | '''-1303.727673'''
| width="150" | '''-0.00914'''
| width="150" | '''6.28E-05'''
| width="150" | '''99.99'''

|-
|}

 

From the above, we can see the predicted high enantiopurity of the reaction favoring the (R) product because of the lower energy of the transition states. To understand the reason, we have to turn to non-covalent interaction (NCI) analysis.

[[File:NCI shi fructose styrene.png|700px|center]]

To complement the NCI analysis, a QTAIM (Quantum Theory of Atoms in Molecules) analysis is conducted as well.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''(R)-styrene transition state'''
| width="200" | '''(S)-styrene transition state'''
|- align="center"
| width="100" | '''[[File:QTAIM R.png|400px|center]]'''
| width="100" | '''[[File:QTAIM S.png|400px|center]]'''
|- align="center"
| colspan="2" width="100" | '''Comments'''
|-
| colspan="2" width="100" | '''Unsurprisingly, QTAIM analysis has also shown that (R)-styrene/Shi catalyst has more interactions with one another. While (R)-styrene has 2 strong interactions, (S)-styrene has only one with the catalyst. Besides, the phenyl ring of (R)-styrene also confers additional positive interaction with the catalyst. QTAIM analysis has also show several interactions between the C=C geminal hydrogen of (R)-styrene intreacting with the oxygen atoms on the dioxacyclopentane ring'''
|-
|}

 

===== '''(R,R) and (S,S)-Stilbene transition state''' =====

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R,R)-Stilbene oxide'''
| width="150" | '''(S,S)-Stilbene oxide'''
|- align="center"
| width="150" | ''' Structure of Transition State '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Stilbene RR ts.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>SS stilbene oxide ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| colspan="2" | [[File:Shi fructose stilbene.png|700px|center]]

|-
|}

 

However, unlike styrene, trans-stilbene seems to approach perpendicularly to the dioxirane. This is proposed to be due to the steric interactions (marked in purple). Based on first inspection, it seems that (S,S)-Stilbene oxide has more steric interactions than (R,R)-Stilbene oxide. Although unsubstantial, it seems like my guess was correct. The (R,R)-stilbene/Shi catalyst transition state is lower in energy.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1534.687808'''
| width="100" | '''-1534.683440'''
| width="150" | '''0.004368'''
| width="150" | '''9.08E-3'''
| width="150" | '''98.20'''

|-
|}

 

NCI Analysis is also done for trans-stilbene

[[File:NCI stilbene.png|700px|center]]

==== '''Jacobsen Catalyst''' ====

For this section, cis-beta methyl styrene transition state will be analyzed.

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-3383.259559'''
| width="100" | '''-3383.251060'''
| width="150" | '''-0.008499'''
| width="150" | '''1.24E-04'''
| width="150" | '''99.98'''
|- align="center"
| width="100" | '''-3383.253442'''
| width="100" | '''-3383.250270'''
| width="150" | '''-0.003172'''
| width="150" | '''3.48E-02'''
| width="150" | '''93.27'''
|-
|}

 

As is obvious from here, the (S,R) transition state is more stable than the (R,S) transition state. Both transition states are exo with respect to the catalyst.

It is not immediately apparent just by looking at the molecule to determine which spatial groups have interactions with one another. Therefore, an NCI analysis is conducted again.

[[File:NCI Jacobsen.png|700px|center]]

=== Bibliography ===

1. David C. Forbes, Sampada V. Bettigeri,Samit A. Patrawala, Susanna C. Pischek, and Michael C. Standen, Tetrahedron, 2009, 65(1), 70-76

2. Hui Lina, Jing Qiaoa, Yan Liua, Zhong-Liu Wu, Journal of Molecular Catalysis B: Enzymatic, 2010, 67, 236-241

3. Niwa,Takashi, Nakada,Masahisa, Journal of the American Chemistry , 2012, 134, 13538-13541

4. Arlette Solladié-Cavallo, Anh Diep-Vohuule, Tetrahedron: Asymmetry, 1996, 7(6), 1783-1788

5. Vito Capriati, Saverio Florio, Renzo Luisi,Filippo Maria Perna, Antonio Salomone, Francesco Gasparrini, Org. Lett., 2005, 7 (22), 4895-4898

6. Wong O.Andrea, Wang Bin, Zhao Mei-Xin, Shi Yian, Journal of Organic Chemistry, 2009, 74, 6335-6338

7. Alan B. McEwen, Paul v. R. Schleyer, Journal of The American Chemical Society, 2002, 108(4), 250-253

8. Halgren T. A. J. Comput. Chem., 1999, 20, 720-729.

9. J. Hanson,J. Chem. Educ., 2001, 78, 1266

Rep:Mod:Computationalreport1C

2013-11-22T18:02:31Z

Xc2611: /* Bibliography */

= '''Synthesis and Computational Lab: 1C''' =
== '''Part 1: Introduction to Molecular Mechanics''' ==
=== '''Introduction to MMFF94 and MMFF94s''' ===

With the improvement of computational data and computer processing power, the usage of molecular mechanics/dynamics forcefield has become very integrated in predicting properties of chemical molecules. A molecular mechanics/dynamics forcefield should be able to predict characteristics such as molecular geometries, conformational/stereoisomeric energies, vibrational frequencies etc. to a reasonable accuracy as compared to experimental-derived values.

Building on work from Kollman et al. s’ AMBER forcefield and Allinger et al. s’ MM1, MM2, MM3 and MM4, Merck Research Laboratories have managed to optimized and improved the previous computational algorithms and produced MMFF94 (Merck Molecular Force Field 94). One of the most prominent advantages of MMFF94 over other preceeding work is its enhanced prediction accuracy. The reason lies in the fact that MMFF94’s core parameterization utilizes an unprecedently large amount of computational data obtained from ab initio calculations1.

Subsequently after the development of MMFF94, a new “static” variant of the MMFF was introduced i.e. the MMFF94s. Unlike MMFF94 that was developed for the use of molecular dynamics simulations (which can be expensive), MMFF94s was developed with the purpose of energy minimization studies in mind. Although both systems provide identical results for most systems, they differ for amides and unsaturated amines which contain resonance-delocalized trigonal nitrogen atoms2.

In this computational exercise, MMFF94s is used predominantly as oppose to the alternative Universal Force Field (UFF). Although versatile across the entire periodic table, UFF is derived from simple rules and atomic parameters such as fixed hybridization that increases the likelihood of erroneous structural and energetic predictions3.

=== '''Forms of MMFF94s''' ===

Steric energy of a molecule is the energy arise due to its geometry or conformation. Energy minimization of steric energy process ensures that the molecule is in its lowest energy conformation.

MMFF94s assumes that the total steric energy of a molecule can be found by the sum of a few specific interactions in a molecule.

ES = EBS + EAB + E SB + ET + EOOP + EVdW + EEE

'''where the bonded interactions are:'''

ES = Total Steric energy

EBS = Total Bond Stretching energy

EAB = Total Angle Bending energy

ESB = Total Stretch Bending energy

ET = Total Torsional Energy

EOOP = Total Out-Of-Plane Bending energy, and

'''where the non-bonded interactions are:'''

EVdW = Total Van der Waals Energy

EEE = Total Electrostatic Energy

{| border="1" cellspacing="1" cellpadding="10"
|-
| width="300" align="center" | '''Types of Energies'''
! width="600" align="center" | '''Explanation'''
|-
| colspan="2" style="text-align: center;" | '''Bonded Interactions'''
|-
| width="300" align="center" | '''Total Bond Stretching Energy'''
! width="600" align="left" | The total bond stretching energy is related to the vibration energy of the molecules in comparison to the equilibrium bond length. Whenever a bond deviates from the equilibrium bond length, the energy value increases.

MMFF94s uses a quartic function that has the force constant term (relate to bond strength). The quartic function term is superior to the cubic function term (used in MM2) in the sense that it avoid the “cubic stretch catastrophe” where progressive elongation of molecule bond length leads to negative infinity.
|-
| width="300" align="center" | '''Total Angle Bending Energy'''
! width="600" align="left" | Similar to Total Bond Stretching Energy, the total angle bending energy is also related to the vibration energy of the molecules about the equilibrium bond length. However, unlike EBS that measures the bond strength, EAB is associated with the stiffness of the molecules based on the Hookiean potential. Whenever bond angles deviate from the norm during vibration, this energy term increases as well.
|-
| width="300" align="center" | '''Total Stretch-Bending Energy'''
! width="600" align="left" | This energy term takes into account of the energy due to increase in bond length when bond angle between two atoms changes.
|-
| width="300" align="center" | '''Total Torsional Energy'''
! width="600" align="left" | Total torsional energy is the energy required for intermolecular rotation about the bonds. In molecule mechanics, however, this term is often used as a correction that must be added or subtracted to the total energy of the molecule to fit a quantum mechanical calculation about the dihedral angles of bonds.
|-
| width="300" align="center" | '''Total Out-Of-Plane Bending Energy'''
! width="600" align="left" | This energy term refers to the energy needed to deform the dihedral angle (zero degrees) of a planar group of atoms such as carbonyl or amide functional groups.
|-
| colspan="2" style="text-align: center;" | '''Non-Bonded Interactions'''
|-
| width="300" align="center" | '''Total Van der Waals Energy'''
! width="600" align="left" | The total Van der Waals energy term examines the intramolecular interactions such as repulsion or attraction between non-bonded atoms in the molecule. This term is crucial in determining the preferred conformation of the molecule.

MMFF94s employs the novel “Buffered-14-7”. The name is derived from a buffering constant and the 14th and 7th power dependencies of the repulsive and attractive energy in the equation.
|-
| width="300" align="center" | '''Total Electrostatic Energy'''
! width="600" align="left" | The total electrostatic energy functions take into account of the Coulombic potential and partial charge/dipole/atomic point charges interactions within the molecule.
|-

|}

 

== '''Part 2 : Conformational Analysis Using Molecular Mechanics''' ==
=== '''The Hydrogenation of Cyclopentadiene Dimer''' ===

==== '''Endo and exo adduct from the Dimerization of Cyclopentadiene''' ====
Cyclopentadiene will undergo dimerization by Diels-alder reaction to form either an endo or exo adduct.

[[File:XcwDimerization of CP.png|500px|center]]

==== '''Stereoselectivity of Dimerization of Cyclopentadiene''' ====
Although the exo adduct is thermodynamically more stable than the endo adduct, the endo adduct is form preferentially. Using the QST2 method, the transition state of the Diels Alder dimerization was found. It was discovered that due to the secondary orbital interactions in the endo transition state, the endo dimer is formed preferentially (the kinetic product). Hence, it is proven that the Diels Alder dimerization between two cyclopentadiene are kinetically controlled.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Transition State of Dimerization of Cyclopentadiene'''
| '''Imaginary Stretch Frequency (-881.25) of the Endo Transition State (click to animate)'''
| '''Secondary Orbital Interaction (Red overlapping orbitals)'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<uploadedFileContents>EndotsDCPD2.mol
</uploadedFileContents>
</jmolApplet></jmol>
| [[File:Xcwendotsimaginary.gif|300px|center]]
| [[File:XcwSecondary orbital interaction1.jpg|300px|center]]
|-
|}

 

==== '''Asynchronous Bond Formation of Dimerization of Cyclopentadiene''' ====

The initial study of the molecular orbitals of the transition states seemed a bit peculiar. Instead of getting a LUMO with symmetrical orbitals, the calculations showed a HOMO that is asymetric at the carbons where the new sigma bonds will be formed. Running an IRC further, it soon became clear that the asymmetry of the HOMO leads to an asychronous bond formation before leading to the product.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''IRC plot following the Endo Transition State '''
| '''IRC following the Endo Transition State (click to animate)'''
| '''Asymmetry of orbitals at the carbons where the new sigma bonds will be formed'''
|- align="center"
| [[File:XcwendotscyclopentadieneIRC.png|300px|center]]
| [[File:XcwendotsIRC.gif|300px|center]]
| [[File:XcwAsynchronous mo.jpg|300px|center]]
|-
|}

 

==== '''Comparison of Energies between the Endo and Exo adduct of Dicyclopentadiene''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Adduct of Dicyclopentadiene dimerization'''
| '''Exo Adduct of Dicyclopentadiene dimerization'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=19,atomno=1,atomno=2; color green;measure 19 1;measure 19 2;</script>
<uploadedFileContents>XcwEndodimer3.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>Exodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=7,atomno=17; color green;measure 17 7;</script>
<uploadedFileContents>XcwExodimer1.mol</uploadedFileContents>
</jmolApplet></jmol>
|-
|}

 

Using MMFF94s ab initio calculations, the energies for the exo dimer and the endo dimer are derived.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Exodimer'''
| '''55.374'''
| 3.543
| 30.772
| -2.041
| -2.728
| 0.015
| 12.800
| 13.014
|-
| '''Endodimer'''
| '''58.191'''
| 3.468
| 33.187
| -2.082
| -2.950
| 0.023
| 12.360
| 14.186
|-
|}

 

The MMFF94s steric energy (after minimization) for the exo dimer is lower than that of the endo dimer. This is reflected by the large difference for the EEE between the endo dimer and the exo dimer due to unfavourable steric repulsion between the two “arched down” cyclopentene rings.

==== '''Hydrogenation of Dicyclopentadiene''' ====

Hydrogenation of the endo dicyclopentadiene (DCPD) would lead to two potential products: dihydro product 1 and dihydro product 2.

[[File:XcwFormation of Dihydro products.png|500px|center]]

Using MMFF94s, the energy of the two dihydro products are calculated.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Dihydro Product 1'''
| '''50.123'''
| 3.308
| 30.864
| -1.927
| 0.060
| 0.015(2)
| 13.281
| 5.121
|-
| '''Dihydro Product 2'''
| '''41.257'''
| 2.823
| 24.685
| -1.657
| -0.379
| 0.000(2)
| 10.639
| 5.147
|-
| '''Tetrahydro Product'''
| '''39.042'''
| 2.730
| 25.151
| -1.676
| 1.287
| 0.000
| 11.551
| 0.000
|}

 

From the MMFF94s calculation, it can be seen that dihydro product 2 has a lower steric energy than dihydro product 1. Therefore, dihydro product 2 is the thermodynamic product for the hydrogenation of dicylopentadiene. And indeed, this was what was observed by Skala et al.. He observed that the first hydrogenation occur at the norborene part of the molecule (rate of hydrogenation several times faster than that in the cyclopentene ring)6. The first heat of hydrogenation at the norborene is 138.8 kJ/mol while the second hydrogenation at the cyclopentene right is 109.5 kJ/mol6.

From the above results, it is also obvious that tetrahydro product is much more stable than either dihydro product. And yet, studies have shown that the tetrahydro product will only form after prolonged hydrogenation under high temperature. However, subjecting DCPD to high temperature leads to low yield due to cracking of DCPD.

Since thermodynamically it is predicted to form favourably, the fact that it does not could only mean that the hydrogenation of DCPD to tetrahydrodicyclopentadiene (TH-DCPD) is kinetically controlled. Most possibly, the transition state of the hydrogenation of DCPD is highly unstable hence it is unlikely to form.

=== '''Atropisomerism in an Intermediate related to the Synthesis of Taxol''' ===

Atropisomerism is a type of stereoisomerism that is form as a result of hindered rotation about a single bond.

[[File:XcwAtropisomerism example.png|500px|center]]

In the case of the 6,6’-dinitro-2,2’-diphenic acid, rotation about the bonds joining the two substituted phenyl rings would have to overcome large steric interaction between the bulky substituents. The barrier of rotation is high enough for the two conformers to be isolated individually.

In the synthesis of taxol, one of the key intermediates exhibit atropisomerism.

==== '''Atropisomerism in Taxol Synthesis''' ====

For the key intermediate, rotation about the carbon-carbon bonds would lead to two types of atropisomers, each with either the carbonyl group poining upwards or downwards in relative to the bridge.

[[File:XcwIntermediate 9 and Intermediate 10.png|500px|center]]

Once again by using MMFF94s ab initio calculations, the steric energies for the two intermediates are illustrated as below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 9'''
| '''70.571'''
| 7.743
| 28.356
| -0.062
| 0.004
| 0.949
| 33.293
| 0.288
|-
| '''Intermediate 10'''
| '''60.553'''
| 7.599
| 18.838
| -0.139
| 0.199
| 0.844
| 33.269
| -0.056
|-

|}

 

Analyzing the data above, the largest energy difference between Intermediate 9 and Intermediate 10 stems from the EAB which is related to the strain of the ring. Intermediate 9 has an excess of 9.518 kcal/mol EAB as compared to Intermediate 10. This comes as a surprise as intermediate 9 is predicted to be more stable alkene.

The rationale behind the prediction of the stability of intermediate 9 stems from the fact that the through-space distance of the upward-pointing carbonyl oxygen with the carbon-carbon is further than the through space distance between the downward-pointing carbonyl oxygen with the -CH2-CH2- fragment at the norbornene part in intermediate 10.

==== '''Hyperstable Olefins''' ====

Intermediate 9 and Intermediate 10 does not react readily with other reagents during functionalization. This is due to the hyperstability effect found in hyperstable olefins.

Hyperstable olefins are alkenes that contain less strain in the ring (i.e. negative olefin strain values) compared to the parent hydrocarbon. To study this further, further MMFF94s calculation was done to compare Intermediate 10 with the parent hydrocarbon.

[[File:XcwIntermediate10andPH.png|500px|center]]

The energies that we calculated are tabulated as shown below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 10'''
| '''44.878 '''
| 5.211
| 15.488
| -0.267
| -1.655
| 0.998
| 25.014
| 0.088
|-
| '''Parent Hydrocarbon'''
| '''50.564'''
| 4.692
| 21.979
| 0.109
| -0.958
| 0.247
| 24.495
| 0.000
|-

|}

 

Scrutinizing the results, the largest energy difference between intermediate 10 and the parent hydrocarbon stems from the Total Angle Bending Energy, EAB. Since the Total Angle bending energy is related to the angle strain in the molecules, it is apparent that the parent hydrocarbon has more ring strain as compared to the bridgehead olefin.

== '''Part 3 : Spectroscopic Simulation Using Quantum Mechanics''' ==
=== '''Spectroscopy of an Intermediate Related to the Synthesis of Taxol''' ===

Molecule 17 and 18 are derivatives of intermediate 9 and 10. In this exercise, MMFF94s is used to predict the 1H and 13C NMR of molecule 17 and molecule 18.

[[File:XcwIntermediate17&18.png|500px|center]]

==== '''NMR Spectra of Molecule 17''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 17.mol
</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwHNMRMolecule 17 Chair Overall NMR.png|500px|center]]
| [[File:XcwHNMRMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.1825
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| The first three results were fairly straight forward to be deduced and correlate wit experimental data.

The hydrogen atom that is geminally attached to the carbon of the double bonds is the most deshielded due to the ring current anisotropic effect of the ring current

The second most deshielded hydrogen atom is the hydrogen atom on the methyl group on the bridge. The hydrogen atom is pointing directly to the oxygen atom of the carbonyl functional group.

The peaks with an integration height of 4 is assigned to the hydrogen atoms in the 1,3-dithiolane ring fragment.

Subsequent analysis of the 1H NMR became very complicated very quickly for two reasons:

1. Gaussian calculations showed some atoms with an integration height of 3. Comparing their file atom number and checking their chemical environment, it is not possible to find any correlation between them.

2. Some of the peaks in the literature remains unresolved and are given as multiplets or grouped together.

|- align="center"
| 52
| 3.1775
| 1
| '''2.99'''
|- align="center"
| 53,52,50,51
| 3.0867
| 4
| '''3.40-3.10'''
|- align="center"
| 42,43,39
| 2.7445
| 3
| ''' '''
|- align="center"
| 49
| 2.6187
| 1
| ''' '''
|- align="center"
| 34
| 2.4371
| 1
| ''' '''
|- align="center"
| 35
| 2.3782
| 1
| ''' '''
|- align="center"
| 40,37,26
| 2.2730
| 3
| ''' '''
|- align="center"
| 30
| 2.1566
| 1
| ''' '''
|- align="center"
| 36
| 2.1033
| 1
| ''' '''
|- align="center"
| 32,28
| 2.0259
| 2
| ''' '''
|- align="center"
| 25
| 1.8535
| 2
| ''' '''
|- align="center"
| 38,46,27
| 1.5898
| 3
| '''1.25'''
|- align="center"
| 29
| 1.4557
| 1
| ''' '''
|- align="center"
| 31
| 1.0123
| 1
| ''' '''
|- align="center"
| 44,48,45
| 0.9087
| 3
| '''1.10'''
|- align="center"
| 47
| 0.8354
| 1
| ''' '''
|- align="center"
| 33
| 0.5790
| 1
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 17 Chair Overall NMR2.png|500px|center]]
| [[File:XcwMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 216.2725
| 1
| '''218.79'''
| rowspan="10" style="text-align:center;"| [[File:XcwMolecule 17 image for CNMR.jpg|600px|center]]
|- align="center"
| 13
| 144.8626
| 1
| '''144.63'''
|- align="center"
| 14
| 124.7193
| 1
| '''125.33'''
|- align="center"
| 3
| 91.3340
| 1
| '''72.88'''
|- align="center"
| 2
| 60.9568
| 1
| '''56.19'''
|- align="center"
| 1
| 57.0811
| 1
| '''52.52'''
|- align="center"
| 10
| 52.4663
| 1
| '''48.50'''
|- align="center"
| 16
| 51.4857
| 1
| '''46.80'''
|- align="center"
| 9
| 46.9196
| 1
| '''45.76'''
|- align="center"
| 23
| 43.8647
| 1
| '''39.80'''
|- align="center"
| 22
| 41.9450
| 1
| '''38.81'''
| Comments
|- align="center"
| 4
| 41.8724
| 1
| '''35.85'''
| rowspan="9" style="text-align:left;"| The carbon bonded to the oxygen atom is the most deshielded, as is shown in the predicted values and the experimental values. There is a deviation between the values. Quite possibly, this is due to the fact that in reality, the carbonyl functional group is pointing slightly towards the equatorial position rather than a lateral position relative to the ring (as is in the input for Gaussian calculation)

Most of the 1CNMR values that was predicted by Gaussian are all within an acceptable range of deviation. However, there is carbon 3 that has significant deviation between the predicted value and experimental value.

Carbon 3 is the carbon bonded to the two sulphurs in the 1,3-dithiolane ring fragment. Such a huge deviation would possibly mean that the conformer that was given as input to Gaussian differs from the literature.

The above NMR spectra was corrected with a level of theory B3LYP/6-31G(d,p) using TMS as reference and in chloroform.

|- align="center"
| 15
| 35.4348
| 1
| '''32.66'''
|- align="center"
| 11
| 31.1964
| 1
| '''28.79'''
|- align="center"
| 6
| 28.9432
| 1
| '''28.29'''
|- align="center"
| 7
| 28.3640
| 1
| '''26.88'''
|- align="center"
| 12
| 27.3767
| 1
| '''25.66'''
|- align="center"
| 17
| 26.3311
| 1
| '''23.86'''
|- align="center"
| 15
| 24.5483
| 1
| '''20.96'''
|- align="center"
| 18
| 19.7788
| 1
| '''18.71'''
|-
|}
 

==== '''NMR Spectra of Molecule 18''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 18 Boat for Image2.mol</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"-
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 18 Chair Overall NMR.png|500px|center]]
| [[File:Molecule 18 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
|- align="center"
| 41
| 5.2832
| 1
| '''5.21'''
|- align="center"
| 50
| 3.3175
| 1
| rowspan="4" style="text-align:centre;"| '''3.00-2.70'''
|- align="center"
| 52
| 3.2153
| 1
|- align="center"
| 51,53
| 3.1161
| 2
|- align="center"
| 34,43
| 2.8606
| 2
|- align="center"
| 38
| 2.4549
| 1
| ''' '''
|- align="center"
| 42
| 2.3968
| 1
| ''' '''
|- align="center"
| 25,29,26
| 2.2796
| 3
| ''' '''
|- align="center"
| 39
| 2.0844
| 1
| ''' '''
|- align="center"
| 40,36
| 1.9699
| 2
| ''' '''
|- align="center"
| 37,24
| 1.8519
| 2
| ''' '''
|- align="center"
| 31,27
| 1.6780
| 2
| ''' '''
|- align="center"
| 28
| 1.6175
| 1
| ''' '''
|- align="center"
| 46,49
| 1.4979
| 2
| ''' '''
|- align="center"
| 35
| 1.4150
| 1
| ''' '''
|- align="center"
| 32
| 1.3531
| 1
| ''' '''
|- align="center"
| 48
| 1.1606
| 1
| ''' '''
|- align="center"
| 33,30,47
| 1.0653
| 3
| '''1.03'''
|- align="center"
| 44,45
| 0.9643
| 2
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 18 Full Spectra'''
| '''13C NMR Spectra of Molecule 18 Truncated Spectra'''
|- align="center"
| [[File:XcwMolecule 18 Boat Overall NMR.png|500px|center]]
| [[File:XcwMolecule 18 Boat zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
|- align="center"
| 8
| 211.8325
| 1
| '''211.49'''
|- align="center"
| 13
| 148.6673
| 1
| '''148.72'''
|- align="center"
| 14
| 118.8373
| 1
| '''120.90'''
|- align="center"
| 3
| 89.0869
| 1
| '''74.61'''
|- align="center"
| 2
| 67.8886
| 1
| '''60.53'''
|- align="center"
| 1
| 56.1133
| 1
| '''51.30'''
|- align="center"
| 10
| 55.5998
| 1
| '''50.94'''
|- align="center"
| 16
| 50.1124
| 1
| '''45.53'''
|- align="center"
| 22
| 48.2030
| 1
| '''43.28'''
|- align="center"
| 23
| 44.2222
| 1
| '''40.82'''
|- align="center"
| 4
| 42.0354
| 1
| '''38.73'''
|- align="center"
| 9
| 37.5865
| 1
| '''36.78'''
|- align="center"
| 6
| 35.3106
| 1
| '''35.47'''
|- align="center"
| 15
| 31.0459
| 1
| '''30.84'''
|- align="center"
| 7
| 28.8476
| 1
| '''30.00'''
|- align="center"
| 12
| 28.6623
| 1
| '''25.56'''
|- align="center"
| 17
| 25.7393
| 1
| '''25.35'''
|- align="center"
| 11
| 25.2603
| 1
| '''22.21'''
|- align="center"
| 18
| 23.3944
| 1
| '''21.39'''
|- align="center"
| 5
| 21.0478
| 1
| '''19.83'''
|-
|}
 

== '''Part 4 : Analysis of the Properties of the Synthesized Alkene Epoxides''' ==
=== '''The two catalytics systems''' ===

Assymmetric epoxidation of prochiral alkenes may lead to product with different stereochemical outcome as illustrated as below. To solve this problem, different types of asymmetric epoxidation catalyst have been synthesized. In this study, we shall be focusing on Shi asymmetric fructose catalyst as well as Jacobsen asymmetric catalyst.

[[File:Asymmetric catalyst.png|400px|center]]

==== ''' The Shi Asymmetric Fructose Catalyst''' ====

Molecule 21 is the stable precursor of molecule 22, the active catalyst. Molecule 21 can be converted to molecule 22 by using either persulfuric acid or potassium peroxymonosulphate.

[[File:Molecule 21 to 23.png|400px|center]]

The transition state of the Shi epoxidation was a subject of debate for a few moments. However, recent studies have led to the conclusion that the spiro transition state is more favored than the planar transition state. The spiro transition state is the transition that has its dioxirane perpendicularly bisecting the alkene double bond. This is thought to be more favourable due to interactions between the lone pairs of the oxygen with the LUMO of the alkene.

[[File:Spiro and planar ts.png|500px|center]]

==== ''' The Jacobsen Asymmetric Catalyst''' ====

Molecule 23 is the stable precursor of molecule 24, the active catalyst. Molecule 23 can be converted to molecule 24 by using sodium perchlorate.

[[File:Salen, 23 and 24.png|400px|center]]

Jacobsen catalyst is biphasic. The first phase involves the transfer of oxygen to molecule 23. Sodium perchlorate oxidizes Mn(III) to Mn(V).

In the second step, Jacobsen catalyst acts via a radical mechanism. It is thought to be so because epoxidation of trans-alkene by Jacobsen catalyst yield cis-alkene as well. A radical mechanism will lead to the lost of stereochemical information of the molecule.

=== ''' Crystal structure of the two catalyst''' ===
==== '''Molecule 21''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 21'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 21 strucutre.png|600px|center]]'''
|-
| style="text-align:center;" width="150" | ''' Bond '''
| style="text-align:center;" width="150"| ''' Bond Lenghts (Angstrom)'''
| style="text-align:center;" | ''' Evaluation'''
|-
| style="text-align:center;"| ''' O1-C1 '''
| style="text-align:center;"| ''' 1.400'''
| rowspan="10" style="text-align:left;"| [[File:Molecule 21 2.png|300px|center]]

The normal bond length of an C-O bond is 1.430 angstrom.

The most interesting aspect here is O4 and O2. The lone pair of O4 is antiperplanar to the sigma* orbital of the carbonyl group while the lone pair of O2 is anti periplanar to the carbonyl pi* orbital. Donation of electron can occur because of the correct symmetry. Due to the mixing of the orbitals, the C2-O2 and C4-O4 has been conferred with a certain degree of double bond character.

However, due to the lone pair on oxygen being now donated to the carbonyl antibonding orbitals, the O2 and O4 is slightly “electron deficient” and electron density will be pulled away from O2 and O4. That would explain why the bond length increase for O2-C7 and O4-C10. Increase in bond length is an indicator of the weakening of the bond.
|-
| style="text-align:center;"|'''O1-C7'''
| style="text-align:center;"|'''1.413'''
|-
| style="text-align:center;"|'''O2-C7'''
| style="text-align:center;"|'''1.441'''
|-
| style="text-align:center;"|'''O2-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O4-C4'''
| style="text-align:center;"|'''1.396'''
|-
| style="text-align:center;"|'''O4-C10'''
| style="text-align:center;"|'''1.439'''
|-
| style="text-align:center;"|'''O5-C10'''
| style="text-align:center;"|'''1.409'''
|-
| style="text-align:center;"|'''O5-C5'''
| style="text-align:center;"|'''1.416'''
|-
| style="text-align:center;"|'''O6-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O6-C6'''
| style="text-align:center;"|'''1.420'''
|-
|}
 

==== '''Molecule 23''' ====

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 23'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 23 struc.png|600px|center]]'''
|-
| The most outstanding feature from this molecule is the fact that is adopt a puckered form of the square base pyramidal form. This is no surprise that the molecule is almost planar due to the electron delocalization around each side of the salen ligand.

The tery-butyl hydrogen are oriented closely to one another. Non-covalent interaction studies indicated that repulsion would occur for H---H bond length that are less than 2.1 angstrom while favourable interaction may be dominant with bond length above 2.4 angstrom. It was discovered that all 4 hydrogens have bond length more than 2.4 angstrom hence there should not be any significant repulsion between them. Instead, certain amount of attractive force will ensue and that contributes to the overall stability of the molecule

|-
|}
 

=== ''' The calculated NMR properties of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | '''
Shift (ppm) Degeneracy
7.4891704929 4.0000
7.2988172444 1.0000
3.6627082199 1.0000
3.1170156088 1.0000
2.5382383043 1.0000 '''
| width="100" | '''
Shift (ppm) Degeneracy
7.4892967873 4.0000
7.2987138125 1.0000
3.6632689921 1.0000
3.1151709109 1.0000
2.5339209685 1.0000

'''
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Styrene R HNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Styrene S HNMR.png|400px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | '''
Shift (ppm) Degeneracy
135.1098747604 1.0000
124.1186533632 1.0000
123.4150641684 1.0000
122.9584694331 2.0000
118.2653162569 1.0000
54.0265785300 1.0000
53.4853575062 1.0000 '''
| width="100" | '''
Shift (ppm) Degeneracy
135.1323742030 1.0000
124.1343038829 1.0000
123.4137039868 1.0000
122.9558208084 2.0000
118.2690258882 1.0000
54.0599580762 1.0000
53.4684920923 1.0000
'''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | ''' [[File:Styrene R CNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Styrene S CNMR.png|400px|center|]]'''
|-
| width="100" | ''' '''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | ''' Shift (ppm) Degeneracy
7.5705724829 2.0000
7.4791732656 8.0000
3.5390102503 2.0000
| width="100" | ''' Shift (ppm) Degeneracy
7.5705651164 2.0000
7.4791779628 8.0000
3.5374502607 2.0000
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Stilbene RR HNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|400px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | ''' Shift (ppm) Degeneracy
134.0942417727 2.0000
124.2206838184 2.0000
123.5192390024 2.0000
123.2125901307 2.0000
123.0785800542 2.0000
118.2583039589 2.0000
66.4212770637 2.0000 '''
| width="100" | ''' Shift (ppm) Degeneracy
134.0899175142 2.0000
124.2224499528 2.0000
123.5180152862 2.0000
123.2113538650 2.0000
123.0745448885 2.0000
118.2635789492 2.0000
66.4249347217 2.0000 '''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | ''' [[File:Stilbene RR CNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|400px|center|]]'''
|-
|}

 

=== ''' Assigning the absolute configuration of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''Predicted ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg'''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg '''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental conditions'''
| width="100" | '''1.00g/100ml, chloroform, 21 degree Celcisus, 589 nm wavelength '''
| width="100" | '''1.02g/100ml (99% ee), chloroform, 25 degree Celsius, 589 nm wavelength '''
| width="100" | '''1.01g/100ml, ethanol, 22 degree Celsius, 589 nm wavelength '''
| width="100" | '''0.6g/100ml, ethanol, 20 degree Celsius, 589 nm wavelength '''
|- align="left"
| width="100" | ''' Predicted VCD Spectrum'''
| width="100" | '''[[File:Styrene R VCD.png|200px|center|]] '''
| width="100" | '''[[File:Styrene S VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene RR VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene SS VCD.png|200px|center|]]'''
|-
|}

 

All the assignments given in the literature reports are correct although the predicted value differs slightly with the experimental values

=== ''' Analysis of the Transition State for Reactions''' ===
==== '''Predicting Enantiomeric Excess based on Transition State energies''' ====

One of the energy output from Gaussian calculation is the “sum of electronic and thermal free energies”. This is Gibbs Free Energy at 298.15K and 1 atm.

Using this term and invoking a variant of the Curtin-Hammett Principle, it is possible to calculate a predicted enantiomeric excess of one enantiomer over the other.

[[File:Ee and transition state energy.png|800px|center]]

Using the derivations from above and equation (4), we analyze the enantiomeric excess of beta-methyl styrene and the results are tabulated as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1343.022970'''
| width="100" | '''-1343.017942'''
| width="150" | '''-0.005028'''
| width="150" | '''4.88E-03'''
| width="150" | '''99.03'''
|- align="center"
| width="100" | '''-1343.019233'''
| width="100" | '''-1343.015603'''
| width="150" | '''-0.003630'''
| width="150" | '''2.14E-02'''
| width="150" | '''95.80'''
|- align="center"
| width="100" | '''-1343.029272'''
| width="100" | '''-1343.023766'''
| width="150" | '''-0.005506'''
| width="150" | '''2.94E-03'''
| width="150" | '''99.41'''
|- align="center"
| width="100" | '''-1343.032443'''
| width="100" | '''-1343.024742'''
| width="150" | '''-0.007701'''
| width="150" | '''2.88E-04'''
| width="150" | '''99.94'''
|-
|}

 

The above hartree units are converted to J/mol for calculation of K where 1 hartress = 4.3597E-18

Studying all the free energies of the (R,R) series and compare them with the (S,S) series, it comes as no surprise that (R,R) product is favoured over (S,S) product as (R,R) is more stable. Indeed, this corresponds with the literature value reporting 92% ee of (R,R) products over that of (S,S).

==== '''Analysis of the Transition State of Epoxidation''' ====
==== '''Shi Fructose Catalyst''' ====
For this section, I will be analyzing the the transition state of 1) styrene and 2) trans-stilbene with the Shi fructose catalyst.

===== '''(R) and (S)-styrene transition state''' =====
The transition state for the formation of (R)-styrene oxide and (S)-styrene oxide are given as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R)-styrene oxide'''
| width="150" | '''(S)-styrene oxide'''
|- align="center"
| width="150" | ''' Structure of Catalyst '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide R.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide S ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| [[File:Steric shi fructose R.png|450px|center]]
| [[File:Steric shi fructose S.png|450px|center]]
|-
|}

 

In the transition state for (R)-styrene, it was discovered that the Re face is reacting with the oxygen of the dioxirane. The phenyl ring is oriented endo with respect to the fructose catalyst. However, the (S)-styrene is reacting at the Si face and the phenyl ring is oriented exo relative to the catalyst.

The approach taken by (R)-styrene and (S)-styrene are restricted to only one due to steric interactions. Therefore, the epoxidation of both styrenes by the Shi catalyst will be stereospecific and retains all the stereochemical information of the reactant. However, whether or not (R)-styrene oxide or (S)-styrene oxide is form is dependent on the relative energies of the transition state. The more stable the transition state, the more likely the product of the transition state will be formed.

So in order to examine this, an example of transition state of both styrenes with Shi catalyst are obtained and analyzed.
 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1303.736813'''
| width="100" | '''-1303.727673'''
| width="150" | '''-0.00914'''
| width="150" | '''6.28E-05'''
| width="150" | '''99.99'''

|-
|}

 

From the above, we can see the predicted high enantiopurity of the reaction favoring the (R) product because of the lower energy of the transition states. To understand the reason, we have to turn to non-covalent interaction (NCI) analysis.

[[File:NCI shi fructose styrene.png|700px|center]]

To complement the NCI analysis, a QTAIM (Quantum Theory of Atoms in Molecules) analysis is conducted as well.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''(R)-styrene transition state'''
| width="200" | '''(S)-styrene transition state'''
|- align="center"
| width="100" | '''[[File:QTAIM R.png|400px|center]]'''
| width="100" | '''[[File:QTAIM S.png|400px|center]]'''
|- align="center"
| colspan="2" width="100" | '''Comments'''
|-
| colspan="2" width="100" | '''Unsurprisingly, QTAIM analysis has also shown that (R)-styrene/Shi catalyst has more interactions with one another. While (R)-styrene has 2 strong interactions, (S)-styrene has only one with the catalyst. Besides, the phenyl ring of (R)-styrene also confers additional positive interaction with the catalyst. QTAIM analysis has also show several interactions between the C=C geminal hydrogen of (R)-styrene intreacting with the oxygen atoms on the dioxacyclopentane ring'''
|-
|}

 

===== '''(R,R) and (S,S)-Stilbene transition state''' =====

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R,R)-Stilbene oxide'''
| width="150" | '''(S,S)-Stilbene oxide'''
|- align="center"
| width="150" | ''' Structure of Transition State '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Stilbene RR ts.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>SS stilbene oxide ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| colspan="2" | [[File:Shi fructose stilbene.png|700px|center]]

|-
|}

 

However, unlike styrene, trans-stilbene seems to approach perpendicularly to the dioxirane. This is proposed to be due to the steric interactions (marked in purple). Based on first inspection, it seems that (S,S)-Stilbene oxide has more steric interactions than (R,R)-Stilbene oxide. Although unsubstantial, it seems like my guess was correct. The (R,R)-stilbene/Shi catalyst transition state is lower in energy.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1534.687808'''
| width="100" | '''-1534.683440'''
| width="150" | '''0.004368'''
| width="150" | '''9.08E-3'''
| width="150" | '''98.20'''

|-
|}

 

NCI Analysis is also done for trans-stilbene

[[File:NCI stilbene.png|700px|center]]

==== '''Jacobsen Catalyst''' ====

For this section, cis-beta methyl styrene transition state will be analyzed.

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-3383.259559'''
| width="100" | '''-3383.251060'''
| width="150" | '''-0.008499'''
| width="150" | '''1.24E-04'''
| width="150" | '''99.98'''
|- align="center"
| width="100" | '''-3383.253442'''
| width="100" | '''-3383.250270'''
| width="150" | '''-0.003172'''
| width="150" | '''3.48E-02'''
| width="150" | '''93.27'''
|-
|}

 

As is obvious from here, the (S,R) transition state is more stable than the (R,S) transition state. Both transition states are exo with respect to the catalyst.

It is not immediately apparent just by looking at the molecule to determine which spatial groups have interactions with one another. Therefore, an NCI analysis is conducted again.

[[File:NCI Jacobsen.png|700px|center]]

=== Bibliography ===

1. David C. Forbes, Sampada V. Bettigeri,Samit A. Patrawala, Susanna C. Pischek, and Michael C. Standen, Tetrahedron, 2009, 65(1), 70-76

2. Hui Lina, Jing Qiaoa, Yan Liua, Zhong-Liu Wu, '''Journal of Molecular Catalysis B: Enzymatic''', 2010, 67, 236-241

3. Niwa,Takashi, Nakada,Masahisa, Journal of the American Chemistry , 2012, 134, 13538-13541

4. Arlette Solladié-Cavallo, Anh Diep-Vohuule, Tetrahedron: Asymmetry, 1996, 7(6), 1783-1788

5. Vito Capriati, Saverio Florio, Renzo Luisi,Filippo Maria Perna, Antonio Salomone, Francesco Gasparrini, Org. Lett., 2005, 7 (22), 4895-4898

6. Wong O.Andrea, Wang Bin, Zhao Mei-Xin, Shi Yian, Journal of Organic Chemistry, 2009, 74, 6335-6338

7.

Rep:Mod:Computationalreport1C

2013-11-22T18:02:01Z

Xc2611: /* Bibliography */

= '''Synthesis and Computational Lab: 1C''' =
== '''Part 1: Introduction to Molecular Mechanics''' ==
=== '''Introduction to MMFF94 and MMFF94s''' ===

With the improvement of computational data and computer processing power, the usage of molecular mechanics/dynamics forcefield has become very integrated in predicting properties of chemical molecules. A molecular mechanics/dynamics forcefield should be able to predict characteristics such as molecular geometries, conformational/stereoisomeric energies, vibrational frequencies etc. to a reasonable accuracy as compared to experimental-derived values.

Building on work from Kollman et al. s’ AMBER forcefield and Allinger et al. s’ MM1, MM2, MM3 and MM4, Merck Research Laboratories have managed to optimized and improved the previous computational algorithms and produced MMFF94 (Merck Molecular Force Field 94). One of the most prominent advantages of MMFF94 over other preceeding work is its enhanced prediction accuracy. The reason lies in the fact that MMFF94’s core parameterization utilizes an unprecedently large amount of computational data obtained from ab initio calculations1.

Subsequently after the development of MMFF94, a new “static” variant of the MMFF was introduced i.e. the MMFF94s. Unlike MMFF94 that was developed for the use of molecular dynamics simulations (which can be expensive), MMFF94s was developed with the purpose of energy minimization studies in mind. Although both systems provide identical results for most systems, they differ for amides and unsaturated amines which contain resonance-delocalized trigonal nitrogen atoms2.

In this computational exercise, MMFF94s is used predominantly as oppose to the alternative Universal Force Field (UFF). Although versatile across the entire periodic table, UFF is derived from simple rules and atomic parameters such as fixed hybridization that increases the likelihood of erroneous structural and energetic predictions3.

=== '''Forms of MMFF94s''' ===

Steric energy of a molecule is the energy arise due to its geometry or conformation. Energy minimization of steric energy process ensures that the molecule is in its lowest energy conformation.

MMFF94s assumes that the total steric energy of a molecule can be found by the sum of a few specific interactions in a molecule.

ES = EBS + EAB + E SB + ET + EOOP + EVdW + EEE

'''where the bonded interactions are:'''

ES = Total Steric energy

EBS = Total Bond Stretching energy

EAB = Total Angle Bending energy

ESB = Total Stretch Bending energy

ET = Total Torsional Energy

EOOP = Total Out-Of-Plane Bending energy, and

'''where the non-bonded interactions are:'''

EVdW = Total Van der Waals Energy

EEE = Total Electrostatic Energy

{| border="1" cellspacing="1" cellpadding="10"
|-
| width="300" align="center" | '''Types of Energies'''
! width="600" align="center" | '''Explanation'''
|-
| colspan="2" style="text-align: center;" | '''Bonded Interactions'''
|-
| width="300" align="center" | '''Total Bond Stretching Energy'''
! width="600" align="left" | The total bond stretching energy is related to the vibration energy of the molecules in comparison to the equilibrium bond length. Whenever a bond deviates from the equilibrium bond length, the energy value increases.

MMFF94s uses a quartic function that has the force constant term (relate to bond strength). The quartic function term is superior to the cubic function term (used in MM2) in the sense that it avoid the “cubic stretch catastrophe” where progressive elongation of molecule bond length leads to negative infinity.
|-
| width="300" align="center" | '''Total Angle Bending Energy'''
! width="600" align="left" | Similar to Total Bond Stretching Energy, the total angle bending energy is also related to the vibration energy of the molecules about the equilibrium bond length. However, unlike EBS that measures the bond strength, EAB is associated with the stiffness of the molecules based on the Hookiean potential. Whenever bond angles deviate from the norm during vibration, this energy term increases as well.
|-
| width="300" align="center" | '''Total Stretch-Bending Energy'''
! width="600" align="left" | This energy term takes into account of the energy due to increase in bond length when bond angle between two atoms changes.
|-
| width="300" align="center" | '''Total Torsional Energy'''
! width="600" align="left" | Total torsional energy is the energy required for intermolecular rotation about the bonds. In molecule mechanics, however, this term is often used as a correction that must be added or subtracted to the total energy of the molecule to fit a quantum mechanical calculation about the dihedral angles of bonds.
|-
| width="300" align="center" | '''Total Out-Of-Plane Bending Energy'''
! width="600" align="left" | This energy term refers to the energy needed to deform the dihedral angle (zero degrees) of a planar group of atoms such as carbonyl or amide functional groups.
|-
| colspan="2" style="text-align: center;" | '''Non-Bonded Interactions'''
|-
| width="300" align="center" | '''Total Van der Waals Energy'''
! width="600" align="left" | The total Van der Waals energy term examines the intramolecular interactions such as repulsion or attraction between non-bonded atoms in the molecule. This term is crucial in determining the preferred conformation of the molecule.

MMFF94s employs the novel “Buffered-14-7”. The name is derived from a buffering constant and the 14th and 7th power dependencies of the repulsive and attractive energy in the equation.
|-
| width="300" align="center" | '''Total Electrostatic Energy'''
! width="600" align="left" | The total electrostatic energy functions take into account of the Coulombic potential and partial charge/dipole/atomic point charges interactions within the molecule.
|-

|}

 

== '''Part 2 : Conformational Analysis Using Molecular Mechanics''' ==
=== '''The Hydrogenation of Cyclopentadiene Dimer''' ===

==== '''Endo and exo adduct from the Dimerization of Cyclopentadiene''' ====
Cyclopentadiene will undergo dimerization by Diels-alder reaction to form either an endo or exo adduct.

[[File:XcwDimerization of CP.png|500px|center]]

==== '''Stereoselectivity of Dimerization of Cyclopentadiene''' ====
Although the exo adduct is thermodynamically more stable than the endo adduct, the endo adduct is form preferentially. Using the QST2 method, the transition state of the Diels Alder dimerization was found. It was discovered that due to the secondary orbital interactions in the endo transition state, the endo dimer is formed preferentially (the kinetic product). Hence, it is proven that the Diels Alder dimerization between two cyclopentadiene are kinetically controlled.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Transition State of Dimerization of Cyclopentadiene'''
| '''Imaginary Stretch Frequency (-881.25) of the Endo Transition State (click to animate)'''
| '''Secondary Orbital Interaction (Red overlapping orbitals)'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<uploadedFileContents>EndotsDCPD2.mol
</uploadedFileContents>
</jmolApplet></jmol>
| [[File:Xcwendotsimaginary.gif|300px|center]]
| [[File:XcwSecondary orbital interaction1.jpg|300px|center]]
|-
|}

 

==== '''Asynchronous Bond Formation of Dimerization of Cyclopentadiene''' ====

The initial study of the molecular orbitals of the transition states seemed a bit peculiar. Instead of getting a LUMO with symmetrical orbitals, the calculations showed a HOMO that is asymetric at the carbons where the new sigma bonds will be formed. Running an IRC further, it soon became clear that the asymmetry of the HOMO leads to an asychronous bond formation before leading to the product.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''IRC plot following the Endo Transition State '''
| '''IRC following the Endo Transition State (click to animate)'''
| '''Asymmetry of orbitals at the carbons where the new sigma bonds will be formed'''
|- align="center"
| [[File:XcwendotscyclopentadieneIRC.png|300px|center]]
| [[File:XcwendotsIRC.gif|300px|center]]
| [[File:XcwAsynchronous mo.jpg|300px|center]]
|-
|}

 

==== '''Comparison of Energies between the Endo and Exo adduct of Dicyclopentadiene''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Adduct of Dicyclopentadiene dimerization'''
| '''Exo Adduct of Dicyclopentadiene dimerization'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=19,atomno=1,atomno=2; color green;measure 19 1;measure 19 2;</script>
<uploadedFileContents>XcwEndodimer3.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>Exodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=7,atomno=17; color green;measure 17 7;</script>
<uploadedFileContents>XcwExodimer1.mol</uploadedFileContents>
</jmolApplet></jmol>
|-
|}

 

Using MMFF94s ab initio calculations, the energies for the exo dimer and the endo dimer are derived.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Exodimer'''
| '''55.374'''
| 3.543
| 30.772
| -2.041
| -2.728
| 0.015
| 12.800
| 13.014
|-
| '''Endodimer'''
| '''58.191'''
| 3.468
| 33.187
| -2.082
| -2.950
| 0.023
| 12.360
| 14.186
|-
|}

 

The MMFF94s steric energy (after minimization) for the exo dimer is lower than that of the endo dimer. This is reflected by the large difference for the EEE between the endo dimer and the exo dimer due to unfavourable steric repulsion between the two “arched down” cyclopentene rings.

==== '''Hydrogenation of Dicyclopentadiene''' ====

Hydrogenation of the endo dicyclopentadiene (DCPD) would lead to two potential products: dihydro product 1 and dihydro product 2.

[[File:XcwFormation of Dihydro products.png|500px|center]]

Using MMFF94s, the energy of the two dihydro products are calculated.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Dihydro Product 1'''
| '''50.123'''
| 3.308
| 30.864
| -1.927
| 0.060
| 0.015(2)
| 13.281
| 5.121
|-
| '''Dihydro Product 2'''
| '''41.257'''
| 2.823
| 24.685
| -1.657
| -0.379
| 0.000(2)
| 10.639
| 5.147
|-
| '''Tetrahydro Product'''
| '''39.042'''
| 2.730
| 25.151
| -1.676
| 1.287
| 0.000
| 11.551
| 0.000
|}

 

From the MMFF94s calculation, it can be seen that dihydro product 2 has a lower steric energy than dihydro product 1. Therefore, dihydro product 2 is the thermodynamic product for the hydrogenation of dicylopentadiene. And indeed, this was what was observed by Skala et al.. He observed that the first hydrogenation occur at the norborene part of the molecule (rate of hydrogenation several times faster than that in the cyclopentene ring)6. The first heat of hydrogenation at the norborene is 138.8 kJ/mol while the second hydrogenation at the cyclopentene right is 109.5 kJ/mol6.

From the above results, it is also obvious that tetrahydro product is much more stable than either dihydro product. And yet, studies have shown that the tetrahydro product will only form after prolonged hydrogenation under high temperature. However, subjecting DCPD to high temperature leads to low yield due to cracking of DCPD.

Since thermodynamically it is predicted to form favourably, the fact that it does not could only mean that the hydrogenation of DCPD to tetrahydrodicyclopentadiene (TH-DCPD) is kinetically controlled. Most possibly, the transition state of the hydrogenation of DCPD is highly unstable hence it is unlikely to form.

=== '''Atropisomerism in an Intermediate related to the Synthesis of Taxol''' ===

Atropisomerism is a type of stereoisomerism that is form as a result of hindered rotation about a single bond.

[[File:XcwAtropisomerism example.png|500px|center]]

In the case of the 6,6’-dinitro-2,2’-diphenic acid, rotation about the bonds joining the two substituted phenyl rings would have to overcome large steric interaction between the bulky substituents. The barrier of rotation is high enough for the two conformers to be isolated individually.

In the synthesis of taxol, one of the key intermediates exhibit atropisomerism.

==== '''Atropisomerism in Taxol Synthesis''' ====

For the key intermediate, rotation about the carbon-carbon bonds would lead to two types of atropisomers, each with either the carbonyl group poining upwards or downwards in relative to the bridge.

[[File:XcwIntermediate 9 and Intermediate 10.png|500px|center]]

Once again by using MMFF94s ab initio calculations, the steric energies for the two intermediates are illustrated as below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 9'''
| '''70.571'''
| 7.743
| 28.356
| -0.062
| 0.004
| 0.949
| 33.293
| 0.288
|-
| '''Intermediate 10'''
| '''60.553'''
| 7.599
| 18.838
| -0.139
| 0.199
| 0.844
| 33.269
| -0.056
|-

|}

 

Analyzing the data above, the largest energy difference between Intermediate 9 and Intermediate 10 stems from the EAB which is related to the strain of the ring. Intermediate 9 has an excess of 9.518 kcal/mol EAB as compared to Intermediate 10. This comes as a surprise as intermediate 9 is predicted to be more stable alkene.

The rationale behind the prediction of the stability of intermediate 9 stems from the fact that the through-space distance of the upward-pointing carbonyl oxygen with the carbon-carbon is further than the through space distance between the downward-pointing carbonyl oxygen with the -CH2-CH2- fragment at the norbornene part in intermediate 10.

==== '''Hyperstable Olefins''' ====

Intermediate 9 and Intermediate 10 does not react readily with other reagents during functionalization. This is due to the hyperstability effect found in hyperstable olefins.

Hyperstable olefins are alkenes that contain less strain in the ring (i.e. negative olefin strain values) compared to the parent hydrocarbon. To study this further, further MMFF94s calculation was done to compare Intermediate 10 with the parent hydrocarbon.

[[File:XcwIntermediate10andPH.png|500px|center]]

The energies that we calculated are tabulated as shown below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 10'''
| '''44.878 '''
| 5.211
| 15.488
| -0.267
| -1.655
| 0.998
| 25.014
| 0.088
|-
| '''Parent Hydrocarbon'''
| '''50.564'''
| 4.692
| 21.979
| 0.109
| -0.958
| 0.247
| 24.495
| 0.000
|-

|}

 

Scrutinizing the results, the largest energy difference between intermediate 10 and the parent hydrocarbon stems from the Total Angle Bending Energy, EAB. Since the Total Angle bending energy is related to the angle strain in the molecules, it is apparent that the parent hydrocarbon has more ring strain as compared to the bridgehead olefin.

== '''Part 3 : Spectroscopic Simulation Using Quantum Mechanics''' ==
=== '''Spectroscopy of an Intermediate Related to the Synthesis of Taxol''' ===

Molecule 17 and 18 are derivatives of intermediate 9 and 10. In this exercise, MMFF94s is used to predict the 1H and 13C NMR of molecule 17 and molecule 18.

[[File:XcwIntermediate17&18.png|500px|center]]

==== '''NMR Spectra of Molecule 17''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 17.mol
</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwHNMRMolecule 17 Chair Overall NMR.png|500px|center]]
| [[File:XcwHNMRMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.1825
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| The first three results were fairly straight forward to be deduced and correlate wit experimental data.

The hydrogen atom that is geminally attached to the carbon of the double bonds is the most deshielded due to the ring current anisotropic effect of the ring current

The second most deshielded hydrogen atom is the hydrogen atom on the methyl group on the bridge. The hydrogen atom is pointing directly to the oxygen atom of the carbonyl functional group.

The peaks with an integration height of 4 is assigned to the hydrogen atoms in the 1,3-dithiolane ring fragment.

Subsequent analysis of the 1H NMR became very complicated very quickly for two reasons:

1. Gaussian calculations showed some atoms with an integration height of 3. Comparing their file atom number and checking their chemical environment, it is not possible to find any correlation between them.

2. Some of the peaks in the literature remains unresolved and are given as multiplets or grouped together.

|- align="center"
| 52
| 3.1775
| 1
| '''2.99'''
|- align="center"
| 53,52,50,51
| 3.0867
| 4
| '''3.40-3.10'''
|- align="center"
| 42,43,39
| 2.7445
| 3
| ''' '''
|- align="center"
| 49
| 2.6187
| 1
| ''' '''
|- align="center"
| 34
| 2.4371
| 1
| ''' '''
|- align="center"
| 35
| 2.3782
| 1
| ''' '''
|- align="center"
| 40,37,26
| 2.2730
| 3
| ''' '''
|- align="center"
| 30
| 2.1566
| 1
| ''' '''
|- align="center"
| 36
| 2.1033
| 1
| ''' '''
|- align="center"
| 32,28
| 2.0259
| 2
| ''' '''
|- align="center"
| 25
| 1.8535
| 2
| ''' '''
|- align="center"
| 38,46,27
| 1.5898
| 3
| '''1.25'''
|- align="center"
| 29
| 1.4557
| 1
| ''' '''
|- align="center"
| 31
| 1.0123
| 1
| ''' '''
|- align="center"
| 44,48,45
| 0.9087
| 3
| '''1.10'''
|- align="center"
| 47
| 0.8354
| 1
| ''' '''
|- align="center"
| 33
| 0.5790
| 1
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 17 Chair Overall NMR2.png|500px|center]]
| [[File:XcwMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 216.2725
| 1
| '''218.79'''
| rowspan="10" style="text-align:center;"| [[File:XcwMolecule 17 image for CNMR.jpg|600px|center]]
|- align="center"
| 13
| 144.8626
| 1
| '''144.63'''
|- align="center"
| 14
| 124.7193
| 1
| '''125.33'''
|- align="center"
| 3
| 91.3340
| 1
| '''72.88'''
|- align="center"
| 2
| 60.9568
| 1
| '''56.19'''
|- align="center"
| 1
| 57.0811
| 1
| '''52.52'''
|- align="center"
| 10
| 52.4663
| 1
| '''48.50'''
|- align="center"
| 16
| 51.4857
| 1
| '''46.80'''
|- align="center"
| 9
| 46.9196
| 1
| '''45.76'''
|- align="center"
| 23
| 43.8647
| 1
| '''39.80'''
|- align="center"
| 22
| 41.9450
| 1
| '''38.81'''
| Comments
|- align="center"
| 4
| 41.8724
| 1
| '''35.85'''
| rowspan="9" style="text-align:left;"| The carbon bonded to the oxygen atom is the most deshielded, as is shown in the predicted values and the experimental values. There is a deviation between the values. Quite possibly, this is due to the fact that in reality, the carbonyl functional group is pointing slightly towards the equatorial position rather than a lateral position relative to the ring (as is in the input for Gaussian calculation)

Most of the 1CNMR values that was predicted by Gaussian are all within an acceptable range of deviation. However, there is carbon 3 that has significant deviation between the predicted value and experimental value.

Carbon 3 is the carbon bonded to the two sulphurs in the 1,3-dithiolane ring fragment. Such a huge deviation would possibly mean that the conformer that was given as input to Gaussian differs from the literature.

The above NMR spectra was corrected with a level of theory B3LYP/6-31G(d,p) using TMS as reference and in chloroform.

|- align="center"
| 15
| 35.4348
| 1
| '''32.66'''
|- align="center"
| 11
| 31.1964
| 1
| '''28.79'''
|- align="center"
| 6
| 28.9432
| 1
| '''28.29'''
|- align="center"
| 7
| 28.3640
| 1
| '''26.88'''
|- align="center"
| 12
| 27.3767
| 1
| '''25.66'''
|- align="center"
| 17
| 26.3311
| 1
| '''23.86'''
|- align="center"
| 15
| 24.5483
| 1
| '''20.96'''
|- align="center"
| 18
| 19.7788
| 1
| '''18.71'''
|-
|}
 

==== '''NMR Spectra of Molecule 18''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 18 Boat for Image2.mol</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"-
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 18 Chair Overall NMR.png|500px|center]]
| [[File:Molecule 18 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
|- align="center"
| 41
| 5.2832
| 1
| '''5.21'''
|- align="center"
| 50
| 3.3175
| 1
| rowspan="4" style="text-align:centre;"| '''3.00-2.70'''
|- align="center"
| 52
| 3.2153
| 1
|- align="center"
| 51,53
| 3.1161
| 2
|- align="center"
| 34,43
| 2.8606
| 2
|- align="center"
| 38
| 2.4549
| 1
| ''' '''
|- align="center"
| 42
| 2.3968
| 1
| ''' '''
|- align="center"
| 25,29,26
| 2.2796
| 3
| ''' '''
|- align="center"
| 39
| 2.0844
| 1
| ''' '''
|- align="center"
| 40,36
| 1.9699
| 2
| ''' '''
|- align="center"
| 37,24
| 1.8519
| 2
| ''' '''
|- align="center"
| 31,27
| 1.6780
| 2
| ''' '''
|- align="center"
| 28
| 1.6175
| 1
| ''' '''
|- align="center"
| 46,49
| 1.4979
| 2
| ''' '''
|- align="center"
| 35
| 1.4150
| 1
| ''' '''
|- align="center"
| 32
| 1.3531
| 1
| ''' '''
|- align="center"
| 48
| 1.1606
| 1
| ''' '''
|- align="center"
| 33,30,47
| 1.0653
| 3
| '''1.03'''
|- align="center"
| 44,45
| 0.9643
| 2
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 18 Full Spectra'''
| '''13C NMR Spectra of Molecule 18 Truncated Spectra'''
|- align="center"
| [[File:XcwMolecule 18 Boat Overall NMR.png|500px|center]]
| [[File:XcwMolecule 18 Boat zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
|- align="center"
| 8
| 211.8325
| 1
| '''211.49'''
|- align="center"
| 13
| 148.6673
| 1
| '''148.72'''
|- align="center"
| 14
| 118.8373
| 1
| '''120.90'''
|- align="center"
| 3
| 89.0869
| 1
| '''74.61'''
|- align="center"
| 2
| 67.8886
| 1
| '''60.53'''
|- align="center"
| 1
| 56.1133
| 1
| '''51.30'''
|- align="center"
| 10
| 55.5998
| 1
| '''50.94'''
|- align="center"
| 16
| 50.1124
| 1
| '''45.53'''
|- align="center"
| 22
| 48.2030
| 1
| '''43.28'''
|- align="center"
| 23
| 44.2222
| 1
| '''40.82'''
|- align="center"
| 4
| 42.0354
| 1
| '''38.73'''
|- align="center"
| 9
| 37.5865
| 1
| '''36.78'''
|- align="center"
| 6
| 35.3106
| 1
| '''35.47'''
|- align="center"
| 15
| 31.0459
| 1
| '''30.84'''
|- align="center"
| 7
| 28.8476
| 1
| '''30.00'''
|- align="center"
| 12
| 28.6623
| 1
| '''25.56'''
|- align="center"
| 17
| 25.7393
| 1
| '''25.35'''
|- align="center"
| 11
| 25.2603
| 1
| '''22.21'''
|- align="center"
| 18
| 23.3944
| 1
| '''21.39'''
|- align="center"
| 5
| 21.0478
| 1
| '''19.83'''
|-
|}
 

== '''Part 4 : Analysis of the Properties of the Synthesized Alkene Epoxides''' ==
=== '''The two catalytics systems''' ===

Assymmetric epoxidation of prochiral alkenes may lead to product with different stereochemical outcome as illustrated as below. To solve this problem, different types of asymmetric epoxidation catalyst have been synthesized. In this study, we shall be focusing on Shi asymmetric fructose catalyst as well as Jacobsen asymmetric catalyst.

[[File:Asymmetric catalyst.png|400px|center]]

==== ''' The Shi Asymmetric Fructose Catalyst''' ====

Molecule 21 is the stable precursor of molecule 22, the active catalyst. Molecule 21 can be converted to molecule 22 by using either persulfuric acid or potassium peroxymonosulphate.

[[File:Molecule 21 to 23.png|400px|center]]

The transition state of the Shi epoxidation was a subject of debate for a few moments. However, recent studies have led to the conclusion that the spiro transition state is more favored than the planar transition state. The spiro transition state is the transition that has its dioxirane perpendicularly bisecting the alkene double bond. This is thought to be more favourable due to interactions between the lone pairs of the oxygen with the LUMO of the alkene.

[[File:Spiro and planar ts.png|500px|center]]

==== ''' The Jacobsen Asymmetric Catalyst''' ====

Molecule 23 is the stable precursor of molecule 24, the active catalyst. Molecule 23 can be converted to molecule 24 by using sodium perchlorate.

[[File:Salen, 23 and 24.png|400px|center]]

Jacobsen catalyst is biphasic. The first phase involves the transfer of oxygen to molecule 23. Sodium perchlorate oxidizes Mn(III) to Mn(V).

In the second step, Jacobsen catalyst acts via a radical mechanism. It is thought to be so because epoxidation of trans-alkene by Jacobsen catalyst yield cis-alkene as well. A radical mechanism will lead to the lost of stereochemical information of the molecule.

=== ''' Crystal structure of the two catalyst''' ===
==== '''Molecule 21''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 21'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 21 strucutre.png|600px|center]]'''
|-
| style="text-align:center;" width="150" | ''' Bond '''
| style="text-align:center;" width="150"| ''' Bond Lenghts (Angstrom)'''
| style="text-align:center;" | ''' Evaluation'''
|-
| style="text-align:center;"| ''' O1-C1 '''
| style="text-align:center;"| ''' 1.400'''
| rowspan="10" style="text-align:left;"| [[File:Molecule 21 2.png|300px|center]]

The normal bond length of an C-O bond is 1.430 angstrom.

The most interesting aspect here is O4 and O2. The lone pair of O4 is antiperplanar to the sigma* orbital of the carbonyl group while the lone pair of O2 is anti periplanar to the carbonyl pi* orbital. Donation of electron can occur because of the correct symmetry. Due to the mixing of the orbitals, the C2-O2 and C4-O4 has been conferred with a certain degree of double bond character.

However, due to the lone pair on oxygen being now donated to the carbonyl antibonding orbitals, the O2 and O4 is slightly “electron deficient” and electron density will be pulled away from O2 and O4. That would explain why the bond length increase for O2-C7 and O4-C10. Increase in bond length is an indicator of the weakening of the bond.
|-
| style="text-align:center;"|'''O1-C7'''
| style="text-align:center;"|'''1.413'''
|-
| style="text-align:center;"|'''O2-C7'''
| style="text-align:center;"|'''1.441'''
|-
| style="text-align:center;"|'''O2-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O4-C4'''
| style="text-align:center;"|'''1.396'''
|-
| style="text-align:center;"|'''O4-C10'''
| style="text-align:center;"|'''1.439'''
|-
| style="text-align:center;"|'''O5-C10'''
| style="text-align:center;"|'''1.409'''
|-
| style="text-align:center;"|'''O5-C5'''
| style="text-align:center;"|'''1.416'''
|-
| style="text-align:center;"|'''O6-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O6-C6'''
| style="text-align:center;"|'''1.420'''
|-
|}
 

==== '''Molecule 23''' ====

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 23'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 23 struc.png|600px|center]]'''
|-
| The most outstanding feature from this molecule is the fact that is adopt a puckered form of the square base pyramidal form. This is no surprise that the molecule is almost planar due to the electron delocalization around each side of the salen ligand.

The tery-butyl hydrogen are oriented closely to one another. Non-covalent interaction studies indicated that repulsion would occur for H---H bond length that are less than 2.1 angstrom while favourable interaction may be dominant with bond length above 2.4 angstrom. It was discovered that all 4 hydrogens have bond length more than 2.4 angstrom hence there should not be any significant repulsion between them. Instead, certain amount of attractive force will ensue and that contributes to the overall stability of the molecule

|-
|}
 

=== ''' The calculated NMR properties of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | '''
Shift (ppm) Degeneracy
7.4891704929 4.0000
7.2988172444 1.0000
3.6627082199 1.0000
3.1170156088 1.0000
2.5382383043 1.0000 '''
| width="100" | '''
Shift (ppm) Degeneracy
7.4892967873 4.0000
7.2987138125 1.0000
3.6632689921 1.0000
3.1151709109 1.0000
2.5339209685 1.0000

'''
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Styrene R HNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Styrene S HNMR.png|400px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | '''
Shift (ppm) Degeneracy
135.1098747604 1.0000
124.1186533632 1.0000
123.4150641684 1.0000
122.9584694331 2.0000
118.2653162569 1.0000
54.0265785300 1.0000
53.4853575062 1.0000 '''
| width="100" | '''
Shift (ppm) Degeneracy
135.1323742030 1.0000
124.1343038829 1.0000
123.4137039868 1.0000
122.9558208084 2.0000
118.2690258882 1.0000
54.0599580762 1.0000
53.4684920923 1.0000
'''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | ''' [[File:Styrene R CNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Styrene S CNMR.png|400px|center|]]'''
|-
| width="100" | ''' '''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | ''' Shift (ppm) Degeneracy
7.5705724829 2.0000
7.4791732656 8.0000
3.5390102503 2.0000
| width="100" | ''' Shift (ppm) Degeneracy
7.5705651164 2.0000
7.4791779628 8.0000
3.5374502607 2.0000
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Stilbene RR HNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|400px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | ''' Shift (ppm) Degeneracy
134.0942417727 2.0000
124.2206838184 2.0000
123.5192390024 2.0000
123.2125901307 2.0000
123.0785800542 2.0000
118.2583039589 2.0000
66.4212770637 2.0000 '''
| width="100" | ''' Shift (ppm) Degeneracy
134.0899175142 2.0000
124.2224499528 2.0000
123.5180152862 2.0000
123.2113538650 2.0000
123.0745448885 2.0000
118.2635789492 2.0000
66.4249347217 2.0000 '''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | ''' [[File:Stilbene RR CNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|400px|center|]]'''
|-
|}

 

=== ''' Assigning the absolute configuration of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''Predicted ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg'''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg '''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental conditions'''
| width="100" | '''1.00g/100ml, chloroform, 21 degree Celcisus, 589 nm wavelength '''
| width="100" | '''1.02g/100ml (99% ee), chloroform, 25 degree Celsius, 589 nm wavelength '''
| width="100" | '''1.01g/100ml, ethanol, 22 degree Celsius, 589 nm wavelength '''
| width="100" | '''0.6g/100ml, ethanol, 20 degree Celsius, 589 nm wavelength '''
|- align="left"
| width="100" | ''' Predicted VCD Spectrum'''
| width="100" | '''[[File:Styrene R VCD.png|200px|center|]] '''
| width="100" | '''[[File:Styrene S VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene RR VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene SS VCD.png|200px|center|]]'''
|-
|}

 

All the assignments given in the literature reports are correct although the predicted value differs slightly with the experimental values

=== ''' Analysis of the Transition State for Reactions''' ===
==== '''Predicting Enantiomeric Excess based on Transition State energies''' ====

One of the energy output from Gaussian calculation is the “sum of electronic and thermal free energies”. This is Gibbs Free Energy at 298.15K and 1 atm.

Using this term and invoking a variant of the Curtin-Hammett Principle, it is possible to calculate a predicted enantiomeric excess of one enantiomer over the other.

[[File:Ee and transition state energy.png|800px|center]]

Using the derivations from above and equation (4), we analyze the enantiomeric excess of beta-methyl styrene and the results are tabulated as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1343.022970'''
| width="100" | '''-1343.017942'''
| width="150" | '''-0.005028'''
| width="150" | '''4.88E-03'''
| width="150" | '''99.03'''
|- align="center"
| width="100" | '''-1343.019233'''
| width="100" | '''-1343.015603'''
| width="150" | '''-0.003630'''
| width="150" | '''2.14E-02'''
| width="150" | '''95.80'''
|- align="center"
| width="100" | '''-1343.029272'''
| width="100" | '''-1343.023766'''
| width="150" | '''-0.005506'''
| width="150" | '''2.94E-03'''
| width="150" | '''99.41'''
|- align="center"
| width="100" | '''-1343.032443'''
| width="100" | '''-1343.024742'''
| width="150" | '''-0.007701'''
| width="150" | '''2.88E-04'''
| width="150" | '''99.94'''
|-
|}

 

The above hartree units are converted to J/mol for calculation of K where 1 hartress = 4.3597E-18

Studying all the free energies of the (R,R) series and compare them with the (S,S) series, it comes as no surprise that (R,R) product is favoured over (S,S) product as (R,R) is more stable. Indeed, this corresponds with the literature value reporting 92% ee of (R,R) products over that of (S,S).

==== '''Analysis of the Transition State of Epoxidation''' ====
==== '''Shi Fructose Catalyst''' ====
For this section, I will be analyzing the the transition state of 1) styrene and 2) trans-stilbene with the Shi fructose catalyst.

===== '''(R) and (S)-styrene transition state''' =====
The transition state for the formation of (R)-styrene oxide and (S)-styrene oxide are given as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R)-styrene oxide'''
| width="150" | '''(S)-styrene oxide'''
|- align="center"
| width="150" | ''' Structure of Catalyst '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide R.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide S ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| [[File:Steric shi fructose R.png|450px|center]]
| [[File:Steric shi fructose S.png|450px|center]]
|-
|}

 

In the transition state for (R)-styrene, it was discovered that the Re face is reacting with the oxygen of the dioxirane. The phenyl ring is oriented endo with respect to the fructose catalyst. However, the (S)-styrene is reacting at the Si face and the phenyl ring is oriented exo relative to the catalyst.

The approach taken by (R)-styrene and (S)-styrene are restricted to only one due to steric interactions. Therefore, the epoxidation of both styrenes by the Shi catalyst will be stereospecific and retains all the stereochemical information of the reactant. However, whether or not (R)-styrene oxide or (S)-styrene oxide is form is dependent on the relative energies of the transition state. The more stable the transition state, the more likely the product of the transition state will be formed.

So in order to examine this, an example of transition state of both styrenes with Shi catalyst are obtained and analyzed.
 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1303.736813'''
| width="100" | '''-1303.727673'''
| width="150" | '''-0.00914'''
| width="150" | '''6.28E-05'''
| width="150" | '''99.99'''

|-
|}

 

From the above, we can see the predicted high enantiopurity of the reaction favoring the (R) product because of the lower energy of the transition states. To understand the reason, we have to turn to non-covalent interaction (NCI) analysis.

[[File:NCI shi fructose styrene.png|700px|center]]

To complement the NCI analysis, a QTAIM (Quantum Theory of Atoms in Molecules) analysis is conducted as well.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''(R)-styrene transition state'''
| width="200" | '''(S)-styrene transition state'''
|- align="center"
| width="100" | '''[[File:QTAIM R.png|400px|center]]'''
| width="100" | '''[[File:QTAIM S.png|400px|center]]'''
|- align="center"
| colspan="2" width="100" | '''Comments'''
|-
| colspan="2" width="100" | '''Unsurprisingly, QTAIM analysis has also shown that (R)-styrene/Shi catalyst has more interactions with one another. While (R)-styrene has 2 strong interactions, (S)-styrene has only one with the catalyst. Besides, the phenyl ring of (R)-styrene also confers additional positive interaction with the catalyst. QTAIM analysis has also show several interactions between the C=C geminal hydrogen of (R)-styrene intreacting with the oxygen atoms on the dioxacyclopentane ring'''
|-
|}

 

===== '''(R,R) and (S,S)-Stilbene transition state''' =====

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R,R)-Stilbene oxide'''
| width="150" | '''(S,S)-Stilbene oxide'''
|- align="center"
| width="150" | ''' Structure of Transition State '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Stilbene RR ts.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>SS stilbene oxide ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| colspan="2" | [[File:Shi fructose stilbene.png|700px|center]]

|-
|}

 

However, unlike styrene, trans-stilbene seems to approach perpendicularly to the dioxirane. This is proposed to be due to the steric interactions (marked in purple). Based on first inspection, it seems that (S,S)-Stilbene oxide has more steric interactions than (R,R)-Stilbene oxide. Although unsubstantial, it seems like my guess was correct. The (R,R)-stilbene/Shi catalyst transition state is lower in energy.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1534.687808'''
| width="100" | '''-1534.683440'''
| width="150" | '''0.004368'''
| width="150" | '''9.08E-3'''
| width="150" | '''98.20'''

|-
|}

 

NCI Analysis is also done for trans-stilbene

[[File:NCI stilbene.png|700px|center]]

==== '''Jacobsen Catalyst''' ====

For this section, cis-beta methyl styrene transition state will be analyzed.

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-3383.259559'''
| width="100" | '''-3383.251060'''
| width="150" | '''-0.008499'''
| width="150" | '''1.24E-04'''
| width="150" | '''99.98'''
|- align="center"
| width="100" | '''-3383.253442'''
| width="100" | '''-3383.250270'''
| width="150" | '''-0.003172'''
| width="150" | '''3.48E-02'''
| width="150" | '''93.27'''
|-
|}

 

As is obvious from here, the (S,R) transition state is more stable than the (R,S) transition state. Both transition states are exo with respect to the catalyst.

It is not immediately apparent just by looking at the molecule to determine which spatial groups have interactions with one another. Therefore, an NCI analysis is conducted again.

[[File:NCI Jacobsen.png|700px|center]]

=== Bibliography ===

1. David C. Forbes, Sampada V. Bettigeri,Samit A. Patrawala, Susanna C. Pischek, and Michael C. Standen, Tetrahedron, 2009, 65(1), 70-76
2. Hui Lina, Jing Qiaoa, Yan Liua, Zhong-Liu Wu, '''Journal of Molecular Catalysis B: Enzymatic''', 2010, 67, 236-241
3. Niwa,Takashi, Nakada,Masahisa, Journal of the American Chemistry , 2012, 134, 13538-13541
4. Arlette Solladié-Cavallo, Anh Diep-Vohuule, Tetrahedron: Asymmetry, 1996, 7(6), 1783-1788
5. Vito Capriati, Saverio Florio, Renzo Luisi,Filippo Maria Perna, Antonio Salomone, Francesco Gasparrini, Org. Lett., 2005, 7 (22), 4895-4898
6. Wong O.Andrea, Wang Bin, Zhao Mei-Xin, Shi Yian, Journal of Organic Chemistry, 2009, 74, 6335-6338
7.

Rep:Mod:Computationalreport1C

2013-11-22T17:49:22Z

Xc2611: /* Jacobsen Catalyst */

Rep:Mod:Computationalreport1C

2013-11-22T17:48:37Z

Xc2611: /* 13C NMR Spectra of Molecule 18 */

Rep:Mod:Computationalreport1C

2013-11-22T17:48:08Z

Xc2611: /* 13C NMR Spectra of Molecule 18 */

= '''Synthesis and Computational Lab: 1C''' =
== '''Part 1: Introduction to Molecular Mechanics''' ==
=== '''Introduction to MMFF94 and MMFF94s''' ===

With the improvement of computational data and computer processing power, the usage of molecular mechanics/dynamics forcefield has become very integrated in predicting properties of chemical molecules. A molecular mechanics/dynamics forcefield should be able to predict characteristics such as molecular geometries, conformational/stereoisomeric energies, vibrational frequencies etc. to a reasonable accuracy as compared to experimental-derived values.

Building on work from Kollman et al. s’ AMBER forcefield and Allinger et al. s’ MM1, MM2, MM3 and MM4, Merck Research Laboratories have managed to optimized and improved the previous computational algorithms and produced MMFF94 (Merck Molecular Force Field 94). One of the most prominent advantages of MMFF94 over other preceeding work is its enhanced prediction accuracy. The reason lies in the fact that MMFF94’s core parameterization utilizes an unprecedently large amount of computational data obtained from ab initio calculations1.

Subsequently after the development of MMFF94, a new “static” variant of the MMFF was introduced i.e. the MMFF94s. Unlike MMFF94 that was developed for the use of molecular dynamics simulations (which can be expensive), MMFF94s was developed with the purpose of energy minimization studies in mind. Although both systems provide identical results for most systems, they differ for amides and unsaturated amines which contain resonance-delocalized trigonal nitrogen atoms2.

In this computational exercise, MMFF94s is used predominantly as oppose to the alternative Universal Force Field (UFF). Although versatile across the entire periodic table, UFF is derived from simple rules and atomic parameters such as fixed hybridization that increases the likelihood of erroneous structural and energetic predictions3.

=== '''Forms of MMFF94s''' ===

Steric energy of a molecule is the energy arise due to its geometry or conformation. Energy minimization of steric energy process ensures that the molecule is in its lowest energy conformation.

MMFF94s assumes that the total steric energy of a molecule can be found by the sum of a few specific interactions in a molecule.

ES = EBS + EAB + E SB + ET + EOOP + EVdW + EEE

'''where the bonded interactions are:'''

ES = Total Steric energy

EBS = Total Bond Stretching energy

EAB = Total Angle Bending energy

ESB = Total Stretch Bending energy

ET = Total Torsional Energy

EOOP = Total Out-Of-Plane Bending energy, and

'''where the non-bonded interactions are:'''

EVdW = Total Van der Waals Energy

EEE = Total Electrostatic Energy

{| border="1" cellspacing="1" cellpadding="10"
|-
| width="300" align="center" | '''Types of Energies'''
! width="600" align="center" | '''Explanation'''
|-
| colspan="2" style="text-align: center;" | '''Bonded Interactions'''
|-
| width="300" align="center" | '''Total Bond Stretching Energy'''
! width="600" align="left" | The total bond stretching energy is related to the vibration energy of the molecules in comparison to the equilibrium bond length. Whenever a bond deviates from the equilibrium bond length, the energy value increases.

MMFF94s uses a quartic function that has the force constant term (relate to bond strength). The quartic function term is superior to the cubic function term (used in MM2) in the sense that it avoid the “cubic stretch catastrophe” where progressive elongation of molecule bond length leads to negative infinity.
|-
| width="300" align="center" | '''Total Angle Bending Energy'''
! width="600" align="left" | Similar to Total Bond Stretching Energy, the total angle bending energy is also related to the vibration energy of the molecules about the equilibrium bond length. However, unlike EBS that measures the bond strength, EAB is associated with the stiffness of the molecules based on the Hookiean potential. Whenever bond angles deviate from the norm during vibration, this energy term increases as well.
|-
| width="300" align="center" | '''Total Stretch-Bending Energy'''
! width="600" align="left" | This energy term takes into account of the energy due to increase in bond length when bond angle between two atoms changes.
|-
| width="300" align="center" | '''Total Torsional Energy'''
! width="600" align="left" | Total torsional energy is the energy required for intermolecular rotation about the bonds. In molecule mechanics, however, this term is often used as a correction that must be added or subtracted to the total energy of the molecule to fit a quantum mechanical calculation about the dihedral angles of bonds.
|-
| width="300" align="center" | '''Total Out-Of-Plane Bending Energy'''
! width="600" align="left" | This energy term refers to the energy needed to deform the dihedral angle (zero degrees) of a planar group of atoms such as carbonyl or amide functional groups.
|-
| colspan="2" style="text-align: center;" | '''Non-Bonded Interactions'''
|-
| width="300" align="center" | '''Total Van der Waals Energy'''
! width="600" align="left" | The total Van der Waals energy term examines the intramolecular interactions such as repulsion or attraction between non-bonded atoms in the molecule. This term is crucial in determining the preferred conformation of the molecule.

MMFF94s employs the novel “Buffered-14-7”. The name is derived from a buffering constant and the 14th and 7th power dependencies of the repulsive and attractive energy in the equation.
|-
| width="300" align="center" | '''Total Electrostatic Energy'''
! width="600" align="left" | The total electrostatic energy functions take into account of the Coulombic potential and partial charge/dipole/atomic point charges interactions within the molecule.
|-

|}

 

== '''Part 2 : Conformational Analysis Using Molecular Mechanics''' ==
=== '''The Hydrogenation of Cyclopentadiene Dimer''' ===

==== '''Endo and exo adduct from the Dimerization of Cyclopentadiene''' ====
Cyclopentadiene will undergo dimerization by Diels-alder reaction to form either an endo or exo adduct.

[[File:XcwDimerization of CP.png|500px|center]]

==== '''Stereoselectivity of Dimerization of Cyclopentadiene''' ====
Although the exo adduct is thermodynamically more stable than the endo adduct, the endo adduct is form preferentially. Using the QST2 method, the transition state of the Diels Alder dimerization was found. It was discovered that due to the secondary orbital interactions in the endo transition state, the endo dimer is formed preferentially (the kinetic product). Hence, it is proven that the Diels Alder dimerization between two cyclopentadiene are kinetically controlled.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Transition State of Dimerization of Cyclopentadiene'''
| '''Imaginary Stretch Frequency (-881.25) of the Endo Transition State (click to animate)'''
| '''Secondary Orbital Interaction (Red overlapping orbitals)'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<uploadedFileContents>EndotsDCPD2.mol
</uploadedFileContents>
</jmolApplet></jmol>
| [[File:Xcwendotsimaginary.gif|300px|center]]
| [[File:XcwSecondary orbital interaction1.jpg|300px|center]]
|-
|}

 

==== '''Asynchronous Bond Formation of Dimerization of Cyclopentadiene''' ====

The initial study of the molecular orbitals of the transition states seemed a bit peculiar. Instead of getting a LUMO with symmetrical orbitals, the calculations showed a HOMO that is asymetric at the carbons where the new sigma bonds will be formed. Running an IRC further, it soon became clear that the asymmetry of the HOMO leads to an asychronous bond formation before leading to the product.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''IRC plot following the Endo Transition State '''
| '''IRC following the Endo Transition State (click to animate)'''
| '''Asymmetry of orbitals at the carbons where the new sigma bonds will be formed'''
|- align="center"
| [[File:XcwendotscyclopentadieneIRC.png|300px|center]]
| [[File:XcwendotsIRC.gif|300px|center]]
| [[File:XcwAsynchronous mo.jpg|300px|center]]
|-
|}

 

==== '''Comparison of Energies between the Endo and Exo adduct of Dicyclopentadiene''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Adduct of Dicyclopentadiene dimerization'''
| '''Exo Adduct of Dicyclopentadiene dimerization'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=19,atomno=1,atomno=2; color green;measure 19 1;measure 19 2;</script>
<uploadedFileContents>XcwEndodimer3.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>Exodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=7,atomno=17; color green;measure 17 7;</script>
<uploadedFileContents>XcwExodimer1.mol</uploadedFileContents>
</jmolApplet></jmol>
|-
|}

 

Using MMFF94s ab initio calculations, the energies for the exo dimer and the endo dimer are derived.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Exodimer'''
| '''55.374'''
| 3.543
| 30.772
| -2.041
| -2.728
| 0.015
| 12.800
| 13.014
|-
| '''Endodimer'''
| '''58.191'''
| 3.468
| 33.187
| -2.082
| -2.950
| 0.023
| 12.360
| 14.186
|-
|}

 

The MMFF94s steric energy (after minimization) for the exo dimer is lower than that of the endo dimer. This is reflected by the large difference for the EEE between the endo dimer and the exo dimer due to unfavourable steric repulsion between the two “arched down” cyclopentene rings.

==== '''Hydrogenation of Dicyclopentadiene''' ====

Hydrogenation of the endo dicyclopentadiene (DCPD) would lead to two potential products: dihydro product 1 and dihydro product 2.

[[File:XcwFormation of Dihydro products.png|500px|center]]

Using MMFF94s, the energy of the two dihydro products are calculated.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Dihydro Product 1'''
| '''50.123'''
| 3.308
| 30.864
| -1.927
| 0.060
| 0.015(2)
| 13.281
| 5.121
|-
| '''Dihydro Product 2'''
| '''41.257'''
| 2.823
| 24.685
| -1.657
| -0.379
| 0.000(2)
| 10.639
| 5.147
|-
| '''Tetrahydro Product'''
| '''39.042'''
| 2.730
| 25.151
| -1.676
| 1.287
| 0.000
| 11.551
| 0.000
|}

 

From the MMFF94s calculation, it can be seen that dihydro product 2 has a lower steric energy than dihydro product 1. Therefore, dihydro product 2 is the thermodynamic product for the hydrogenation of dicylopentadiene. And indeed, this was what was observed by Skala et al.. He observed that the first hydrogenation occur at the norborene part of the molecule (rate of hydrogenation several times faster than that in the cyclopentene ring)6. The first heat of hydrogenation at the norborene is 138.8 kJ/mol while the second hydrogenation at the cyclopentene right is 109.5 kJ/mol6.

From the above results, it is also obvious that tetrahydro product is much more stable than either dihydro product. And yet, studies have shown that the tetrahydro product will only form after prolonged hydrogenation under high temperature. However, subjecting DCPD to high temperature leads to low yield due to cracking of DCPD.

Since thermodynamically it is predicted to form favourably, the fact that it does not could only mean that the hydrogenation of DCPD to tetrahydrodicyclopentadiene (TH-DCPD) is kinetically controlled. Most possibly, the transition state of the hydrogenation of DCPD is highly unstable hence it is unlikely to form.

=== '''Atropisomerism in an Intermediate related to the Synthesis of Taxol''' ===

Atropisomerism is a type of stereoisomerism that is form as a result of hindered rotation about a single bond.

[[File:XcwAtropisomerism example.png|500px|center]]

In the case of the 6,6’-dinitro-2,2’-diphenic acid, rotation about the bonds joining the two substituted phenyl rings would have to overcome large steric interaction between the bulky substituents. The barrier of rotation is high enough for the two conformers to be isolated individually.

In the synthesis of taxol, one of the key intermediates exhibit atropisomerism.

==== '''Atropisomerism in Taxol Synthesis''' ====

For the key intermediate, rotation about the carbon-carbon bonds would lead to two types of atropisomers, each with either the carbonyl group poining upwards or downwards in relative to the bridge.

[[File:XcwIntermediate 9 and Intermediate 10.png|500px|center]]

Once again by using MMFF94s ab initio calculations, the steric energies for the two intermediates are illustrated as below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 9'''
| '''70.571'''
| 7.743
| 28.356
| -0.062
| 0.004
| 0.949
| 33.293
| 0.288
|-
| '''Intermediate 10'''
| '''60.553'''
| 7.599
| 18.838
| -0.139
| 0.199
| 0.844
| 33.269
| -0.056
|-

|}

 

Analyzing the data above, the largest energy difference between Intermediate 9 and Intermediate 10 stems from the EAB which is related to the strain of the ring. Intermediate 9 has an excess of 9.518 kcal/mol EAB as compared to Intermediate 10. This comes as a surprise as intermediate 9 is predicted to be more stable alkene.

The rationale behind the prediction of the stability of intermediate 9 stems from the fact that the through-space distance of the upward-pointing carbonyl oxygen with the carbon-carbon is further than the through space distance between the downward-pointing carbonyl oxygen with the -CH2-CH2- fragment at the norbornene part in intermediate 10.

==== '''Hyperstable Olefins''' ====

Intermediate 9 and Intermediate 10 does not react readily with other reagents during functionalization. This is due to the hyperstability effect found in hyperstable olefins.

Hyperstable olefins are alkenes that contain less strain in the ring (i.e. negative olefin strain values) compared to the parent hydrocarbon. To study this further, further MMFF94s calculation was done to compare Intermediate 10 with the parent hydrocarbon.

[[File:XcwIntermediate10andPH.png|500px|center]]

The energies that we calculated are tabulated as shown below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 10'''
| '''44.878 '''
| 5.211
| 15.488
| -0.267
| -1.655
| 0.998
| 25.014
| 0.088
|-
| '''Parent Hydrocarbon'''
| '''50.564'''
| 4.692
| 21.979
| 0.109
| -0.958
| 0.247
| 24.495
| 0.000
|-

|}

 

Scrutinizing the results, the largest energy difference between intermediate 10 and the parent hydrocarbon stems from the Total Angle Bending Energy, EAB. Since the Total Angle bending energy is related to the angle strain in the molecules, it is apparent that the parent hydrocarbon has more ring strain as compared to the bridgehead olefin.

== '''Part 3 : Spectroscopic Simulation Using Quantum Mechanics''' ==
=== '''Spectroscopy of an Intermediate Related to the Synthesis of Taxol''' ===

Molecule 17 and 18 are derivatives of intermediate 9 and 10. In this exercise, MMFF94s is used to predict the 1H and 13C NMR of molecule 17 and molecule 18.

[[File:XcwIntermediate17&18.png|500px|center]]

==== '''NMR Spectra of Molecule 17''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 17.mol
</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwHNMRMolecule 17 Chair Overall NMR.png|500px|center]]
| [[File:XcwHNMRMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.1825
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| The first three results were fairly straight forward to be deduced and correlate wit experimental data.

The hydrogen atom that is geminally attached to the carbon of the double bonds is the most deshielded due to the ring current anisotropic effect of the ring current

The second most deshielded hydrogen atom is the hydrogen atom on the methyl group on the bridge. The hydrogen atom is pointing directly to the oxygen atom of the carbonyl functional group.

The peaks with an integration height of 4 is assigned to the hydrogen atoms in the 1,3-dithiolane ring fragment.

Subsequent analysis of the 1H NMR became very complicated very quickly for two reasons:

1. Gaussian calculations showed some atoms with an integration height of 3. Comparing their file atom number and checking their chemical environment, it is not possible to find any correlation between them.

2. Some of the peaks in the literature remains unresolved and are given as multiplets or grouped together.

|- align="center"
| 52
| 3.1775
| 1
| '''2.99'''
|- align="center"
| 53,52,50,51
| 3.0867
| 4
| '''3.40-3.10'''
|- align="center"
| 42,43,39
| 2.7445
| 3
| ''' '''
|- align="center"
| 49
| 2.6187
| 1
| ''' '''
|- align="center"
| 34
| 2.4371
| 1
| ''' '''
|- align="center"
| 35
| 2.3782
| 1
| ''' '''
|- align="center"
| 40,37,26
| 2.2730
| 3
| ''' '''
|- align="center"
| 30
| 2.1566
| 1
| ''' '''
|- align="center"
| 36
| 2.1033
| 1
| ''' '''
|- align="center"
| 32,28
| 2.0259
| 2
| ''' '''
|- align="center"
| 25
| 1.8535
| 2
| ''' '''
|- align="center"
| 38,46,27
| 1.5898
| 3
| '''1.25'''
|- align="center"
| 29
| 1.4557
| 1
| ''' '''
|- align="center"
| 31
| 1.0123
| 1
| ''' '''
|- align="center"
| 44,48,45
| 0.9087
| 3
| '''1.10'''
|- align="center"
| 47
| 0.8354
| 1
| ''' '''
|- align="center"
| 33
| 0.5790
| 1
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 17 Chair Overall NMR2.png|500px|center]]
| [[File:XcwMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 216.2725
| 1
| '''218.79'''
| rowspan="10" style="text-align:center;"| [[File:XcwMolecule 17 image for CNMR.jpg|600px|center]]
|- align="center"
| 13
| 144.8626
| 1
| '''144.63'''
|- align="center"
| 14
| 124.7193
| 1
| '''125.33'''
|- align="center"
| 3
| 91.3340
| 1
| '''72.88'''
|- align="center"
| 2
| 60.9568
| 1
| '''56.19'''
|- align="center"
| 1
| 57.0811
| 1
| '''52.52'''
|- align="center"
| 10
| 52.4663
| 1
| '''48.50'''
|- align="center"
| 16
| 51.4857
| 1
| '''46.80'''
|- align="center"
| 9
| 46.9196
| 1
| '''45.76'''
|- align="center"
| 23
| 43.8647
| 1
| '''39.80'''
|- align="center"
| 22
| 41.9450
| 1
| '''38.81'''
| Comments
|- align="center"
| 4
| 41.8724
| 1
| '''35.85'''
| rowspan="9" style="text-align:left;"| The carbon bonded to the oxygen atom is the most deshielded, as is shown in the predicted values and the experimental values. There is a deviation between the values. Quite possibly, this is due to the fact that in reality, the carbonyl functional group is pointing slightly towards the equatorial position rather than a lateral position relative to the ring (as is in the input for Gaussian calculation)

Most of the 1CNMR values that was predicted by Gaussian are all within an acceptable range of deviation. However, there is carbon 3 that has significant deviation between the predicted value and experimental value.

Carbon 3 is the carbon bonded to the two sulphurs in the 1,3-dithiolane ring fragment. Such a huge deviation would possibly mean that the conformer that was given as input to Gaussian differs from the literature.

The above NMR spectra was corrected with a level of theory B3LYP/6-31G(d,p) using TMS as reference and in chloroform.

|- align="center"
| 15
| 35.4348
| 1
| '''32.66'''
|- align="center"
| 11
| 31.1964
| 1
| '''28.79'''
|- align="center"
| 6
| 28.9432
| 1
| '''28.29'''
|- align="center"
| 7
| 28.3640
| 1
| '''26.88'''
|- align="center"
| 12
| 27.3767
| 1
| '''25.66'''
|- align="center"
| 17
| 26.3311
| 1
| '''23.86'''
|- align="center"
| 15
| 24.5483
| 1
| '''20.96'''
|- align="center"
| 18
| 19.7788
| 1
| '''18.71'''
|-
|}
 

==== '''NMR Spectra of Molecule 18''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 18 Boat for Image2.mol</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"-
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 18 Chair Overall NMR.png|500px|center]]
| [[File:Molecule 18 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
|- align="center"
| 41
| 5.2832
| 1
| '''5.21'''
|- align="center"
| 50
| 3.3175
| 1
| rowspan="4" style="text-align:centre;"| '''3.00-2.70'''
|- align="center"
| 52
| 3.2153
| 1
|- align="center"
| 51,53
| 3.1161
| 2
|- align="center"
| 34,43
| 2.8606
| 2
|- align="center"
| 38
| 2.4549
| 1
| ''' '''
|- align="center"
| 42
| 2.3968
| 1
| ''' '''
|- align="center"
| 25,29,26
| 2.2796
| 3
| ''' '''
|- align="center"
| 39
| 2.0844
| 1
| ''' '''
|- align="center"
| 40,36
| 1.9699
| 2
| ''' '''
|- align="center"
| 37,24
| 1.8519
| 2
| ''' '''
|- align="center"
| 31,27
| 1.6780
| 2
| ''' '''
|- align="center"
| 28
| 1.6175
| 1
| ''' '''
|- align="center"
| 46,49
| 1.4979
| 2
| ''' '''
|- align="center"
| 35
| 1.4150
| 1
| ''' '''
|- align="center"
| 32
| 1.3531
| 1
| ''' '''
|- align="center"
| 48
| 1.1606
| 1
| ''' '''
|- align="center"
| 33,30,47
| 1.0653
| 3
| '''1.03'''
|- align="center"
| 44,45
| 0.9643
| 2
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 18 Full Spectra'''
| '''13C NMR Spectra of Molecule 18 Truncated Spectra'''
|- align="center"
| [[File:XcwMolecule 18 Boat Overall NMR.png|500px|center]]
| [[File:XcwMolecule 18 Boat zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
|- align="center"
| 8
| 211.8325
| 1
| '''211.49'''
|- align="center"
| 13
| 148.6673
| 1
| '''148.72'''
|- align="center"
| 14
| 118.8373
| 1
| '''120.90'''
|- align="center"
| 3
| 89.0869
| 1
| '''74.61'''
|- align="center"
| 2
| 67.8886
| 1
| '''60.53'''
|- align="center"
| 1
| 56.1133
| 1
| '''51.30'''
|- align="center"
| 10
| 55.5998
| 1
| '''50.94'''
|- align="center"
| 16
| 50.1124
| 1
| '''45.53'''
|- align="center"
| 22
| 48.2030
| 1
| '''43.28'''
|- align="center"
| 23
| 44.2222
| 1
| '''40.82'''
|- align="center"
| 4
| 42.0354
| 1
| '''38.73'''
| Comments
|- align="center"
| 9
| 37.5865
| 1
| '''36.78'''
|- align="center"
| 6
| 35.3106
| 1
| '''35.47'''
|- align="center"
| 15
| 31.0459
| 1
| '''30.84'''
|- align="center"
| 7
| 28.8476
| 1
| '''30.00'''
|- align="center"
| 12
| 28.6623
| 1
| '''25.56'''
|- align="center"
| 17
| 25.7393
| 1
| '''25.35'''
|- align="center"
| 11
| 25.2603
| 1
| '''22.21'''
|- align="center"
| 18
| 23.3944
| 1
| '''21.39'''
|- align="center"
| 5
| 21.0478
| 1
| '''19.83'''
|-
|}
 

== '''Part 4 : Analysis of the Properties of the Synthesized Alkene Epoxides''' ==
=== '''The two catalytics systems''' ===

Assymmetric epoxidation of prochiral alkenes may lead to product with different stereochemical outcome as illustrated as below. To solve this problem, different types of asymmetric epoxidation catalyst have been synthesized. In this study, we shall be focusing on Shi asymmetric fructose catalyst as well as Jacobsen asymmetric catalyst.

[[File:Asymmetric catalyst.png|400px|center]]

==== ''' The Shi Asymmetric Fructose Catalyst''' ====

Molecule 21 is the stable precursor of molecule 22, the active catalyst. Molecule 21 can be converted to molecule 22 by using either persulfuric acid or potassium peroxymonosulphate.

[[File:Molecule 21 to 23.png|400px|center]]

The transition state of the Shi epoxidation was a subject of debate for a few moments. However, recent studies have led to the conclusion that the spiro transition state is more favored than the planar transition state. The spiro transition state is the transition that has its dioxirane perpendicularly bisecting the alkene double bond. This is thought to be more favourable due to interactions between the lone pairs of the oxygen with the LUMO of the alkene.

[[File:Spiro and planar ts.png|500px|center]]

==== ''' The Jacobsen Asymmetric Catalyst''' ====

Molecule 23 is the stable precursor of molecule 24, the active catalyst. Molecule 23 can be converted to molecule 24 by using sodium perchlorate.

[[File:Salen, 23 and 24.png|400px|center]]

Jacobsen catalyst is biphasic. The first phase involves the transfer of oxygen to molecule 23. Sodium perchlorate oxidizes Mn(III) to Mn(V).

In the second step, Jacobsen catalyst acts via a radical mechanism. It is thought to be so because epoxidation of trans-alkene by Jacobsen catalyst yield cis-alkene as well. A radical mechanism will lead to the lost of stereochemical information of the molecule.

=== ''' Crystal structure of the two catalyst''' ===
==== '''Molecule 21''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 21'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 21 strucutre.png|600px|center]]'''
|-
| style="text-align:center;" width="150" | ''' Bond '''
| style="text-align:center;" width="150"| ''' Bond Lenghts (Angstrom)'''
| style="text-align:center;" | ''' Evaluation'''
|-
| style="text-align:center;"| ''' O1-C1 '''
| style="text-align:center;"| ''' 1.400'''
| rowspan="10" style="text-align:left;"| [[File:Molecule 21 2.png|300px|center]]

The normal bond length of an C-O bond is 1.430 angstrom.

The most interesting aspect here is O4 and O2. The lone pair of O4 is antiperplanar to the sigma* orbital of the carbonyl group while the lone pair of O2 is anti periplanar to the carbonyl pi* orbital. Donation of electron can occur because of the correct symmetry. Due to the mixing of the orbitals, the C2-O2 and C4-O4 has been conferred with a certain degree of double bond character.

However, due to the lone pair on oxygen being now donated to the carbonyl antibonding orbitals, the O2 and O4 is slightly “electron deficient” and electron density will be pulled away from O2 and O4. That would explain why the bond length increase for O2-C7 and O4-C10. Increase in bond length is an indicator of the weakening of the bond.
|-
| style="text-align:center;"|'''O1-C7'''
| style="text-align:center;"|'''1.413'''
|-
| style="text-align:center;"|'''O2-C7'''
| style="text-align:center;"|'''1.441'''
|-
| style="text-align:center;"|'''O2-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O4-C4'''
| style="text-align:center;"|'''1.396'''
|-
| style="text-align:center;"|'''O4-C10'''
| style="text-align:center;"|'''1.439'''
|-
| style="text-align:center;"|'''O5-C10'''
| style="text-align:center;"|'''1.409'''
|-
| style="text-align:center;"|'''O5-C5'''
| style="text-align:center;"|'''1.416'''
|-
| style="text-align:center;"|'''O6-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O6-C6'''
| style="text-align:center;"|'''1.420'''
|-
|}
 

==== '''Molecule 23''' ====

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 23'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 23 struc.png|600px|center]]'''
|-
| The most outstanding feature from this molecule is the fact that is adopt a puckered form of the square base pyramidal form. This is no surprise that the molecule is almost planar due to the electron delocalization around each side of the salen ligand.

The tery-butyl hydrogen are oriented closely to one another. Non-covalent interaction studies indicated that repulsion would occur for H---H bond length that are less than 2.1 angstrom while favourable interaction may be dominant with bond length above 2.4 angstrom. It was discovered that all 4 hydrogens have bond length more than 2.4 angstrom hence there should not be any significant repulsion between them. Instead, certain amount of attractive force will ensue and that contributes to the overall stability of the molecule

|-
|}
 

=== ''' The calculated NMR properties of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | '''
Shift (ppm) Degeneracy
7.4891704929 4.0000
7.2988172444 1.0000
3.6627082199 1.0000
3.1170156088 1.0000
2.5382383043 1.0000 '''
| width="100" | '''
Shift (ppm) Degeneracy
7.4892967873 4.0000
7.2987138125 1.0000
3.6632689921 1.0000
3.1151709109 1.0000
2.5339209685 1.0000

'''
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Styrene R HNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Styrene S HNMR.png|400px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | '''
Shift (ppm) Degeneracy
135.1098747604 1.0000
124.1186533632 1.0000
123.4150641684 1.0000
122.9584694331 2.0000
118.2653162569 1.0000
54.0265785300 1.0000
53.4853575062 1.0000 '''
| width="100" | '''
Shift (ppm) Degeneracy
135.1323742030 1.0000
124.1343038829 1.0000
123.4137039868 1.0000
122.9558208084 2.0000
118.2690258882 1.0000
54.0599580762 1.0000
53.4684920923 1.0000
'''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | ''' [[File:Styrene R CNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Styrene S CNMR.png|400px|center|]]'''
|-
| width="100" | ''' '''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | ''' Shift (ppm) Degeneracy
7.5705724829 2.0000
7.4791732656 8.0000
3.5390102503 2.0000
| width="100" | ''' Shift (ppm) Degeneracy
7.5705651164 2.0000
7.4791779628 8.0000
3.5374502607 2.0000
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Stilbene RR HNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|400px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | ''' Shift (ppm) Degeneracy
134.0942417727 2.0000
124.2206838184 2.0000
123.5192390024 2.0000
123.2125901307 2.0000
123.0785800542 2.0000
118.2583039589 2.0000
66.4212770637 2.0000 '''
| width="100" | ''' Shift (ppm) Degeneracy
134.0899175142 2.0000
124.2224499528 2.0000
123.5180152862 2.0000
123.2113538650 2.0000
123.0745448885 2.0000
118.2635789492 2.0000
66.4249347217 2.0000 '''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | ''' [[File:Stilbene RR CNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|400px|center|]]'''
|-
|}

 

=== ''' Assigning the absolute configuration of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''Predicted ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg'''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg '''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental conditions'''
| width="100" | '''1.00g/100ml, chloroform, 21 degree Celcisus, 589 nm wavelength '''
| width="100" | '''1.02g/100ml (99% ee), chloroform, 25 degree Celsius, 589 nm wavelength '''
| width="100" | '''1.01g/100ml, ethanol, 22 degree Celsius, 589 nm wavelength '''
| width="100" | '''0.6g/100ml, ethanol, 20 degree Celsius, 589 nm wavelength '''
|- align="left"
| width="100" | ''' Predicted VCD Spectrum'''
| width="100" | '''[[File:Styrene R VCD.png|200px|center|]] '''
| width="100" | '''[[File:Styrene S VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene RR VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene SS VCD.png|200px|center|]]'''
|-
|}

 

All the assignments given in the literature reports are correct although the predicted value differs slightly with the experimental values

=== ''' Analysis of the Transition State for Reactions''' ===
==== '''Predicting Enantiomeric Excess based on Transition State energies''' ====

One of the energy output from Gaussian calculation is the “sum of electronic and thermal free energies”. This is Gibbs Free Energy at 298.15K and 1 atm.

Using this term and invoking a variant of the Curtin-Hammett Principle, it is possible to calculate a predicted enantiomeric excess of one enantiomer over the other.

[[File:Ee and transition state energy.png|800px|center]]

Using the derivations from above and equation (4), we analyze the enantiomeric excess of beta-methyl styrene and the results are tabulated as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1343.022970'''
| width="100" | '''-1343.017942'''
| width="150" | '''-0.005028'''
| width="150" | '''4.88E-03'''
| width="150" | '''99.03'''
|- align="center"
| width="100" | '''-1343.019233'''
| width="100" | '''-1343.015603'''
| width="150" | '''-0.003630'''
| width="150" | '''2.14E-02'''
| width="150" | '''95.80'''
|- align="center"
| width="100" | '''-1343.029272'''
| width="100" | '''-1343.023766'''
| width="150" | '''-0.005506'''
| width="150" | '''2.94E-03'''
| width="150" | '''99.41'''
|- align="center"
| width="100" | '''-1343.032443'''
| width="100" | '''-1343.024742'''
| width="150" | '''-0.007701'''
| width="150" | '''2.88E-04'''
| width="150" | '''99.94'''
|-
|}

 

The above hartree units are converted to J/mol for calculation of K where 1 hartress = 4.3597E-18

Studying all the free energies of the (R,R) series and compare them with the (S,S) series, it comes as no surprise that (R,R) product is favoured over (S,S) product as (R,R) is more stable. Indeed, this corresponds with the literature value reporting 92% ee of (R,R) products over that of (S,S).

==== '''Analysis of the Transition State of Epoxidation''' ====
==== '''Shi Fructose Catalyst''' ====
For this section, I will be analyzing the the transition state of 1) styrene and 2) trans-stilbene with the Shi fructose catalyst.

===== '''(R) and (S)-styrene transition state''' =====
The transition state for the formation of (R)-styrene oxide and (S)-styrene oxide are given as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R)-styrene oxide'''
| width="150" | '''(S)-styrene oxide'''
|- align="center"
| width="150" | ''' Structure of Catalyst '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide R.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide S ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| [[File:Steric shi fructose R.png|450px|center]]
| [[File:Steric shi fructose S.png|450px|center]]
|-
|}

 

In the transition state for (R)-styrene, it was discovered that the Re face is reacting with the oxygen of the dioxirane. The phenyl ring is oriented endo with respect to the fructose catalyst. However, the (S)-styrene is reacting at the Si face and the phenyl ring is oriented exo relative to the catalyst.

The approach taken by (R)-styrene and (S)-styrene are restricted to only one due to steric interactions. Therefore, the epoxidation of both styrenes by the Shi catalyst will be stereospecific and retains all the stereochemical information of the reactant. However, whether or not (R)-styrene oxide or (S)-styrene oxide is form is dependent on the relative energies of the transition state. The more stable the transition state, the more likely the product of the transition state will be formed.

So in order to examine this, an example of transition state of both styrenes with Shi catalyst are obtained and analyzed.
 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1303.736813'''
| width="100" | '''-1303.727673'''
| width="150" | '''-0.00914'''
| width="150" | '''6.28E-05'''
| width="150" | '''99.99'''

|-
|}

 

From the above, we can see the predicted high enantiopurity of the reaction favoring the (R) product because of the lower energy of the transition states. To understand the reason, we have to turn to non-covalent interaction (NCI) analysis.

[[File:NCI shi fructose styrene.png|700px|center]]

To complement the NCI analysis, a QTAIM (Quantum Theory of Atoms in Molecules) analysis is conducted as well.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''(R)-styrene transition state'''
| width="200" | '''(S)-styrene transition state'''
|- align="center"
| width="100" | '''[[File:QTAIM R.png|400px|center]]'''
| width="100" | '''[[File:QTAIM S.png|400px|center]]'''
|- align="center"
| colspan="2" width="100" | '''Comments'''
|-
| colspan="2" width="100" | '''Unsurprisingly, QTAIM analysis has also shown that (R)-styrene/Shi catalyst has more interactions with one another. While (R)-styrene has 2 strong interactions, (S)-styrene has only one with the catalyst. Besides, the phenyl ring of (R)-styrene also confers additional positive interaction with the catalyst. QTAIM analysis has also show several interactions between the C=C geminal hydrogen of (R)-styrene intreacting with the oxygen atoms on the dioxacyclopentane ring'''
|-
|}

 

===== '''(R,R) and (S,S)-Stilbene transition state''' =====

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R,R)-Stilbene oxide'''
| width="150" | '''(S,S)-Stilbene oxide'''
|- align="center"
| width="150" | ''' Structure of Transition State '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Stilbene RR ts.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>SS stilbene oxide ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| colspan="2" | [[File:Shi fructose stilbene.png|700px|center]]

|-
|}

 

However, unlike styrene, trans-stilbene seems to approach perpendicularly to the dioxirane. This is proposed to be due to the steric interactions (marked in purple). Based on first inspection, it seems that (S,S)-Stilbene oxide has more steric interactions than (R,R)-Stilbene oxide. Although unsubstantial, it seems like my guess was correct. The (R,R)-stilbene/Shi catalyst transition state is lower in energy.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1534.687808'''
| width="100" | '''-1534.683440'''
| width="150" | '''0.004368'''
| width="150" | '''9.08E-3'''
| width="150" | '''98.20'''

|-
|}

 

NCI Analysis is also done for trans-stilbene

[[File:NCI stilbene.png|700px|center]]

==== '''Jacobsen Catalyst''' ====

For this section, cis-beta methyl styrene transition state will be analyzed.

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-3383.259559'''
| width="100" | '''-3383.251060'''
| width="150" | '''-0.008499'''
| width="150" | '''1.24E-04'''
| width="150" | '''99.98'''
|- align="center"
| width="100" | '''-3383.253442'''
| width="100" | '''-3383.250270'''
| width="150" | '''-0.003172'''
| width="150" | '''3.48E-02'''
| width="150" | '''93.27'''
|-
|}

 

As is obvious from here, the (S,R) transition state is more stable than the (R,S) transition state. Both transition states are exo with respect to the catalyst.

It is not immediately apparent just by looking at the molecule to determine which spatial groups have interactions with one another. Therefore, an NCI analysis is conducted again.

[[File:NCI Jacobsen.png|700px|center]]

Rep:Mod:Computationalreport1C

2013-11-22T17:47:33Z

Xc2611: /* 1H NMR Spectra of Molecule 18 */

= '''Synthesis and Computational Lab: 1C''' =
== '''Part 1: Introduction to Molecular Mechanics''' ==
=== '''Introduction to MMFF94 and MMFF94s''' ===

With the improvement of computational data and computer processing power, the usage of molecular mechanics/dynamics forcefield has become very integrated in predicting properties of chemical molecules. A molecular mechanics/dynamics forcefield should be able to predict characteristics such as molecular geometries, conformational/stereoisomeric energies, vibrational frequencies etc. to a reasonable accuracy as compared to experimental-derived values.

Building on work from Kollman et al. s’ AMBER forcefield and Allinger et al. s’ MM1, MM2, MM3 and MM4, Merck Research Laboratories have managed to optimized and improved the previous computational algorithms and produced MMFF94 (Merck Molecular Force Field 94). One of the most prominent advantages of MMFF94 over other preceeding work is its enhanced prediction accuracy. The reason lies in the fact that MMFF94’s core parameterization utilizes an unprecedently large amount of computational data obtained from ab initio calculations1.

Subsequently after the development of MMFF94, a new “static” variant of the MMFF was introduced i.e. the MMFF94s. Unlike MMFF94 that was developed for the use of molecular dynamics simulations (which can be expensive), MMFF94s was developed with the purpose of energy minimization studies in mind. Although both systems provide identical results for most systems, they differ for amides and unsaturated amines which contain resonance-delocalized trigonal nitrogen atoms2.

In this computational exercise, MMFF94s is used predominantly as oppose to the alternative Universal Force Field (UFF). Although versatile across the entire periodic table, UFF is derived from simple rules and atomic parameters such as fixed hybridization that increases the likelihood of erroneous structural and energetic predictions3.

=== '''Forms of MMFF94s''' ===

Steric energy of a molecule is the energy arise due to its geometry or conformation. Energy minimization of steric energy process ensures that the molecule is in its lowest energy conformation.

MMFF94s assumes that the total steric energy of a molecule can be found by the sum of a few specific interactions in a molecule.

ES = EBS + EAB + E SB + ET + EOOP + EVdW + EEE

'''where the bonded interactions are:'''

ES = Total Steric energy

EBS = Total Bond Stretching energy

EAB = Total Angle Bending energy

ESB = Total Stretch Bending energy

ET = Total Torsional Energy

EOOP = Total Out-Of-Plane Bending energy, and

'''where the non-bonded interactions are:'''

EVdW = Total Van der Waals Energy

EEE = Total Electrostatic Energy

{| border="1" cellspacing="1" cellpadding="10"
|-
| width="300" align="center" | '''Types of Energies'''
! width="600" align="center" | '''Explanation'''
|-
| colspan="2" style="text-align: center;" | '''Bonded Interactions'''
|-
| width="300" align="center" | '''Total Bond Stretching Energy'''
! width="600" align="left" | The total bond stretching energy is related to the vibration energy of the molecules in comparison to the equilibrium bond length. Whenever a bond deviates from the equilibrium bond length, the energy value increases.

MMFF94s uses a quartic function that has the force constant term (relate to bond strength). The quartic function term is superior to the cubic function term (used in MM2) in the sense that it avoid the “cubic stretch catastrophe” where progressive elongation of molecule bond length leads to negative infinity.
|-
| width="300" align="center" | '''Total Angle Bending Energy'''
! width="600" align="left" | Similar to Total Bond Stretching Energy, the total angle bending energy is also related to the vibration energy of the molecules about the equilibrium bond length. However, unlike EBS that measures the bond strength, EAB is associated with the stiffness of the molecules based on the Hookiean potential. Whenever bond angles deviate from the norm during vibration, this energy term increases as well.
|-
| width="300" align="center" | '''Total Stretch-Bending Energy'''
! width="600" align="left" | This energy term takes into account of the energy due to increase in bond length when bond angle between two atoms changes.
|-
| width="300" align="center" | '''Total Torsional Energy'''
! width="600" align="left" | Total torsional energy is the energy required for intermolecular rotation about the bonds. In molecule mechanics, however, this term is often used as a correction that must be added or subtracted to the total energy of the molecule to fit a quantum mechanical calculation about the dihedral angles of bonds.
|-
| width="300" align="center" | '''Total Out-Of-Plane Bending Energy'''
! width="600" align="left" | This energy term refers to the energy needed to deform the dihedral angle (zero degrees) of a planar group of atoms such as carbonyl or amide functional groups.
|-
| colspan="2" style="text-align: center;" | '''Non-Bonded Interactions'''
|-
| width="300" align="center" | '''Total Van der Waals Energy'''
! width="600" align="left" | The total Van der Waals energy term examines the intramolecular interactions such as repulsion or attraction between non-bonded atoms in the molecule. This term is crucial in determining the preferred conformation of the molecule.

MMFF94s employs the novel “Buffered-14-7”. The name is derived from a buffering constant and the 14th and 7th power dependencies of the repulsive and attractive energy in the equation.
|-
| width="300" align="center" | '''Total Electrostatic Energy'''
! width="600" align="left" | The total electrostatic energy functions take into account of the Coulombic potential and partial charge/dipole/atomic point charges interactions within the molecule.
|-

|}

 

== '''Part 2 : Conformational Analysis Using Molecular Mechanics''' ==
=== '''The Hydrogenation of Cyclopentadiene Dimer''' ===

==== '''Endo and exo adduct from the Dimerization of Cyclopentadiene''' ====
Cyclopentadiene will undergo dimerization by Diels-alder reaction to form either an endo or exo adduct.

[[File:XcwDimerization of CP.png|500px|center]]

==== '''Stereoselectivity of Dimerization of Cyclopentadiene''' ====
Although the exo adduct is thermodynamically more stable than the endo adduct, the endo adduct is form preferentially. Using the QST2 method, the transition state of the Diels Alder dimerization was found. It was discovered that due to the secondary orbital interactions in the endo transition state, the endo dimer is formed preferentially (the kinetic product). Hence, it is proven that the Diels Alder dimerization between two cyclopentadiene are kinetically controlled.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Transition State of Dimerization of Cyclopentadiene'''
| '''Imaginary Stretch Frequency (-881.25) of the Endo Transition State (click to animate)'''
| '''Secondary Orbital Interaction (Red overlapping orbitals)'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<uploadedFileContents>EndotsDCPD2.mol
</uploadedFileContents>
</jmolApplet></jmol>
| [[File:Xcwendotsimaginary.gif|300px|center]]
| [[File:XcwSecondary orbital interaction1.jpg|300px|center]]
|-
|}

 

==== '''Asynchronous Bond Formation of Dimerization of Cyclopentadiene''' ====

The initial study of the molecular orbitals of the transition states seemed a bit peculiar. Instead of getting a LUMO with symmetrical orbitals, the calculations showed a HOMO that is asymetric at the carbons where the new sigma bonds will be formed. Running an IRC further, it soon became clear that the asymmetry of the HOMO leads to an asychronous bond formation before leading to the product.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''IRC plot following the Endo Transition State '''
| '''IRC following the Endo Transition State (click to animate)'''
| '''Asymmetry of orbitals at the carbons where the new sigma bonds will be formed'''
|- align="center"
| [[File:XcwendotscyclopentadieneIRC.png|300px|center]]
| [[File:XcwendotsIRC.gif|300px|center]]
| [[File:XcwAsynchronous mo.jpg|300px|center]]
|-
|}

 

==== '''Comparison of Energies between the Endo and Exo adduct of Dicyclopentadiene''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Adduct of Dicyclopentadiene dimerization'''
| '''Exo Adduct of Dicyclopentadiene dimerization'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=19,atomno=1,atomno=2; color green;measure 19 1;measure 19 2;</script>
<uploadedFileContents>XcwEndodimer3.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>Exodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=7,atomno=17; color green;measure 17 7;</script>
<uploadedFileContents>XcwExodimer1.mol</uploadedFileContents>
</jmolApplet></jmol>
|-
|}

 

Using MMFF94s ab initio calculations, the energies for the exo dimer and the endo dimer are derived.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Exodimer'''
| '''55.374'''
| 3.543
| 30.772
| -2.041
| -2.728
| 0.015
| 12.800
| 13.014
|-
| '''Endodimer'''
| '''58.191'''
| 3.468
| 33.187
| -2.082
| -2.950
| 0.023
| 12.360
| 14.186
|-
|}

 

The MMFF94s steric energy (after minimization) for the exo dimer is lower than that of the endo dimer. This is reflected by the large difference for the EEE between the endo dimer and the exo dimer due to unfavourable steric repulsion between the two “arched down” cyclopentene rings.

==== '''Hydrogenation of Dicyclopentadiene''' ====

Hydrogenation of the endo dicyclopentadiene (DCPD) would lead to two potential products: dihydro product 1 and dihydro product 2.

[[File:XcwFormation of Dihydro products.png|500px|center]]

Using MMFF94s, the energy of the two dihydro products are calculated.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Dihydro Product 1'''
| '''50.123'''
| 3.308
| 30.864
| -1.927
| 0.060
| 0.015(2)
| 13.281
| 5.121
|-
| '''Dihydro Product 2'''
| '''41.257'''
| 2.823
| 24.685
| -1.657
| -0.379
| 0.000(2)
| 10.639
| 5.147
|-
| '''Tetrahydro Product'''
| '''39.042'''
| 2.730
| 25.151
| -1.676
| 1.287
| 0.000
| 11.551
| 0.000
|}

 

From the MMFF94s calculation, it can be seen that dihydro product 2 has a lower steric energy than dihydro product 1. Therefore, dihydro product 2 is the thermodynamic product for the hydrogenation of dicylopentadiene. And indeed, this was what was observed by Skala et al.. He observed that the first hydrogenation occur at the norborene part of the molecule (rate of hydrogenation several times faster than that in the cyclopentene ring)6. The first heat of hydrogenation at the norborene is 138.8 kJ/mol while the second hydrogenation at the cyclopentene right is 109.5 kJ/mol6.

From the above results, it is also obvious that tetrahydro product is much more stable than either dihydro product. And yet, studies have shown that the tetrahydro product will only form after prolonged hydrogenation under high temperature. However, subjecting DCPD to high temperature leads to low yield due to cracking of DCPD.

Since thermodynamically it is predicted to form favourably, the fact that it does not could only mean that the hydrogenation of DCPD to tetrahydrodicyclopentadiene (TH-DCPD) is kinetically controlled. Most possibly, the transition state of the hydrogenation of DCPD is highly unstable hence it is unlikely to form.

=== '''Atropisomerism in an Intermediate related to the Synthesis of Taxol''' ===

Atropisomerism is a type of stereoisomerism that is form as a result of hindered rotation about a single bond.

[[File:XcwAtropisomerism example.png|500px|center]]

In the case of the 6,6’-dinitro-2,2’-diphenic acid, rotation about the bonds joining the two substituted phenyl rings would have to overcome large steric interaction between the bulky substituents. The barrier of rotation is high enough for the two conformers to be isolated individually.

In the synthesis of taxol, one of the key intermediates exhibit atropisomerism.

==== '''Atropisomerism in Taxol Synthesis''' ====

For the key intermediate, rotation about the carbon-carbon bonds would lead to two types of atropisomers, each with either the carbonyl group poining upwards or downwards in relative to the bridge.

[[File:XcwIntermediate 9 and Intermediate 10.png|500px|center]]

Once again by using MMFF94s ab initio calculations, the steric energies for the two intermediates are illustrated as below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 9'''
| '''70.571'''
| 7.743
| 28.356
| -0.062
| 0.004
| 0.949
| 33.293
| 0.288
|-
| '''Intermediate 10'''
| '''60.553'''
| 7.599
| 18.838
| -0.139
| 0.199
| 0.844
| 33.269
| -0.056
|-

|}

 

Analyzing the data above, the largest energy difference between Intermediate 9 and Intermediate 10 stems from the EAB which is related to the strain of the ring. Intermediate 9 has an excess of 9.518 kcal/mol EAB as compared to Intermediate 10. This comes as a surprise as intermediate 9 is predicted to be more stable alkene.

The rationale behind the prediction of the stability of intermediate 9 stems from the fact that the through-space distance of the upward-pointing carbonyl oxygen with the carbon-carbon is further than the through space distance between the downward-pointing carbonyl oxygen with the -CH2-CH2- fragment at the norbornene part in intermediate 10.

==== '''Hyperstable Olefins''' ====

Intermediate 9 and Intermediate 10 does not react readily with other reagents during functionalization. This is due to the hyperstability effect found in hyperstable olefins.

Hyperstable olefins are alkenes that contain less strain in the ring (i.e. negative olefin strain values) compared to the parent hydrocarbon. To study this further, further MMFF94s calculation was done to compare Intermediate 10 with the parent hydrocarbon.

[[File:XcwIntermediate10andPH.png|500px|center]]

The energies that we calculated are tabulated as shown below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 10'''
| '''44.878 '''
| 5.211
| 15.488
| -0.267
| -1.655
| 0.998
| 25.014
| 0.088
|-
| '''Parent Hydrocarbon'''
| '''50.564'''
| 4.692
| 21.979
| 0.109
| -0.958
| 0.247
| 24.495
| 0.000
|-

|}

 

Scrutinizing the results, the largest energy difference between intermediate 10 and the parent hydrocarbon stems from the Total Angle Bending Energy, EAB. Since the Total Angle bending energy is related to the angle strain in the molecules, it is apparent that the parent hydrocarbon has more ring strain as compared to the bridgehead olefin.

== '''Part 3 : Spectroscopic Simulation Using Quantum Mechanics''' ==
=== '''Spectroscopy of an Intermediate Related to the Synthesis of Taxol''' ===

Molecule 17 and 18 are derivatives of intermediate 9 and 10. In this exercise, MMFF94s is used to predict the 1H and 13C NMR of molecule 17 and molecule 18.

[[File:XcwIntermediate17&18.png|500px|center]]

==== '''NMR Spectra of Molecule 17''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 17.mol
</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwHNMRMolecule 17 Chair Overall NMR.png|500px|center]]
| [[File:XcwHNMRMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.1825
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| The first three results were fairly straight forward to be deduced and correlate wit experimental data.

The hydrogen atom that is geminally attached to the carbon of the double bonds is the most deshielded due to the ring current anisotropic effect of the ring current

The second most deshielded hydrogen atom is the hydrogen atom on the methyl group on the bridge. The hydrogen atom is pointing directly to the oxygen atom of the carbonyl functional group.

The peaks with an integration height of 4 is assigned to the hydrogen atoms in the 1,3-dithiolane ring fragment.

Subsequent analysis of the 1H NMR became very complicated very quickly for two reasons:

1. Gaussian calculations showed some atoms with an integration height of 3. Comparing their file atom number and checking their chemical environment, it is not possible to find any correlation between them.

2. Some of the peaks in the literature remains unresolved and are given as multiplets or grouped together.

|- align="center"
| 52
| 3.1775
| 1
| '''2.99'''
|- align="center"
| 53,52,50,51
| 3.0867
| 4
| '''3.40-3.10'''
|- align="center"
| 42,43,39
| 2.7445
| 3
| ''' '''
|- align="center"
| 49
| 2.6187
| 1
| ''' '''
|- align="center"
| 34
| 2.4371
| 1
| ''' '''
|- align="center"
| 35
| 2.3782
| 1
| ''' '''
|- align="center"
| 40,37,26
| 2.2730
| 3
| ''' '''
|- align="center"
| 30
| 2.1566
| 1
| ''' '''
|- align="center"
| 36
| 2.1033
| 1
| ''' '''
|- align="center"
| 32,28
| 2.0259
| 2
| ''' '''
|- align="center"
| 25
| 1.8535
| 2
| ''' '''
|- align="center"
| 38,46,27
| 1.5898
| 3
| '''1.25'''
|- align="center"
| 29
| 1.4557
| 1
| ''' '''
|- align="center"
| 31
| 1.0123
| 1
| ''' '''
|- align="center"
| 44,48,45
| 0.9087
| 3
| '''1.10'''
|- align="center"
| 47
| 0.8354
| 1
| ''' '''
|- align="center"
| 33
| 0.5790
| 1
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 17 Chair Overall NMR2.png|500px|center]]
| [[File:XcwMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 216.2725
| 1
| '''218.79'''
| rowspan="10" style="text-align:center;"| [[File:XcwMolecule 17 image for CNMR.jpg|600px|center]]
|- align="center"
| 13
| 144.8626
| 1
| '''144.63'''
|- align="center"
| 14
| 124.7193
| 1
| '''125.33'''
|- align="center"
| 3
| 91.3340
| 1
| '''72.88'''
|- align="center"
| 2
| 60.9568
| 1
| '''56.19'''
|- align="center"
| 1
| 57.0811
| 1
| '''52.52'''
|- align="center"
| 10
| 52.4663
| 1
| '''48.50'''
|- align="center"
| 16
| 51.4857
| 1
| '''46.80'''
|- align="center"
| 9
| 46.9196
| 1
| '''45.76'''
|- align="center"
| 23
| 43.8647
| 1
| '''39.80'''
|- align="center"
| 22
| 41.9450
| 1
| '''38.81'''
| Comments
|- align="center"
| 4
| 41.8724
| 1
| '''35.85'''
| rowspan="9" style="text-align:left;"| The carbon bonded to the oxygen atom is the most deshielded, as is shown in the predicted values and the experimental values. There is a deviation between the values. Quite possibly, this is due to the fact that in reality, the carbonyl functional group is pointing slightly towards the equatorial position rather than a lateral position relative to the ring (as is in the input for Gaussian calculation)

Most of the 1CNMR values that was predicted by Gaussian are all within an acceptable range of deviation. However, there is carbon 3 that has significant deviation between the predicted value and experimental value.

Carbon 3 is the carbon bonded to the two sulphurs in the 1,3-dithiolane ring fragment. Such a huge deviation would possibly mean that the conformer that was given as input to Gaussian differs from the literature.

The above NMR spectra was corrected with a level of theory B3LYP/6-31G(d,p) using TMS as reference and in chloroform.

|- align="center"
| 15
| 35.4348
| 1
| '''32.66'''
|- align="center"
| 11
| 31.1964
| 1
| '''28.79'''
|- align="center"
| 6
| 28.9432
| 1
| '''28.29'''
|- align="center"
| 7
| 28.3640
| 1
| '''26.88'''
|- align="center"
| 12
| 27.3767
| 1
| '''25.66'''
|- align="center"
| 17
| 26.3311
| 1
| '''23.86'''
|- align="center"
| 15
| 24.5483
| 1
| '''20.96'''
|- align="center"
| 18
| 19.7788
| 1
| '''18.71'''
|-
|}
 

==== '''NMR Spectra of Molecule 18''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 18 Boat for Image2.mol</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"-
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 18 Chair Overall NMR.png|500px|center]]
| [[File:Molecule 18 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
|- align="center"
| 41
| 5.2832
| 1
| '''5.21'''
|- align="center"
| 50
| 3.3175
| 1
| rowspan="4" style="text-align:centre;"| '''3.00-2.70'''
|- align="center"
| 52
| 3.2153
| 1
|- align="center"
| 51,53
| 3.1161
| 2
|- align="center"
| 34,43
| 2.8606
| 2
|- align="center"
| 38
| 2.4549
| 1
| ''' '''
|- align="center"
| 42
| 2.3968
| 1
| ''' '''
|- align="center"
| 25,29,26
| 2.2796
| 3
| ''' '''
|- align="center"
| 39
| 2.0844
| 1
| ''' '''
|- align="center"
| 40,36
| 1.9699
| 2
| ''' '''
|- align="center"
| 37,24
| 1.8519
| 2
| ''' '''
|- align="center"
| 31,27
| 1.6780
| 2
| ''' '''
|- align="center"
| 28
| 1.6175
| 1
| ''' '''
|- align="center"
| 46,49
| 1.4979
| 2
| ''' '''
|- align="center"
| 35
| 1.4150
| 1
| ''' '''
|- align="center"
| 32
| 1.3531
| 1
| ''' '''
|- align="center"
| 48
| 1.1606
| 1
| ''' '''
|- align="center"
| 33,30,47
| 1.0653
| 3
| '''1.03'''
|- align="center"
| 44,45
| 0.9643
| 2
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 18 Full Spectra'''
| '''13C NMR Spectra of Molecule 18 Truncated Spectra'''
|- align="center"
| [[File:XcwMolecule 18 Boat Overall NMR.png|500px|center]]
| [[File:XcwMolecule 18 Boat zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
|- align="center"
| 8
| 211.8325
| 1
| '''211.49'''
|- align="center"
| 13
| 148.6673
| 1
| '''148.72'''
|- align="center"
| 14
| 118.8373
| 1
| '''120.90'''
|- align="center"
| 3
| 89.0869
| 1
| '''74.61'''
|- align="center"
| 2
| 67.8886
| 1
| '''60.53'''
|- align="center"
| 1
| 56.1133
| 1
| '''51.30'''
|- align="center"
| 10
| 55.5998
| 1
| '''50.94'''
|- align="center"
| 16
| 50.1124
| 1
| '''45.53'''
|- align="center"
| 22
| 48.2030
| 1
| '''43.28'''
|- align="center"
| 23
| 44.2222
| 1
| '''40.82'''
|- align="center"
| 4
| 42.0354
| 1
| '''38.73'''
| Comments
|- align="center"
| 9
| 37.5865
| 1
| '''36.78'''
| rowspan="9" style="text-align:left;"| ''' '''
|- align="center"
| 6
| 35.3106
| 1
| '''35.47'''
|- align="center"
| 15
| 31.0459
| 1
| '''30.84'''
|- align="center"
| 7
| 28.8476
| 1
| '''30.00'''
|- align="center"
| 12
| 28.6623
| 1
| '''25.56'''
|- align="center"
| 17
| 25.7393
| 1
| '''25.35'''
|- align="center"
| 11
| 25.2603
| 1
| '''22.21'''
|- align="center"
| 18
| 23.3944
| 1
| '''21.39'''
|- align="center"
| 5
| 21.0478
| 1
| '''19.83'''
|-
|}
 

== '''Part 4 : Analysis of the Properties of the Synthesized Alkene Epoxides''' ==
=== '''The two catalytics systems''' ===

Assymmetric epoxidation of prochiral alkenes may lead to product with different stereochemical outcome as illustrated as below. To solve this problem, different types of asymmetric epoxidation catalyst have been synthesized. In this study, we shall be focusing on Shi asymmetric fructose catalyst as well as Jacobsen asymmetric catalyst.

[[File:Asymmetric catalyst.png|400px|center]]

==== ''' The Shi Asymmetric Fructose Catalyst''' ====

Molecule 21 is the stable precursor of molecule 22, the active catalyst. Molecule 21 can be converted to molecule 22 by using either persulfuric acid or potassium peroxymonosulphate.

[[File:Molecule 21 to 23.png|400px|center]]

The transition state of the Shi epoxidation was a subject of debate for a few moments. However, recent studies have led to the conclusion that the spiro transition state is more favored than the planar transition state. The spiro transition state is the transition that has its dioxirane perpendicularly bisecting the alkene double bond. This is thought to be more favourable due to interactions between the lone pairs of the oxygen with the LUMO of the alkene.

[[File:Spiro and planar ts.png|500px|center]]

==== ''' The Jacobsen Asymmetric Catalyst''' ====

Molecule 23 is the stable precursor of molecule 24, the active catalyst. Molecule 23 can be converted to molecule 24 by using sodium perchlorate.

[[File:Salen, 23 and 24.png|400px|center]]

Jacobsen catalyst is biphasic. The first phase involves the transfer of oxygen to molecule 23. Sodium perchlorate oxidizes Mn(III) to Mn(V).

In the second step, Jacobsen catalyst acts via a radical mechanism. It is thought to be so because epoxidation of trans-alkene by Jacobsen catalyst yield cis-alkene as well. A radical mechanism will lead to the lost of stereochemical information of the molecule.

=== ''' Crystal structure of the two catalyst''' ===
==== '''Molecule 21''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 21'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 21 strucutre.png|600px|center]]'''
|-
| style="text-align:center;" width="150" | ''' Bond '''
| style="text-align:center;" width="150"| ''' Bond Lenghts (Angstrom)'''
| style="text-align:center;" | ''' Evaluation'''
|-
| style="text-align:center;"| ''' O1-C1 '''
| style="text-align:center;"| ''' 1.400'''
| rowspan="10" style="text-align:left;"| [[File:Molecule 21 2.png|300px|center]]

The normal bond length of an C-O bond is 1.430 angstrom.

The most interesting aspect here is O4 and O2. The lone pair of O4 is antiperplanar to the sigma* orbital of the carbonyl group while the lone pair of O2 is anti periplanar to the carbonyl pi* orbital. Donation of electron can occur because of the correct symmetry. Due to the mixing of the orbitals, the C2-O2 and C4-O4 has been conferred with a certain degree of double bond character.

However, due to the lone pair on oxygen being now donated to the carbonyl antibonding orbitals, the O2 and O4 is slightly “electron deficient” and electron density will be pulled away from O2 and O4. That would explain why the bond length increase for O2-C7 and O4-C10. Increase in bond length is an indicator of the weakening of the bond.
|-
| style="text-align:center;"|'''O1-C7'''
| style="text-align:center;"|'''1.413'''
|-
| style="text-align:center;"|'''O2-C7'''
| style="text-align:center;"|'''1.441'''
|-
| style="text-align:center;"|'''O2-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O4-C4'''
| style="text-align:center;"|'''1.396'''
|-
| style="text-align:center;"|'''O4-C10'''
| style="text-align:center;"|'''1.439'''
|-
| style="text-align:center;"|'''O5-C10'''
| style="text-align:center;"|'''1.409'''
|-
| style="text-align:center;"|'''O5-C5'''
| style="text-align:center;"|'''1.416'''
|-
| style="text-align:center;"|'''O6-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O6-C6'''
| style="text-align:center;"|'''1.420'''
|-
|}
 

==== '''Molecule 23''' ====

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 23'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 23 struc.png|600px|center]]'''
|-
| The most outstanding feature from this molecule is the fact that is adopt a puckered form of the square base pyramidal form. This is no surprise that the molecule is almost planar due to the electron delocalization around each side of the salen ligand.

The tery-butyl hydrogen are oriented closely to one another. Non-covalent interaction studies indicated that repulsion would occur for H---H bond length that are less than 2.1 angstrom while favourable interaction may be dominant with bond length above 2.4 angstrom. It was discovered that all 4 hydrogens have bond length more than 2.4 angstrom hence there should not be any significant repulsion between them. Instead, certain amount of attractive force will ensue and that contributes to the overall stability of the molecule

|-
|}
 

=== ''' The calculated NMR properties of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | '''
Shift (ppm) Degeneracy
7.4891704929 4.0000
7.2988172444 1.0000
3.6627082199 1.0000
3.1170156088 1.0000
2.5382383043 1.0000 '''
| width="100" | '''
Shift (ppm) Degeneracy
7.4892967873 4.0000
7.2987138125 1.0000
3.6632689921 1.0000
3.1151709109 1.0000
2.5339209685 1.0000

'''
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Styrene R HNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Styrene S HNMR.png|400px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | '''
Shift (ppm) Degeneracy
135.1098747604 1.0000
124.1186533632 1.0000
123.4150641684 1.0000
122.9584694331 2.0000
118.2653162569 1.0000
54.0265785300 1.0000
53.4853575062 1.0000 '''
| width="100" | '''
Shift (ppm) Degeneracy
135.1323742030 1.0000
124.1343038829 1.0000
123.4137039868 1.0000
122.9558208084 2.0000
118.2690258882 1.0000
54.0599580762 1.0000
53.4684920923 1.0000
'''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | ''' [[File:Styrene R CNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Styrene S CNMR.png|400px|center|]]'''
|-
| width="100" | ''' '''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | ''' Shift (ppm) Degeneracy
7.5705724829 2.0000
7.4791732656 8.0000
3.5390102503 2.0000
| width="100" | ''' Shift (ppm) Degeneracy
7.5705651164 2.0000
7.4791779628 8.0000
3.5374502607 2.0000
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Stilbene RR HNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|400px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | ''' Shift (ppm) Degeneracy
134.0942417727 2.0000
124.2206838184 2.0000
123.5192390024 2.0000
123.2125901307 2.0000
123.0785800542 2.0000
118.2583039589 2.0000
66.4212770637 2.0000 '''
| width="100" | ''' Shift (ppm) Degeneracy
134.0899175142 2.0000
124.2224499528 2.0000
123.5180152862 2.0000
123.2113538650 2.0000
123.0745448885 2.0000
118.2635789492 2.0000
66.4249347217 2.0000 '''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | ''' [[File:Stilbene RR CNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|400px|center|]]'''
|-
|}

 

=== ''' Assigning the absolute configuration of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''Predicted ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg'''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg '''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental conditions'''
| width="100" | '''1.00g/100ml, chloroform, 21 degree Celcisus, 589 nm wavelength '''
| width="100" | '''1.02g/100ml (99% ee), chloroform, 25 degree Celsius, 589 nm wavelength '''
| width="100" | '''1.01g/100ml, ethanol, 22 degree Celsius, 589 nm wavelength '''
| width="100" | '''0.6g/100ml, ethanol, 20 degree Celsius, 589 nm wavelength '''
|- align="left"
| width="100" | ''' Predicted VCD Spectrum'''
| width="100" | '''[[File:Styrene R VCD.png|200px|center|]] '''
| width="100" | '''[[File:Styrene S VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene RR VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene SS VCD.png|200px|center|]]'''
|-
|}

 

All the assignments given in the literature reports are correct although the predicted value differs slightly with the experimental values

=== ''' Analysis of the Transition State for Reactions''' ===
==== '''Predicting Enantiomeric Excess based on Transition State energies''' ====

One of the energy output from Gaussian calculation is the “sum of electronic and thermal free energies”. This is Gibbs Free Energy at 298.15K and 1 atm.

Using this term and invoking a variant of the Curtin-Hammett Principle, it is possible to calculate a predicted enantiomeric excess of one enantiomer over the other.

[[File:Ee and transition state energy.png|800px|center]]

Using the derivations from above and equation (4), we analyze the enantiomeric excess of beta-methyl styrene and the results are tabulated as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1343.022970'''
| width="100" | '''-1343.017942'''
| width="150" | '''-0.005028'''
| width="150" | '''4.88E-03'''
| width="150" | '''99.03'''
|- align="center"
| width="100" | '''-1343.019233'''
| width="100" | '''-1343.015603'''
| width="150" | '''-0.003630'''
| width="150" | '''2.14E-02'''
| width="150" | '''95.80'''
|- align="center"
| width="100" | '''-1343.029272'''
| width="100" | '''-1343.023766'''
| width="150" | '''-0.005506'''
| width="150" | '''2.94E-03'''
| width="150" | '''99.41'''
|- align="center"
| width="100" | '''-1343.032443'''
| width="100" | '''-1343.024742'''
| width="150" | '''-0.007701'''
| width="150" | '''2.88E-04'''
| width="150" | '''99.94'''
|-
|}

 

The above hartree units are converted to J/mol for calculation of K where 1 hartress = 4.3597E-18

Studying all the free energies of the (R,R) series and compare them with the (S,S) series, it comes as no surprise that (R,R) product is favoured over (S,S) product as (R,R) is more stable. Indeed, this corresponds with the literature value reporting 92% ee of (R,R) products over that of (S,S).

==== '''Analysis of the Transition State of Epoxidation''' ====
==== '''Shi Fructose Catalyst''' ====
For this section, I will be analyzing the the transition state of 1) styrene and 2) trans-stilbene with the Shi fructose catalyst.

===== '''(R) and (S)-styrene transition state''' =====
The transition state for the formation of (R)-styrene oxide and (S)-styrene oxide are given as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R)-styrene oxide'''
| width="150" | '''(S)-styrene oxide'''
|- align="center"
| width="150" | ''' Structure of Catalyst '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide R.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide S ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| [[File:Steric shi fructose R.png|450px|center]]
| [[File:Steric shi fructose S.png|450px|center]]
|-
|}

 

In the transition state for (R)-styrene, it was discovered that the Re face is reacting with the oxygen of the dioxirane. The phenyl ring is oriented endo with respect to the fructose catalyst. However, the (S)-styrene is reacting at the Si face and the phenyl ring is oriented exo relative to the catalyst.

The approach taken by (R)-styrene and (S)-styrene are restricted to only one due to steric interactions. Therefore, the epoxidation of both styrenes by the Shi catalyst will be stereospecific and retains all the stereochemical information of the reactant. However, whether or not (R)-styrene oxide or (S)-styrene oxide is form is dependent on the relative energies of the transition state. The more stable the transition state, the more likely the product of the transition state will be formed.

So in order to examine this, an example of transition state of both styrenes with Shi catalyst are obtained and analyzed.
 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1303.736813'''
| width="100" | '''-1303.727673'''
| width="150" | '''-0.00914'''
| width="150" | '''6.28E-05'''
| width="150" | '''99.99'''

|-
|}

 

From the above, we can see the predicted high enantiopurity of the reaction favoring the (R) product because of the lower energy of the transition states. To understand the reason, we have to turn to non-covalent interaction (NCI) analysis.

[[File:NCI shi fructose styrene.png|700px|center]]

To complement the NCI analysis, a QTAIM (Quantum Theory of Atoms in Molecules) analysis is conducted as well.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''(R)-styrene transition state'''
| width="200" | '''(S)-styrene transition state'''
|- align="center"
| width="100" | '''[[File:QTAIM R.png|400px|center]]'''
| width="100" | '''[[File:QTAIM S.png|400px|center]]'''
|- align="center"
| colspan="2" width="100" | '''Comments'''
|-
| colspan="2" width="100" | '''Unsurprisingly, QTAIM analysis has also shown that (R)-styrene/Shi catalyst has more interactions with one another. While (R)-styrene has 2 strong interactions, (S)-styrene has only one with the catalyst. Besides, the phenyl ring of (R)-styrene also confers additional positive interaction with the catalyst. QTAIM analysis has also show several interactions between the C=C geminal hydrogen of (R)-styrene intreacting with the oxygen atoms on the dioxacyclopentane ring'''
|-
|}

 

===== '''(R,R) and (S,S)-Stilbene transition state''' =====

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R,R)-Stilbene oxide'''
| width="150" | '''(S,S)-Stilbene oxide'''
|- align="center"
| width="150" | ''' Structure of Transition State '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Stilbene RR ts.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>SS stilbene oxide ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| colspan="2" | [[File:Shi fructose stilbene.png|700px|center]]

|-
|}

 

However, unlike styrene, trans-stilbene seems to approach perpendicularly to the dioxirane. This is proposed to be due to the steric interactions (marked in purple). Based on first inspection, it seems that (S,S)-Stilbene oxide has more steric interactions than (R,R)-Stilbene oxide. Although unsubstantial, it seems like my guess was correct. The (R,R)-stilbene/Shi catalyst transition state is lower in energy.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1534.687808'''
| width="100" | '''-1534.683440'''
| width="150" | '''0.004368'''
| width="150" | '''9.08E-3'''
| width="150" | '''98.20'''

|-
|}

 

NCI Analysis is also done for trans-stilbene

[[File:NCI stilbene.png|700px|center]]

==== '''Jacobsen Catalyst''' ====

For this section, cis-beta methyl styrene transition state will be analyzed.

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-3383.259559'''
| width="100" | '''-3383.251060'''
| width="150" | '''-0.008499'''
| width="150" | '''1.24E-04'''
| width="150" | '''99.98'''
|- align="center"
| width="100" | '''-3383.253442'''
| width="100" | '''-3383.250270'''
| width="150" | '''-0.003172'''
| width="150" | '''3.48E-02'''
| width="150" | '''93.27'''
|-
|}

 

As is obvious from here, the (S,R) transition state is more stable than the (R,S) transition state. Both transition states are exo with respect to the catalyst.

It is not immediately apparent just by looking at the molecule to determine which spatial groups have interactions with one another. Therefore, an NCI analysis is conducted again.

[[File:NCI Jacobsen.png|700px|center]]

Rep:Mod:Computationalreport1C

2013-11-22T17:45:15Z

Xc2611: /* 13C NMR Spectra of Molecule 18 */

= '''Synthesis and Computational Lab: 1C''' =
== '''Part 1: Introduction to Molecular Mechanics''' ==
=== '''Introduction to MMFF94 and MMFF94s''' ===

With the improvement of computational data and computer processing power, the usage of molecular mechanics/dynamics forcefield has become very integrated in predicting properties of chemical molecules. A molecular mechanics/dynamics forcefield should be able to predict characteristics such as molecular geometries, conformational/stereoisomeric energies, vibrational frequencies etc. to a reasonable accuracy as compared to experimental-derived values.

Building on work from Kollman et al. s’ AMBER forcefield and Allinger et al. s’ MM1, MM2, MM3 and MM4, Merck Research Laboratories have managed to optimized and improved the previous computational algorithms and produced MMFF94 (Merck Molecular Force Field 94). One of the most prominent advantages of MMFF94 over other preceeding work is its enhanced prediction accuracy. The reason lies in the fact that MMFF94’s core parameterization utilizes an unprecedently large amount of computational data obtained from ab initio calculations1.

Subsequently after the development of MMFF94, a new “static” variant of the MMFF was introduced i.e. the MMFF94s. Unlike MMFF94 that was developed for the use of molecular dynamics simulations (which can be expensive), MMFF94s was developed with the purpose of energy minimization studies in mind. Although both systems provide identical results for most systems, they differ for amides and unsaturated amines which contain resonance-delocalized trigonal nitrogen atoms2.

In this computational exercise, MMFF94s is used predominantly as oppose to the alternative Universal Force Field (UFF). Although versatile across the entire periodic table, UFF is derived from simple rules and atomic parameters such as fixed hybridization that increases the likelihood of erroneous structural and energetic predictions3.

=== '''Forms of MMFF94s''' ===

Steric energy of a molecule is the energy arise due to its geometry or conformation. Energy minimization of steric energy process ensures that the molecule is in its lowest energy conformation.

MMFF94s assumes that the total steric energy of a molecule can be found by the sum of a few specific interactions in a molecule.

ES = EBS + EAB + E SB + ET + EOOP + EVdW + EEE

'''where the bonded interactions are:'''

ES = Total Steric energy

EBS = Total Bond Stretching energy

EAB = Total Angle Bending energy

ESB = Total Stretch Bending energy

ET = Total Torsional Energy

EOOP = Total Out-Of-Plane Bending energy, and

'''where the non-bonded interactions are:'''

EVdW = Total Van der Waals Energy

EEE = Total Electrostatic Energy

{| border="1" cellspacing="1" cellpadding="10"
|-
| width="300" align="center" | '''Types of Energies'''
! width="600" align="center" | '''Explanation'''
|-
| colspan="2" style="text-align: center;" | '''Bonded Interactions'''
|-
| width="300" align="center" | '''Total Bond Stretching Energy'''
! width="600" align="left" | The total bond stretching energy is related to the vibration energy of the molecules in comparison to the equilibrium bond length. Whenever a bond deviates from the equilibrium bond length, the energy value increases.

MMFF94s uses a quartic function that has the force constant term (relate to bond strength). The quartic function term is superior to the cubic function term (used in MM2) in the sense that it avoid the “cubic stretch catastrophe” where progressive elongation of molecule bond length leads to negative infinity.
|-
| width="300" align="center" | '''Total Angle Bending Energy'''
! width="600" align="left" | Similar to Total Bond Stretching Energy, the total angle bending energy is also related to the vibration energy of the molecules about the equilibrium bond length. However, unlike EBS that measures the bond strength, EAB is associated with the stiffness of the molecules based on the Hookiean potential. Whenever bond angles deviate from the norm during vibration, this energy term increases as well.
|-
| width="300" align="center" | '''Total Stretch-Bending Energy'''
! width="600" align="left" | This energy term takes into account of the energy due to increase in bond length when bond angle between two atoms changes.
|-
| width="300" align="center" | '''Total Torsional Energy'''
! width="600" align="left" | Total torsional energy is the energy required for intermolecular rotation about the bonds. In molecule mechanics, however, this term is often used as a correction that must be added or subtracted to the total energy of the molecule to fit a quantum mechanical calculation about the dihedral angles of bonds.
|-
| width="300" align="center" | '''Total Out-Of-Plane Bending Energy'''
! width="600" align="left" | This energy term refers to the energy needed to deform the dihedral angle (zero degrees) of a planar group of atoms such as carbonyl or amide functional groups.
|-
| colspan="2" style="text-align: center;" | '''Non-Bonded Interactions'''
|-
| width="300" align="center" | '''Total Van der Waals Energy'''
! width="600" align="left" | The total Van der Waals energy term examines the intramolecular interactions such as repulsion or attraction between non-bonded atoms in the molecule. This term is crucial in determining the preferred conformation of the molecule.

MMFF94s employs the novel “Buffered-14-7”. The name is derived from a buffering constant and the 14th and 7th power dependencies of the repulsive and attractive energy in the equation.
|-
| width="300" align="center" | '''Total Electrostatic Energy'''
! width="600" align="left" | The total electrostatic energy functions take into account of the Coulombic potential and partial charge/dipole/atomic point charges interactions within the molecule.
|-

|}

 

== '''Part 2 : Conformational Analysis Using Molecular Mechanics''' ==
=== '''The Hydrogenation of Cyclopentadiene Dimer''' ===

==== '''Endo and exo adduct from the Dimerization of Cyclopentadiene''' ====
Cyclopentadiene will undergo dimerization by Diels-alder reaction to form either an endo or exo adduct.

[[File:XcwDimerization of CP.png|500px|center]]

==== '''Stereoselectivity of Dimerization of Cyclopentadiene''' ====
Although the exo adduct is thermodynamically more stable than the endo adduct, the endo adduct is form preferentially. Using the QST2 method, the transition state of the Diels Alder dimerization was found. It was discovered that due to the secondary orbital interactions in the endo transition state, the endo dimer is formed preferentially (the kinetic product). Hence, it is proven that the Diels Alder dimerization between two cyclopentadiene are kinetically controlled.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Transition State of Dimerization of Cyclopentadiene'''
| '''Imaginary Stretch Frequency (-881.25) of the Endo Transition State (click to animate)'''
| '''Secondary Orbital Interaction (Red overlapping orbitals)'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<uploadedFileContents>EndotsDCPD2.mol
</uploadedFileContents>
</jmolApplet></jmol>
| [[File:Xcwendotsimaginary.gif|300px|center]]
| [[File:XcwSecondary orbital interaction1.jpg|300px|center]]
|-
|}

 

==== '''Asynchronous Bond Formation of Dimerization of Cyclopentadiene''' ====

The initial study of the molecular orbitals of the transition states seemed a bit peculiar. Instead of getting a LUMO with symmetrical orbitals, the calculations showed a HOMO that is asymetric at the carbons where the new sigma bonds will be formed. Running an IRC further, it soon became clear that the asymmetry of the HOMO leads to an asychronous bond formation before leading to the product.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''IRC plot following the Endo Transition State '''
| '''IRC following the Endo Transition State (click to animate)'''
| '''Asymmetry of orbitals at the carbons where the new sigma bonds will be formed'''
|- align="center"
| [[File:XcwendotscyclopentadieneIRC.png|300px|center]]
| [[File:XcwendotsIRC.gif|300px|center]]
| [[File:XcwAsynchronous mo.jpg|300px|center]]
|-
|}

 

==== '''Comparison of Energies between the Endo and Exo adduct of Dicyclopentadiene''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Adduct of Dicyclopentadiene dimerization'''
| '''Exo Adduct of Dicyclopentadiene dimerization'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=19,atomno=1,atomno=2; color green;measure 19 1;measure 19 2;</script>
<uploadedFileContents>XcwEndodimer3.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>Exodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=7,atomno=17; color green;measure 17 7;</script>
<uploadedFileContents>XcwExodimer1.mol</uploadedFileContents>
</jmolApplet></jmol>
|-
|}

 

Using MMFF94s ab initio calculations, the energies for the exo dimer and the endo dimer are derived.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Exodimer'''
| '''55.374'''
| 3.543
| 30.772
| -2.041
| -2.728
| 0.015
| 12.800
| 13.014
|-
| '''Endodimer'''
| '''58.191'''
| 3.468
| 33.187
| -2.082
| -2.950
| 0.023
| 12.360
| 14.186
|-
|}

 

The MMFF94s steric energy (after minimization) for the exo dimer is lower than that of the endo dimer. This is reflected by the large difference for the EEE between the endo dimer and the exo dimer due to unfavourable steric repulsion between the two “arched down” cyclopentene rings.

==== '''Hydrogenation of Dicyclopentadiene''' ====

Hydrogenation of the endo dicyclopentadiene (DCPD) would lead to two potential products: dihydro product 1 and dihydro product 2.

[[File:XcwFormation of Dihydro products.png|500px|center]]

Using MMFF94s, the energy of the two dihydro products are calculated.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Dihydro Product 1'''
| '''50.123'''
| 3.308
| 30.864
| -1.927
| 0.060
| 0.015(2)
| 13.281
| 5.121
|-
| '''Dihydro Product 2'''
| '''41.257'''
| 2.823
| 24.685
| -1.657
| -0.379
| 0.000(2)
| 10.639
| 5.147
|-
| '''Tetrahydro Product'''
| '''39.042'''
| 2.730
| 25.151
| -1.676
| 1.287
| 0.000
| 11.551
| 0.000
|}

 

From the MMFF94s calculation, it can be seen that dihydro product 2 has a lower steric energy than dihydro product 1. Therefore, dihydro product 2 is the thermodynamic product for the hydrogenation of dicylopentadiene. And indeed, this was what was observed by Skala et al.. He observed that the first hydrogenation occur at the norborene part of the molecule (rate of hydrogenation several times faster than that in the cyclopentene ring)6. The first heat of hydrogenation at the norborene is 138.8 kJ/mol while the second hydrogenation at the cyclopentene right is 109.5 kJ/mol6.

From the above results, it is also obvious that tetrahydro product is much more stable than either dihydro product. And yet, studies have shown that the tetrahydro product will only form after prolonged hydrogenation under high temperature. However, subjecting DCPD to high temperature leads to low yield due to cracking of DCPD.

Since thermodynamically it is predicted to form favourably, the fact that it does not could only mean that the hydrogenation of DCPD to tetrahydrodicyclopentadiene (TH-DCPD) is kinetically controlled. Most possibly, the transition state of the hydrogenation of DCPD is highly unstable hence it is unlikely to form.

=== '''Atropisomerism in an Intermediate related to the Synthesis of Taxol''' ===

Atropisomerism is a type of stereoisomerism that is form as a result of hindered rotation about a single bond.

[[File:XcwAtropisomerism example.png|500px|center]]

In the case of the 6,6’-dinitro-2,2’-diphenic acid, rotation about the bonds joining the two substituted phenyl rings would have to overcome large steric interaction between the bulky substituents. The barrier of rotation is high enough for the two conformers to be isolated individually.

In the synthesis of taxol, one of the key intermediates exhibit atropisomerism.

==== '''Atropisomerism in Taxol Synthesis''' ====

For the key intermediate, rotation about the carbon-carbon bonds would lead to two types of atropisomers, each with either the carbonyl group poining upwards or downwards in relative to the bridge.

[[File:XcwIntermediate 9 and Intermediate 10.png|500px|center]]

Once again by using MMFF94s ab initio calculations, the steric energies for the two intermediates are illustrated as below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 9'''
| '''70.571'''
| 7.743
| 28.356
| -0.062
| 0.004
| 0.949
| 33.293
| 0.288
|-
| '''Intermediate 10'''
| '''60.553'''
| 7.599
| 18.838
| -0.139
| 0.199
| 0.844
| 33.269
| -0.056
|-

|}

 

Analyzing the data above, the largest energy difference between Intermediate 9 and Intermediate 10 stems from the EAB which is related to the strain of the ring. Intermediate 9 has an excess of 9.518 kcal/mol EAB as compared to Intermediate 10. This comes as a surprise as intermediate 9 is predicted to be more stable alkene.

The rationale behind the prediction of the stability of intermediate 9 stems from the fact that the through-space distance of the upward-pointing carbonyl oxygen with the carbon-carbon is further than the through space distance between the downward-pointing carbonyl oxygen with the -CH2-CH2- fragment at the norbornene part in intermediate 10.

==== '''Hyperstable Olefins''' ====

Intermediate 9 and Intermediate 10 does not react readily with other reagents during functionalization. This is due to the hyperstability effect found in hyperstable olefins.

Hyperstable olefins are alkenes that contain less strain in the ring (i.e. negative olefin strain values) compared to the parent hydrocarbon. To study this further, further MMFF94s calculation was done to compare Intermediate 10 with the parent hydrocarbon.

[[File:XcwIntermediate10andPH.png|500px|center]]

The energies that we calculated are tabulated as shown below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 10'''
| '''44.878 '''
| 5.211
| 15.488
| -0.267
| -1.655
| 0.998
| 25.014
| 0.088
|-
| '''Parent Hydrocarbon'''
| '''50.564'''
| 4.692
| 21.979
| 0.109
| -0.958
| 0.247
| 24.495
| 0.000
|-

|}

 

Scrutinizing the results, the largest energy difference between intermediate 10 and the parent hydrocarbon stems from the Total Angle Bending Energy, EAB. Since the Total Angle bending energy is related to the angle strain in the molecules, it is apparent that the parent hydrocarbon has more ring strain as compared to the bridgehead olefin.

== '''Part 3 : Spectroscopic Simulation Using Quantum Mechanics''' ==
=== '''Spectroscopy of an Intermediate Related to the Synthesis of Taxol''' ===

Molecule 17 and 18 are derivatives of intermediate 9 and 10. In this exercise, MMFF94s is used to predict the 1H and 13C NMR of molecule 17 and molecule 18.

[[File:XcwIntermediate17&18.png|500px|center]]

==== '''NMR Spectra of Molecule 17''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 17.mol
</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwHNMRMolecule 17 Chair Overall NMR.png|500px|center]]
| [[File:XcwHNMRMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.1825
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| The first three results were fairly straight forward to be deduced and correlate wit experimental data.

The hydrogen atom that is geminally attached to the carbon of the double bonds is the most deshielded due to the ring current anisotropic effect of the ring current

The second most deshielded hydrogen atom is the hydrogen atom on the methyl group on the bridge. The hydrogen atom is pointing directly to the oxygen atom of the carbonyl functional group.

The peaks with an integration height of 4 is assigned to the hydrogen atoms in the 1,3-dithiolane ring fragment.

Subsequent analysis of the 1H NMR became very complicated very quickly for two reasons:

1. Gaussian calculations showed some atoms with an integration height of 3. Comparing their file atom number and checking their chemical environment, it is not possible to find any correlation between them.

2. Some of the peaks in the literature remains unresolved and are given as multiplets or grouped together.

|- align="center"
| 52
| 3.1775
| 1
| '''2.99'''
|- align="center"
| 53,52,50,51
| 3.0867
| 4
| '''3.40-3.10'''
|- align="center"
| 42,43,39
| 2.7445
| 3
| ''' '''
|- align="center"
| 49
| 2.6187
| 1
| ''' '''
|- align="center"
| 34
| 2.4371
| 1
| ''' '''
|- align="center"
| 35
| 2.3782
| 1
| ''' '''
|- align="center"
| 40,37,26
| 2.2730
| 3
| ''' '''
|- align="center"
| 30
| 2.1566
| 1
| ''' '''
|- align="center"
| 36
| 2.1033
| 1
| ''' '''
|- align="center"
| 32,28
| 2.0259
| 2
| ''' '''
|- align="center"
| 25
| 1.8535
| 2
| ''' '''
|- align="center"
| 38,46,27
| 1.5898
| 3
| '''1.25'''
|- align="center"
| 29
| 1.4557
| 1
| ''' '''
|- align="center"
| 31
| 1.0123
| 1
| ''' '''
|- align="center"
| 44,48,45
| 0.9087
| 3
| '''1.10'''
|- align="center"
| 47
| 0.8354
| 1
| ''' '''
|- align="center"
| 33
| 0.5790
| 1
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 17 Chair Overall NMR2.png|500px|center]]
| [[File:XcwMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 216.2725
| 1
| '''218.79'''
| rowspan="10" style="text-align:center;"| [[File:XcwMolecule 17 image for CNMR.jpg|600px|center]]
|- align="center"
| 13
| 144.8626
| 1
| '''144.63'''
|- align="center"
| 14
| 124.7193
| 1
| '''125.33'''
|- align="center"
| 3
| 91.3340
| 1
| '''72.88'''
|- align="center"
| 2
| 60.9568
| 1
| '''56.19'''
|- align="center"
| 1
| 57.0811
| 1
| '''52.52'''
|- align="center"
| 10
| 52.4663
| 1
| '''48.50'''
|- align="center"
| 16
| 51.4857
| 1
| '''46.80'''
|- align="center"
| 9
| 46.9196
| 1
| '''45.76'''
|- align="center"
| 23
| 43.8647
| 1
| '''39.80'''
|- align="center"
| 22
| 41.9450
| 1
| '''38.81'''
| Comments
|- align="center"
| 4
| 41.8724
| 1
| '''35.85'''
| rowspan="9" style="text-align:left;"| The carbon bonded to the oxygen atom is the most deshielded, as is shown in the predicted values and the experimental values. There is a deviation between the values. Quite possibly, this is due to the fact that in reality, the carbonyl functional group is pointing slightly towards the equatorial position rather than a lateral position relative to the ring (as is in the input for Gaussian calculation)

Most of the 1CNMR values that was predicted by Gaussian are all within an acceptable range of deviation. However, there is carbon 3 that has significant deviation between the predicted value and experimental value.

Carbon 3 is the carbon bonded to the two sulphurs in the 1,3-dithiolane ring fragment. Such a huge deviation would possibly mean that the conformer that was given as input to Gaussian differs from the literature.

The above NMR spectra was corrected with a level of theory B3LYP/6-31G(d,p) using TMS as reference and in chloroform.

|- align="center"
| 15
| 35.4348
| 1
| '''32.66'''
|- align="center"
| 11
| 31.1964
| 1
| '''28.79'''
|- align="center"
| 6
| 28.9432
| 1
| '''28.29'''
|- align="center"
| 7
| 28.3640
| 1
| '''26.88'''
|- align="center"
| 12
| 27.3767
| 1
| '''25.66'''
|- align="center"
| 17
| 26.3311
| 1
| '''23.86'''
|- align="center"
| 15
| 24.5483
| 1
| '''20.96'''
|- align="center"
| 18
| 19.7788
| 1
| '''18.71'''
|-
|}
 

==== '''NMR Spectra of Molecule 18''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 18 Boat for Image2.mol</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"-
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 18 Chair Overall NMR.png|500px|center]]
| [[File:Molecule 18 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.2832
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| ''' '''
|- align="center"
| 50
| 3.3175
| 1
| rowspan="4" style="text-align:centre;"| '''3.00-2.70'''
|- align="center"
| 52
| 3.2153
| 1
|- align="center"
| 51,53
| 3.1161
| 2
|- align="center"
| 34,43
| 2.8606
| 2
|- align="center"
| 38
| 2.4549
| 1
| ''' '''
|- align="center"
| 42
| 2.3968
| 1
| ''' '''
|- align="center"
| 25,29,26
| 2.2796
| 3
| ''' '''
|- align="center"
| 39
| 2.0844
| 1
| ''' '''
|- align="center"
| 40,36
| 1.9699
| 2
| ''' '''
|- align="center"
| 37,24
| 1.8519
| 2
| ''' '''
|- align="center"
| 31,27
| 1.6780
| 2
| ''' '''
|- align="center"
| 28
| 1.6175
| 1
| ''' '''
|- align="center"
| 46,49
| 1.4979
| 2
| ''' '''
|- align="center"
| 35
| 1.4150
| 1
| ''' '''
|- align="center"
| 32
| 1.3531
| 1
| ''' '''
|- align="center"
| 48
| 1.1606
| 1
| ''' '''
|- align="center"
| 33,30,47
| 1.0653
| 3
| '''1.03'''
|- align="center"
| 44,45
| 0.9643
| 2
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 18 Full Spectra'''
| '''13C NMR Spectra of Molecule 18 Truncated Spectra'''
|- align="center"
| [[File:XcwMolecule 18 Boat Overall NMR.png|500px|center]]
| [[File:XcwMolecule 18 Boat zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
|- align="center"
| 8
| 211.8325
| 1
| '''211.49'''
|- align="center"
| 13
| 148.6673
| 1
| '''148.72'''
|- align="center"
| 14
| 118.8373
| 1
| '''120.90'''
|- align="center"
| 3
| 89.0869
| 1
| '''74.61'''
|- align="center"
| 2
| 67.8886
| 1
| '''60.53'''
|- align="center"
| 1
| 56.1133
| 1
| '''51.30'''
|- align="center"
| 10
| 55.5998
| 1
| '''50.94'''
|- align="center"
| 16
| 50.1124
| 1
| '''45.53'''
|- align="center"
| 22
| 48.2030
| 1
| '''43.28'''
|- align="center"
| 23
| 44.2222
| 1
| '''40.82'''
|- align="center"
| 4
| 42.0354
| 1
| '''38.73'''
| Comments
|- align="center"
| 9
| 37.5865
| 1
| '''36.78'''
| rowspan="9" style="text-align:left;"| ''' '''
|- align="center"
| 6
| 35.3106
| 1
| '''35.47'''
|- align="center"
| 15
| 31.0459
| 1
| '''30.84'''
|- align="center"
| 7
| 28.8476
| 1
| '''30.00'''
|- align="center"
| 12
| 28.6623
| 1
| '''25.56'''
|- align="center"
| 17
| 25.7393
| 1
| '''25.35'''
|- align="center"
| 11
| 25.2603
| 1
| '''22.21'''
|- align="center"
| 18
| 23.3944
| 1
| '''21.39'''
|- align="center"
| 5
| 21.0478
| 1
| '''19.83'''
|-
|}
 

== '''Part 4 : Analysis of the Properties of the Synthesized Alkene Epoxides''' ==
=== '''The two catalytics systems''' ===

Assymmetric epoxidation of prochiral alkenes may lead to product with different stereochemical outcome as illustrated as below. To solve this problem, different types of asymmetric epoxidation catalyst have been synthesized. In this study, we shall be focusing on Shi asymmetric fructose catalyst as well as Jacobsen asymmetric catalyst.

[[File:Asymmetric catalyst.png|400px|center]]

==== ''' The Shi Asymmetric Fructose Catalyst''' ====

Molecule 21 is the stable precursor of molecule 22, the active catalyst. Molecule 21 can be converted to molecule 22 by using either persulfuric acid or potassium peroxymonosulphate.

[[File:Molecule 21 to 23.png|400px|center]]

The transition state of the Shi epoxidation was a subject of debate for a few moments. However, recent studies have led to the conclusion that the spiro transition state is more favored than the planar transition state. The spiro transition state is the transition that has its dioxirane perpendicularly bisecting the alkene double bond. This is thought to be more favourable due to interactions between the lone pairs of the oxygen with the LUMO of the alkene.

[[File:Spiro and planar ts.png|500px|center]]

==== ''' The Jacobsen Asymmetric Catalyst''' ====

Molecule 23 is the stable precursor of molecule 24, the active catalyst. Molecule 23 can be converted to molecule 24 by using sodium perchlorate.

[[File:Salen, 23 and 24.png|400px|center]]

Jacobsen catalyst is biphasic. The first phase involves the transfer of oxygen to molecule 23. Sodium perchlorate oxidizes Mn(III) to Mn(V).

In the second step, Jacobsen catalyst acts via a radical mechanism. It is thought to be so because epoxidation of trans-alkene by Jacobsen catalyst yield cis-alkene as well. A radical mechanism will lead to the lost of stereochemical information of the molecule.

=== ''' Crystal structure of the two catalyst''' ===
==== '''Molecule 21''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 21'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 21 strucutre.png|600px|center]]'''
|-
| style="text-align:center;" width="150" | ''' Bond '''
| style="text-align:center;" width="150"| ''' Bond Lenghts (Angstrom)'''
| style="text-align:center;" | ''' Evaluation'''
|-
| style="text-align:center;"| ''' O1-C1 '''
| style="text-align:center;"| ''' 1.400'''
| rowspan="10" style="text-align:left;"| [[File:Molecule 21 2.png|300px|center]]

The normal bond length of an C-O bond is 1.430 angstrom.

The most interesting aspect here is O4 and O2. The lone pair of O4 is antiperplanar to the sigma* orbital of the carbonyl group while the lone pair of O2 is anti periplanar to the carbonyl pi* orbital. Donation of electron can occur because of the correct symmetry. Due to the mixing of the orbitals, the C2-O2 and C4-O4 has been conferred with a certain degree of double bond character.

However, due to the lone pair on oxygen being now donated to the carbonyl antibonding orbitals, the O2 and O4 is slightly “electron deficient” and electron density will be pulled away from O2 and O4. That would explain why the bond length increase for O2-C7 and O4-C10. Increase in bond length is an indicator of the weakening of the bond.
|-
| style="text-align:center;"|'''O1-C7'''
| style="text-align:center;"|'''1.413'''
|-
| style="text-align:center;"|'''O2-C7'''
| style="text-align:center;"|'''1.441'''
|-
| style="text-align:center;"|'''O2-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O4-C4'''
| style="text-align:center;"|'''1.396'''
|-
| style="text-align:center;"|'''O4-C10'''
| style="text-align:center;"|'''1.439'''
|-
| style="text-align:center;"|'''O5-C10'''
| style="text-align:center;"|'''1.409'''
|-
| style="text-align:center;"|'''O5-C5'''
| style="text-align:center;"|'''1.416'''
|-
| style="text-align:center;"|'''O6-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O6-C6'''
| style="text-align:center;"|'''1.420'''
|-
|}
 

==== '''Molecule 23''' ====

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 23'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 23 struc.png|600px|center]]'''
|-
| The most outstanding feature from this molecule is the fact that is adopt a puckered form of the square base pyramidal form. This is no surprise that the molecule is almost planar due to the electron delocalization around each side of the salen ligand.

The tery-butyl hydrogen are oriented closely to one another. Non-covalent interaction studies indicated that repulsion would occur for H---H bond length that are less than 2.1 angstrom while favourable interaction may be dominant with bond length above 2.4 angstrom. It was discovered that all 4 hydrogens have bond length more than 2.4 angstrom hence there should not be any significant repulsion between them. Instead, certain amount of attractive force will ensue and that contributes to the overall stability of the molecule

|-
|}
 

=== ''' The calculated NMR properties of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | '''
Shift (ppm) Degeneracy
7.4891704929 4.0000
7.2988172444 1.0000
3.6627082199 1.0000
3.1170156088 1.0000
2.5382383043 1.0000 '''
| width="100" | '''
Shift (ppm) Degeneracy
7.4892967873 4.0000
7.2987138125 1.0000
3.6632689921 1.0000
3.1151709109 1.0000
2.5339209685 1.0000

'''
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Styrene R HNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Styrene S HNMR.png|400px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | '''
Shift (ppm) Degeneracy
135.1098747604 1.0000
124.1186533632 1.0000
123.4150641684 1.0000
122.9584694331 2.0000
118.2653162569 1.0000
54.0265785300 1.0000
53.4853575062 1.0000 '''
| width="100" | '''
Shift (ppm) Degeneracy
135.1323742030 1.0000
124.1343038829 1.0000
123.4137039868 1.0000
122.9558208084 2.0000
118.2690258882 1.0000
54.0599580762 1.0000
53.4684920923 1.0000
'''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | ''' [[File:Styrene R CNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Styrene S CNMR.png|400px|center|]]'''
|-
| width="100" | ''' '''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | ''' Shift (ppm) Degeneracy
7.5705724829 2.0000
7.4791732656 8.0000
3.5390102503 2.0000
| width="100" | ''' Shift (ppm) Degeneracy
7.5705651164 2.0000
7.4791779628 8.0000
3.5374502607 2.0000
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Stilbene RR HNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|400px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | ''' Shift (ppm) Degeneracy
134.0942417727 2.0000
124.2206838184 2.0000
123.5192390024 2.0000
123.2125901307 2.0000
123.0785800542 2.0000
118.2583039589 2.0000
66.4212770637 2.0000 '''
| width="100" | ''' Shift (ppm) Degeneracy
134.0899175142 2.0000
124.2224499528 2.0000
123.5180152862 2.0000
123.2113538650 2.0000
123.0745448885 2.0000
118.2635789492 2.0000
66.4249347217 2.0000 '''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | ''' [[File:Stilbene RR CNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|400px|center|]]'''
|-
|}

 

=== ''' Assigning the absolute configuration of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''Predicted ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg'''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg '''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental conditions'''
| width="100" | '''1.00g/100ml, chloroform, 21 degree Celcisus, 589 nm wavelength '''
| width="100" | '''1.02g/100ml (99% ee), chloroform, 25 degree Celsius, 589 nm wavelength '''
| width="100" | '''1.01g/100ml, ethanol, 22 degree Celsius, 589 nm wavelength '''
| width="100" | '''0.6g/100ml, ethanol, 20 degree Celsius, 589 nm wavelength '''
|- align="left"
| width="100" | ''' Predicted VCD Spectrum'''
| width="100" | '''[[File:Styrene R VCD.png|200px|center|]] '''
| width="100" | '''[[File:Styrene S VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene RR VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene SS VCD.png|200px|center|]]'''
|-
|}

 

All the assignments given in the literature reports are correct although the predicted value differs slightly with the experimental values

=== ''' Analysis of the Transition State for Reactions''' ===
==== '''Predicting Enantiomeric Excess based on Transition State energies''' ====

One of the energy output from Gaussian calculation is the “sum of electronic and thermal free energies”. This is Gibbs Free Energy at 298.15K and 1 atm.

Using this term and invoking a variant of the Curtin-Hammett Principle, it is possible to calculate a predicted enantiomeric excess of one enantiomer over the other.

[[File:Ee and transition state energy.png|800px|center]]

Using the derivations from above and equation (4), we analyze the enantiomeric excess of beta-methyl styrene and the results are tabulated as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1343.022970'''
| width="100" | '''-1343.017942'''
| width="150" | '''-0.005028'''
| width="150" | '''4.88E-03'''
| width="150" | '''99.03'''
|- align="center"
| width="100" | '''-1343.019233'''
| width="100" | '''-1343.015603'''
| width="150" | '''-0.003630'''
| width="150" | '''2.14E-02'''
| width="150" | '''95.80'''
|- align="center"
| width="100" | '''-1343.029272'''
| width="100" | '''-1343.023766'''
| width="150" | '''-0.005506'''
| width="150" | '''2.94E-03'''
| width="150" | '''99.41'''
|- align="center"
| width="100" | '''-1343.032443'''
| width="100" | '''-1343.024742'''
| width="150" | '''-0.007701'''
| width="150" | '''2.88E-04'''
| width="150" | '''99.94'''
|-
|}

 

The above hartree units are converted to J/mol for calculation of K where 1 hartress = 4.3597E-18

Studying all the free energies of the (R,R) series and compare them with the (S,S) series, it comes as no surprise that (R,R) product is favoured over (S,S) product as (R,R) is more stable. Indeed, this corresponds with the literature value reporting 92% ee of (R,R) products over that of (S,S).

==== '''Analysis of the Transition State of Epoxidation''' ====
==== '''Shi Fructose Catalyst''' ====
For this section, I will be analyzing the the transition state of 1) styrene and 2) trans-stilbene with the Shi fructose catalyst.

===== '''(R) and (S)-styrene transition state''' =====
The transition state for the formation of (R)-styrene oxide and (S)-styrene oxide are given as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R)-styrene oxide'''
| width="150" | '''(S)-styrene oxide'''
|- align="center"
| width="150" | ''' Structure of Catalyst '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide R.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide S ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| [[File:Steric shi fructose R.png|450px|center]]
| [[File:Steric shi fructose S.png|450px|center]]
|-
|}

 

In the transition state for (R)-styrene, it was discovered that the Re face is reacting with the oxygen of the dioxirane. The phenyl ring is oriented endo with respect to the fructose catalyst. However, the (S)-styrene is reacting at the Si face and the phenyl ring is oriented exo relative to the catalyst.

The approach taken by (R)-styrene and (S)-styrene are restricted to only one due to steric interactions. Therefore, the epoxidation of both styrenes by the Shi catalyst will be stereospecific and retains all the stereochemical information of the reactant. However, whether or not (R)-styrene oxide or (S)-styrene oxide is form is dependent on the relative energies of the transition state. The more stable the transition state, the more likely the product of the transition state will be formed.

So in order to examine this, an example of transition state of both styrenes with Shi catalyst are obtained and analyzed.
 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1303.736813'''
| width="100" | '''-1303.727673'''
| width="150" | '''-0.00914'''
| width="150" | '''6.28E-05'''
| width="150" | '''99.99'''

|-
|}

 

From the above, we can see the predicted high enantiopurity of the reaction favoring the (R) product because of the lower energy of the transition states. To understand the reason, we have to turn to non-covalent interaction (NCI) analysis.

[[File:NCI shi fructose styrene.png|700px|center]]

To complement the NCI analysis, a QTAIM (Quantum Theory of Atoms in Molecules) analysis is conducted as well.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''(R)-styrene transition state'''
| width="200" | '''(S)-styrene transition state'''
|- align="center"
| width="100" | '''[[File:QTAIM R.png|400px|center]]'''
| width="100" | '''[[File:QTAIM S.png|400px|center]]'''
|- align="center"
| colspan="2" width="100" | '''Comments'''
|-
| colspan="2" width="100" | '''Unsurprisingly, QTAIM analysis has also shown that (R)-styrene/Shi catalyst has more interactions with one another. While (R)-styrene has 2 strong interactions, (S)-styrene has only one with the catalyst. Besides, the phenyl ring of (R)-styrene also confers additional positive interaction with the catalyst. QTAIM analysis has also show several interactions between the C=C geminal hydrogen of (R)-styrene intreacting with the oxygen atoms on the dioxacyclopentane ring'''
|-
|}

 

===== '''(R,R) and (S,S)-Stilbene transition state''' =====

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R,R)-Stilbene oxide'''
| width="150" | '''(S,S)-Stilbene oxide'''
|- align="center"
| width="150" | ''' Structure of Transition State '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Stilbene RR ts.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>SS stilbene oxide ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| colspan="2" | [[File:Shi fructose stilbene.png|700px|center]]

|-
|}

 

However, unlike styrene, trans-stilbene seems to approach perpendicularly to the dioxirane. This is proposed to be due to the steric interactions (marked in purple). Based on first inspection, it seems that (S,S)-Stilbene oxide has more steric interactions than (R,R)-Stilbene oxide. Although unsubstantial, it seems like my guess was correct. The (R,R)-stilbene/Shi catalyst transition state is lower in energy.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1534.687808'''
| width="100" | '''-1534.683440'''
| width="150" | '''0.004368'''
| width="150" | '''9.08E-3'''
| width="150" | '''98.20'''

|-
|}

 

NCI Analysis is also done for trans-stilbene

[[File:NCI stilbene.png|700px|center]]

==== '''Jacobsen Catalyst''' ====

For this section, cis-beta methyl styrene transition state will be analyzed.

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-3383.259559'''
| width="100" | '''-3383.251060'''
| width="150" | '''-0.008499'''
| width="150" | '''1.24E-04'''
| width="150" | '''99.98'''
|- align="center"
| width="100" | '''-3383.253442'''
| width="100" | '''-3383.250270'''
| width="150" | '''-0.003172'''
| width="150" | '''3.48E-02'''
| width="150" | '''93.27'''
|-
|}

 

As is obvious from here, the (S,R) transition state is more stable than the (R,S) transition state. Both transition states are exo with respect to the catalyst.

It is not immediately apparent just by looking at the molecule to determine which spatial groups have interactions with one another. Therefore, an NCI analysis is conducted again.

[[File:NCI Jacobsen.png|700px|center]]

Rep:Mod:Computationalreport1C

2013-11-21T23:33:53Z

Xc2611: /* The calculated NMR properties of the product */

= '''Synthesis and Computational Lab: 1C''' =
== '''Part 1: Introduction to Molecular Mechanics''' ==
=== '''Introduction to MMFF94 and MMFF94s''' ===

With the improvement of computational data and computer processing power, the usage of molecular mechanics/dynamics forcefield has become very integrated in predicting properties of chemical molecules. A molecular mechanics/dynamics forcefield should be able to predict characteristics such as molecular geometries, conformational/stereoisomeric energies, vibrational frequencies etc. to a reasonable accuracy as compared to experimental-derived values.

Building on work from Kollman et al. s’ AMBER forcefield and Allinger et al. s’ MM1, MM2, MM3 and MM4, Merck Research Laboratories have managed to optimized and improved the previous computational algorithms and produced MMFF94 (Merck Molecular Force Field 94). One of the most prominent advantages of MMFF94 over other preceeding work is its enhanced prediction accuracy. The reason lies in the fact that MMFF94’s core parameterization utilizes an unprecedently large amount of computational data obtained from ab initio calculations1.

Subsequently after the development of MMFF94, a new “static” variant of the MMFF was introduced i.e. the MMFF94s. Unlike MMFF94 that was developed for the use of molecular dynamics simulations (which can be expensive), MMFF94s was developed with the purpose of energy minimization studies in mind. Although both systems provide identical results for most systems, they differ for amides and unsaturated amines which contain resonance-delocalized trigonal nitrogen atoms2.

In this computational exercise, MMFF94s is used predominantly as oppose to the alternative Universal Force Field (UFF). Although versatile across the entire periodic table, UFF is derived from simple rules and atomic parameters such as fixed hybridization that increases the likelihood of erroneous structural and energetic predictions3.

=== '''Forms of MMFF94s''' ===

Steric energy of a molecule is the energy arise due to its geometry or conformation. Energy minimization of steric energy process ensures that the molecule is in its lowest energy conformation.

MMFF94s assumes that the total steric energy of a molecule can be found by the sum of a few specific interactions in a molecule.

ES = EBS + EAB + E SB + ET + EOOP + EVdW + EEE

'''where the bonded interactions are:'''

ES = Total Steric energy

EBS = Total Bond Stretching energy

EAB = Total Angle Bending energy

ESB = Total Stretch Bending energy

ET = Total Torsional Energy

EOOP = Total Out-Of-Plane Bending energy, and

'''where the non-bonded interactions are:'''

EVdW = Total Van der Waals Energy

EEE = Total Electrostatic Energy

{| border="1" cellspacing="1" cellpadding="10"
|-
| width="300" align="center" | '''Types of Energies'''
! width="600" align="center" | '''Explanation'''
|-
| colspan="2" style="text-align: center;" | '''Bonded Interactions'''
|-
| width="300" align="center" | '''Total Bond Stretching Energy'''
! width="600" align="left" | The total bond stretching energy is related to the vibration energy of the molecules in comparison to the equilibrium bond length. Whenever a bond deviates from the equilibrium bond length, the energy value increases.

MMFF94s uses a quartic function that has the force constant term (relate to bond strength). The quartic function term is superior to the cubic function term (used in MM2) in the sense that it avoid the “cubic stretch catastrophe” where progressive elongation of molecule bond length leads to negative infinity.
|-
| width="300" align="center" | '''Total Angle Bending Energy'''
! width="600" align="left" | Similar to Total Bond Stretching Energy, the total angle bending energy is also related to the vibration energy of the molecules about the equilibrium bond length. However, unlike EBS that measures the bond strength, EAB is associated with the stiffness of the molecules based on the Hookiean potential. Whenever bond angles deviate from the norm during vibration, this energy term increases as well.
|-
| width="300" align="center" | '''Total Stretch-Bending Energy'''
! width="600" align="left" | This energy term takes into account of the energy due to increase in bond length when bond angle between two atoms changes.
|-
| width="300" align="center" | '''Total Torsional Energy'''
! width="600" align="left" | Total torsional energy is the energy required for intermolecular rotation about the bonds. In molecule mechanics, however, this term is often used as a correction that must be added or subtracted to the total energy of the molecule to fit a quantum mechanical calculation about the dihedral angles of bonds.
|-
| width="300" align="center" | '''Total Out-Of-Plane Bending Energy'''
! width="600" align="left" | This energy term refers to the energy needed to deform the dihedral angle (zero degrees) of a planar group of atoms such as carbonyl or amide functional groups.
|-
| colspan="2" style="text-align: center;" | '''Non-Bonded Interactions'''
|-
| width="300" align="center" | '''Total Van der Waals Energy'''
! width="600" align="left" | The total Van der Waals energy term examines the intramolecular interactions such as repulsion or attraction between non-bonded atoms in the molecule. This term is crucial in determining the preferred conformation of the molecule.

MMFF94s employs the novel “Buffered-14-7”. The name is derived from a buffering constant and the 14th and 7th power dependencies of the repulsive and attractive energy in the equation.
|-
| width="300" align="center" | '''Total Electrostatic Energy'''
! width="600" align="left" | The total electrostatic energy functions take into account of the Coulombic potential and partial charge/dipole/atomic point charges interactions within the molecule.
|-

|}

 

== '''Part 2 : Conformational Analysis Using Molecular Mechanics''' ==
=== '''The Hydrogenation of Cyclopentadiene Dimer''' ===

==== '''Endo and exo adduct from the Dimerization of Cyclopentadiene''' ====
Cyclopentadiene will undergo dimerization by Diels-alder reaction to form either an endo or exo adduct.

[[File:XcwDimerization of CP.png|500px|center]]

==== '''Stereoselectivity of Dimerization of Cyclopentadiene''' ====
Although the exo adduct is thermodynamically more stable than the endo adduct, the endo adduct is form preferentially. Using the QST2 method, the transition state of the Diels Alder dimerization was found. It was discovered that due to the secondary orbital interactions in the endo transition state, the endo dimer is formed preferentially (the kinetic product). Hence, it is proven that the Diels Alder dimerization between two cyclopentadiene are kinetically controlled.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Transition State of Dimerization of Cyclopentadiene'''
| '''Imaginary Stretch Frequency (-881.25) of the Endo Transition State (click to animate)'''
| '''Secondary Orbital Interaction (Red overlapping orbitals)'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<uploadedFileContents>EndotsDCPD2.mol
</uploadedFileContents>
</jmolApplet></jmol>
| [[File:Xcwendotsimaginary.gif|300px|center]]
| [[File:XcwSecondary orbital interaction1.jpg|300px|center]]
|-
|}

 

==== '''Asynchronous Bond Formation of Dimerization of Cyclopentadiene''' ====

The initial study of the molecular orbitals of the transition states seemed a bit peculiar. Instead of getting a LUMO with symmetrical orbitals, the calculations showed a HOMO that is asymetric at the carbons where the new sigma bonds will be formed. Running an IRC further, it soon became clear that the asymmetry of the HOMO leads to an asychronous bond formation before leading to the product.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''IRC plot following the Endo Transition State '''
| '''IRC following the Endo Transition State (click to animate)'''
| '''Asymmetry of orbitals at the carbons where the new sigma bonds will be formed'''
|- align="center"
| [[File:XcwendotscyclopentadieneIRC.png|300px|center]]
| [[File:XcwendotsIRC.gif|300px|center]]
| [[File:XcwAsynchronous mo.jpg|300px|center]]
|-
|}

 

==== '''Comparison of Energies between the Endo and Exo adduct of Dicyclopentadiene''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Adduct of Dicyclopentadiene dimerization'''
| '''Exo Adduct of Dicyclopentadiene dimerization'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=19,atomno=1,atomno=2; color green;measure 19 1;measure 19 2;</script>
<uploadedFileContents>XcwEndodimer3.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>Exodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=7,atomno=17; color green;measure 17 7;</script>
<uploadedFileContents>XcwExodimer1.mol</uploadedFileContents>
</jmolApplet></jmol>
|-
|}

 

Using MMFF94s ab initio calculations, the energies for the exo dimer and the endo dimer are derived.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Exodimer'''
| '''55.374'''
| 3.543
| 30.772
| -2.041
| -2.728
| 0.015
| 12.800
| 13.014
|-
| '''Endodimer'''
| '''58.191'''
| 3.468
| 33.187
| -2.082
| -2.950
| 0.023
| 12.360
| 14.186
|-
|}

 

The MMFF94s steric energy (after minimization) for the exo dimer is lower than that of the endo dimer. This is reflected by the large difference for the EEE between the endo dimer and the exo dimer due to unfavourable steric repulsion between the two “arched down” cyclopentene rings.

==== '''Hydrogenation of Dicyclopentadiene''' ====

Hydrogenation of the endo dicyclopentadiene (DCPD) would lead to two potential products: dihydro product 1 and dihydro product 2.

[[File:XcwFormation of Dihydro products.png|500px|center]]

Using MMFF94s, the energy of the two dihydro products are calculated.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Dihydro Product 1'''
| '''50.123'''
| 3.308
| 30.864
| -1.927
| 0.060
| 0.015(2)
| 13.281
| 5.121
|-
| '''Dihydro Product 2'''
| '''41.257'''
| 2.823
| 24.685
| -1.657
| -0.379
| 0.000(2)
| 10.639
| 5.147
|-
| '''Tetrahydro Product'''
| '''39.042'''
| 2.730
| 25.151
| -1.676
| 1.287
| 0.000
| 11.551
| 0.000
|}

 

From the MMFF94s calculation, it can be seen that dihydro product 2 has a lower steric energy than dihydro product 1. Therefore, dihydro product 2 is the thermodynamic product for the hydrogenation of dicylopentadiene. And indeed, this was what was observed by Skala et al.. He observed that the first hydrogenation occur at the norborene part of the molecule (rate of hydrogenation several times faster than that in the cyclopentene ring)6. The first heat of hydrogenation at the norborene is 138.8 kJ/mol while the second hydrogenation at the cyclopentene right is 109.5 kJ/mol6.

From the above results, it is also obvious that tetrahydro product is much more stable than either dihydro product. And yet, studies have shown that the tetrahydro product will only form after prolonged hydrogenation under high temperature. However, subjecting DCPD to high temperature leads to low yield due to cracking of DCPD.

Since thermodynamically it is predicted to form favourably, the fact that it does not could only mean that the hydrogenation of DCPD to tetrahydrodicyclopentadiene (TH-DCPD) is kinetically controlled. Most possibly, the transition state of the hydrogenation of DCPD is highly unstable hence it is unlikely to form.

=== '''Atropisomerism in an Intermediate related to the Synthesis of Taxol''' ===

Atropisomerism is a type of stereoisomerism that is form as a result of hindered rotation about a single bond.

[[File:XcwAtropisomerism example.png|500px|center]]

In the case of the 6,6’-dinitro-2,2’-diphenic acid, rotation about the bonds joining the two substituted phenyl rings would have to overcome large steric interaction between the bulky substituents. The barrier of rotation is high enough for the two conformers to be isolated individually.

In the synthesis of taxol, one of the key intermediates exhibit atropisomerism.

==== '''Atropisomerism in Taxol Synthesis''' ====

For the key intermediate, rotation about the carbon-carbon bonds would lead to two types of atropisomers, each with either the carbonyl group poining upwards or downwards in relative to the bridge.

[[File:XcwIntermediate 9 and Intermediate 10.png|500px|center]]

Once again by using MMFF94s ab initio calculations, the steric energies for the two intermediates are illustrated as below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 9'''
| '''70.571'''
| 7.743
| 28.356
| -0.062
| 0.004
| 0.949
| 33.293
| 0.288
|-
| '''Intermediate 10'''
| '''60.553'''
| 7.599
| 18.838
| -0.139
| 0.199
| 0.844
| 33.269
| -0.056
|-

|}

 

Analyzing the data above, the largest energy difference between Intermediate 9 and Intermediate 10 stems from the EAB which is related to the strain of the ring. Intermediate 9 has an excess of 9.518 kcal/mol EAB as compared to Intermediate 10. This comes as a surprise as intermediate 9 is predicted to be more stable alkene.

The rationale behind the prediction of the stability of intermediate 9 stems from the fact that the through-space distance of the upward-pointing carbonyl oxygen with the carbon-carbon is further than the through space distance between the downward-pointing carbonyl oxygen with the -CH2-CH2- fragment at the norbornene part in intermediate 10.

==== '''Hyperstable Olefins''' ====

Intermediate 9 and Intermediate 10 does not react readily with other reagents during functionalization. This is due to the hyperstability effect found in hyperstable olefins.

Hyperstable olefins are alkenes that contain less strain in the ring (i.e. negative olefin strain values) compared to the parent hydrocarbon. To study this further, further MMFF94s calculation was done to compare Intermediate 10 with the parent hydrocarbon.

[[File:XcwIntermediate10andPH.png|500px|center]]

The energies that we calculated are tabulated as shown below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 10'''
| '''44.878 '''
| 5.211
| 15.488
| -0.267
| -1.655
| 0.998
| 25.014
| 0.088
|-
| '''Parent Hydrocarbon'''
| '''50.564'''
| 4.692
| 21.979
| 0.109
| -0.958
| 0.247
| 24.495
| 0.000
|-

|}

 

Scrutinizing the results, the largest energy difference between intermediate 10 and the parent hydrocarbon stems from the Total Angle Bending Energy, EAB. Since the Total Angle bending energy is related to the angle strain in the molecules, it is apparent that the parent hydrocarbon has more ring strain as compared to the bridgehead olefin.

== '''Part 3 : Spectroscopic Simulation Using Quantum Mechanics''' ==
=== '''Spectroscopy of an Intermediate Related to the Synthesis of Taxol''' ===

Molecule 17 and 18 are derivatives of intermediate 9 and 10. In this exercise, MMFF94s is used to predict the 1H and 13C NMR of molecule 17 and molecule 18.

[[File:XcwIntermediate17&18.png|500px|center]]

==== '''NMR Spectra of Molecule 17''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 17.mol
</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwHNMRMolecule 17 Chair Overall NMR.png|500px|center]]
| [[File:XcwHNMRMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.1825
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| The first three results were fairly straight forward to be deduced and correlate wit experimental data.

The hydrogen atom that is geminally attached to the carbon of the double bonds is the most deshielded due to the ring current anisotropic effect of the ring current

The second most deshielded hydrogen atom is the hydrogen atom on the methyl group on the bridge. The hydrogen atom is pointing directly to the oxygen atom of the carbonyl functional group.

The peaks with an integration height of 4 is assigned to the hydrogen atoms in the 1,3-dithiolane ring fragment.

Subsequent analysis of the 1H NMR became very complicated very quickly for two reasons:

1. Gaussian calculations showed some atoms with an integration height of 3. Comparing their file atom number and checking their chemical environment, it is not possible to find any correlation between them.

2. Some of the peaks in the literature remains unresolved and are given as multiplets or grouped together.

|- align="center"
| 52
| 3.1775
| 1
| '''2.99'''
|- align="center"
| 53,52,50,51
| 3.0867
| 4
| '''3.40-3.10'''
|- align="center"
| 42,43,39
| 2.7445
| 3
| ''' '''
|- align="center"
| 49
| 2.6187
| 1
| ''' '''
|- align="center"
| 34
| 2.4371
| 1
| ''' '''
|- align="center"
| 35
| 2.3782
| 1
| ''' '''
|- align="center"
| 40,37,26
| 2.2730
| 3
| ''' '''
|- align="center"
| 30
| 2.1566
| 1
| ''' '''
|- align="center"
| 36
| 2.1033
| 1
| ''' '''
|- align="center"
| 32,28
| 2.0259
| 2
| ''' '''
|- align="center"
| 25
| 1.8535
| 2
| ''' '''
|- align="center"
| 38,46,27
| 1.5898
| 3
| '''1.25'''
|- align="center"
| 29
| 1.4557
| 1
| ''' '''
|- align="center"
| 31
| 1.0123
| 1
| ''' '''
|- align="center"
| 44,48,45
| 0.9087
| 3
| '''1.10'''
|- align="center"
| 47
| 0.8354
| 1
| ''' '''
|- align="center"
| 33
| 0.5790
| 1
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 17 Chair Overall NMR2.png|500px|center]]
| [[File:XcwMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 216.2725
| 1
| '''218.79'''
| rowspan="10" style="text-align:center;"| [[File:XcwMolecule 17 image for CNMR.jpg|600px|center]]
|- align="center"
| 13
| 144.8626
| 1
| '''144.63'''
|- align="center"
| 14
| 124.7193
| 1
| '''125.33'''
|- align="center"
| 3
| 91.3340
| 1
| '''72.88'''
|- align="center"
| 2
| 60.9568
| 1
| '''56.19'''
|- align="center"
| 1
| 57.0811
| 1
| '''52.52'''
|- align="center"
| 10
| 52.4663
| 1
| '''48.50'''
|- align="center"
| 16
| 51.4857
| 1
| '''46.80'''
|- align="center"
| 9
| 46.9196
| 1
| '''45.76'''
|- align="center"
| 23
| 43.8647
| 1
| '''39.80'''
|- align="center"
| 22
| 41.9450
| 1
| '''38.81'''
| Comments
|- align="center"
| 4
| 41.8724
| 1
| '''35.85'''
| rowspan="9" style="text-align:left;"| The carbon bonded to the oxygen atom is the most deshielded, as is shown in the predicted values and the experimental values. There is a deviation between the values. Quite possibly, this is due to the fact that in reality, the carbonyl functional group is pointing slightly towards the equatorial position rather than a lateral position relative to the ring (as is in the input for Gaussian calculation)

Most of the 1CNMR values that was predicted by Gaussian are all within an acceptable range of deviation. However, there is carbon 3 that has significant deviation between the predicted value and experimental value.

Carbon 3 is the carbon bonded to the two sulphurs in the 1,3-dithiolane ring fragment. Such a huge deviation would possibly mean that the conformer that was given as input to Gaussian differs from the literature.

The above NMR spectra was corrected with a level of theory B3LYP/6-31G(d,p) using TMS as reference and in chloroform.

|- align="center"
| 15
| 35.4348
| 1
| '''32.66'''
|- align="center"
| 11
| 31.1964
| 1
| '''28.79'''
|- align="center"
| 6
| 28.9432
| 1
| '''28.29'''
|- align="center"
| 7
| 28.3640
| 1
| '''26.88'''
|- align="center"
| 12
| 27.3767
| 1
| '''25.66'''
|- align="center"
| 17
| 26.3311
| 1
| '''23.86'''
|- align="center"
| 15
| 24.5483
| 1
| '''20.96'''
|- align="center"
| 18
| 19.7788
| 1
| '''18.71'''
|-
|}
 

==== '''NMR Spectra of Molecule 18''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 18 Boat for Image2.mol</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"-
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 18 Chair Overall NMR.png|500px|center]]
| [[File:Molecule 18 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.2832
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| ''' '''
|- align="center"
| 50
| 3.3175
| 1
| rowspan="4" style="text-align:centre;"| '''3.00-2.70'''
|- align="center"
| 52
| 3.2153
| 1
|- align="center"
| 51,53
| 3.1161
| 2
|- align="center"
| 34,43
| 2.8606
| 2
|- align="center"
| 38
| 2.4549
| 1
| ''' '''
|- align="center"
| 42
| 2.3968
| 1
| ''' '''
|- align="center"
| 25,29,26
| 2.2796
| 3
| ''' '''
|- align="center"
| 39
| 2.0844
| 1
| ''' '''
|- align="center"
| 40,36
| 1.9699
| 2
| ''' '''
|- align="center"
| 37,24
| 1.8519
| 2
| ''' '''
|- align="center"
| 31,27
| 1.6780
| 2
| ''' '''
|- align="center"
| 28
| 1.6175
| 1
| ''' '''
|- align="center"
| 46,49
| 1.4979
| 2
| ''' '''
|- align="center"
| 35
| 1.4150
| 1
| ''' '''
|- align="center"
| 32
| 1.3531
| 1
| ''' '''
|- align="center"
| 48
| 1.1606
| 1
| ''' '''
|- align="center"
| 33,30,47
| 1.0653
| 3
| '''1.03'''
|- align="center"
| 44,45
| 0.9643
| 2
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwMolecule 18 Boat Overall NMR.png|500px|center]]
| [[File:XcwMolecule 18 Boat zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 211.8325
| 1
| '''211.49'''
| rowspan="10" style="text-align:center;"| [[File:Molecule 18 Boat for 13 CNMR.jpg|600px|center]]
|- align="center"
| 13
| 148.6673
| 1
| '''148.72'''
|- align="center"
| 14
| 118.8373
| 1
| '''120.90'''
|- align="center"
| 3
| 89.0869
| 1
| '''74.61'''
|- align="center"
| 2
| 67.8886
| 1
| '''60.53'''
|- align="center"
| 1
| 56.1133
| 1
| '''51.30'''
|- align="center"
| 10
| 55.5998
| 1
| '''50.94'''
|- align="center"
| 16
| 50.1124
| 1
| '''45.53'''
|- align="center"
| 22
| 48.2030
| 1
| '''43.28'''
|- align="center"
| 23
| 44.2222
| 1
| '''40.82'''
|- align="center"
| 4
| 42.0354
| 1
| '''38.73'''
| Comments
|- align="center"
| 9
| 37.5865
| 1
| '''36.78'''
| rowspan="9" style="text-align:left;"| ''' '''
|- align="center"
| 6
| 35.3106
| 1
| '''35.47'''
|- align="center"
| 15
| 31.0459
| 1
| '''30.84'''
|- align="center"
| 7
| 28.8476
| 1
| '''30.00'''
|- align="center"
| 12
| 28.6623
| 1
| '''25.56'''
|- align="center"
| 17
| 25.7393
| 1
| '''25.35'''
|- align="center"
| 11
| 25.2603
| 1
| '''22.21'''
|- align="center"
| 18
| 23.3944
| 1
| '''21.39'''
|- align="center"
| 5
| 21.0478
| 1
| '''19.83'''
|-
|}
 

== '''Part 4 : Analysis of the Properties of the Synthesized Alkene Epoxides''' ==
=== '''The two catalytics systems''' ===

Assymmetric epoxidation of prochiral alkenes may lead to product with different stereochemical outcome as illustrated as below. To solve this problem, different types of asymmetric epoxidation catalyst have been synthesized. In this study, we shall be focusing on Shi asymmetric fructose catalyst as well as Jacobsen asymmetric catalyst.

[[File:Asymmetric catalyst.png|400px|center]]

==== ''' The Shi Asymmetric Fructose Catalyst''' ====

Molecule 21 is the stable precursor of molecule 22, the active catalyst. Molecule 21 can be converted to molecule 22 by using either persulfuric acid or potassium peroxymonosulphate.

[[File:Molecule 21 to 23.png|400px|center]]

The transition state of the Shi epoxidation was a subject of debate for a few moments. However, recent studies have led to the conclusion that the spiro transition state is more favored than the planar transition state. The spiro transition state is the transition that has its dioxirane perpendicularly bisecting the alkene double bond. This is thought to be more favourable due to interactions between the lone pairs of the oxygen with the LUMO of the alkene.

[[File:Spiro and planar ts.png|500px|center]]

==== ''' The Jacobsen Asymmetric Catalyst''' ====

Molecule 23 is the stable precursor of molecule 24, the active catalyst. Molecule 23 can be converted to molecule 24 by using sodium perchlorate.

[[File:Salen, 23 and 24.png|400px|center]]

Jacobsen catalyst is biphasic. The first phase involves the transfer of oxygen to molecule 23. Sodium perchlorate oxidizes Mn(III) to Mn(V).

In the second step, Jacobsen catalyst acts via a radical mechanism. It is thought to be so because epoxidation of trans-alkene by Jacobsen catalyst yield cis-alkene as well. A radical mechanism will lead to the lost of stereochemical information of the molecule.

=== ''' Crystal structure of the two catalyst''' ===
==== '''Molecule 21''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 21'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 21 strucutre.png|600px|center]]'''
|-
| style="text-align:center;" width="150" | ''' Bond '''
| style="text-align:center;" width="150"| ''' Bond Lenghts (Angstrom)'''
| style="text-align:center;" | ''' Evaluation'''
|-
| style="text-align:center;"| ''' O1-C1 '''
| style="text-align:center;"| ''' 1.400'''
| rowspan="10" style="text-align:left;"| [[File:Molecule 21 2.png|300px|center]]

The normal bond length of an C-O bond is 1.430 angstrom.

The most interesting aspect here is O4 and O2. The lone pair of O4 is antiperplanar to the sigma* orbital of the carbonyl group while the lone pair of O2 is anti periplanar to the carbonyl pi* orbital. Donation of electron can occur because of the correct symmetry. Due to the mixing of the orbitals, the C2-O2 and C4-O4 has been conferred with a certain degree of double bond character.

However, due to the lone pair on oxygen being now donated to the carbonyl antibonding orbitals, the O2 and O4 is slightly “electron deficient” and electron density will be pulled away from O2 and O4. That would explain why the bond length increase for O2-C7 and O4-C10. Increase in bond length is an indicator of the weakening of the bond.
|-
| style="text-align:center;"|'''O1-C7'''
| style="text-align:center;"|'''1.413'''
|-
| style="text-align:center;"|'''O2-C7'''
| style="text-align:center;"|'''1.441'''
|-
| style="text-align:center;"|'''O2-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O4-C4'''
| style="text-align:center;"|'''1.396'''
|-
| style="text-align:center;"|'''O4-C10'''
| style="text-align:center;"|'''1.439'''
|-
| style="text-align:center;"|'''O5-C10'''
| style="text-align:center;"|'''1.409'''
|-
| style="text-align:center;"|'''O5-C5'''
| style="text-align:center;"|'''1.416'''
|-
| style="text-align:center;"|'''O6-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O6-C6'''
| style="text-align:center;"|'''1.420'''
|-
|}
 

==== '''Molecule 23''' ====

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 23'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 23 struc.png|600px|center]]'''
|-
| The most outstanding feature from this molecule is the fact that is adopt a puckered form of the square base pyramidal form. This is no surprise that the molecule is almost planar due to the electron delocalization around each side of the salen ligand.

The tery-butyl hydrogen are oriented closely to one another. Non-covalent interaction studies indicated that repulsion would occur for H---H bond length that are less than 2.1 angstrom while favourable interaction may be dominant with bond length above 2.4 angstrom. It was discovered that all 4 hydrogens have bond length more than 2.4 angstrom hence there should not be any significant repulsion between them. Instead, certain amount of attractive force will ensue and that contributes to the overall stability of the molecule

|-
|}
 

=== ''' The calculated NMR properties of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | '''
Shift (ppm) Degeneracy
7.4891704929 4.0000
7.2988172444 1.0000
3.6627082199 1.0000
3.1170156088 1.0000
2.5382383043 1.0000 '''
| width="100" | '''
Shift (ppm) Degeneracy
7.4892967873 4.0000
7.2987138125 1.0000
3.6632689921 1.0000
3.1151709109 1.0000
2.5339209685 1.0000

'''
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Styrene R HNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Styrene S HNMR.png|400px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | '''
Shift (ppm) Degeneracy
135.1098747604 1.0000
124.1186533632 1.0000
123.4150641684 1.0000
122.9584694331 2.0000
118.2653162569 1.0000
54.0265785300 1.0000
53.4853575062 1.0000 '''
| width="100" | '''
Shift (ppm) Degeneracy
135.1323742030 1.0000
124.1343038829 1.0000
123.4137039868 1.0000
122.9558208084 2.0000
118.2690258882 1.0000
54.0599580762 1.0000
53.4684920923 1.0000
'''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | ''' [[File:Styrene R CNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Styrene S CNMR.png|400px|center|]]'''
|-
| width="100" | ''' '''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | ''' Shift (ppm) Degeneracy
7.5705724829 2.0000
7.4791732656 8.0000
3.5390102503 2.0000
| width="100" | ''' Shift (ppm) Degeneracy
7.5705651164 2.0000
7.4791779628 8.0000
3.5374502607 2.0000
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Stilbene RR HNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|400px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | ''' Shift (ppm) Degeneracy
134.0942417727 2.0000
124.2206838184 2.0000
123.5192390024 2.0000
123.2125901307 2.0000
123.0785800542 2.0000
118.2583039589 2.0000
66.4212770637 2.0000 '''
| width="100" | ''' Shift (ppm) Degeneracy
134.0899175142 2.0000
124.2224499528 2.0000
123.5180152862 2.0000
123.2113538650 2.0000
123.0745448885 2.0000
118.2635789492 2.0000
66.4249347217 2.0000 '''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | ''' [[File:Stilbene RR CNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|400px|center|]]'''
|-
|}

 

=== ''' Assigning the absolute configuration of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''Predicted ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg'''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg '''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental conditions'''
| width="100" | '''1.00g/100ml, chloroform, 21 degree Celcisus, 589 nm wavelength '''
| width="100" | '''1.02g/100ml (99% ee), chloroform, 25 degree Celsius, 589 nm wavelength '''
| width="100" | '''1.01g/100ml, ethanol, 22 degree Celsius, 589 nm wavelength '''
| width="100" | '''0.6g/100ml, ethanol, 20 degree Celsius, 589 nm wavelength '''
|- align="left"
| width="100" | ''' Predicted VCD Spectrum'''
| width="100" | '''[[File:Styrene R VCD.png|200px|center|]] '''
| width="100" | '''[[File:Styrene S VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene RR VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene SS VCD.png|200px|center|]]'''
|-
|}

 

All the assignments given in the literature reports are correct although the predicted value differs slightly with the experimental values

=== ''' Analysis of the Transition State for Reactions''' ===
==== '''Predicting Enantiomeric Excess based on Transition State energies''' ====

One of the energy output from Gaussian calculation is the “sum of electronic and thermal free energies”. This is Gibbs Free Energy at 298.15K and 1 atm.

Using this term and invoking a variant of the Curtin-Hammett Principle, it is possible to calculate a predicted enantiomeric excess of one enantiomer over the other.

[[File:Ee and transition state energy.png|800px|center]]

Using the derivations from above and equation (4), we analyze the enantiomeric excess of beta-methyl styrene and the results are tabulated as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1343.022970'''
| width="100" | '''-1343.017942'''
| width="150" | '''-0.005028'''
| width="150" | '''4.88E-03'''
| width="150" | '''99.03'''
|- align="center"
| width="100" | '''-1343.019233'''
| width="100" | '''-1343.015603'''
| width="150" | '''-0.003630'''
| width="150" | '''2.14E-02'''
| width="150" | '''95.80'''
|- align="center"
| width="100" | '''-1343.029272'''
| width="100" | '''-1343.023766'''
| width="150" | '''-0.005506'''
| width="150" | '''2.94E-03'''
| width="150" | '''99.41'''
|- align="center"
| width="100" | '''-1343.032443'''
| width="100" | '''-1343.024742'''
| width="150" | '''-0.007701'''
| width="150" | '''2.88E-04'''
| width="150" | '''99.94'''
|-
|}

 

The above hartree units are converted to J/mol for calculation of K where 1 hartress = 4.3597E-18

Studying all the free energies of the (R,R) series and compare them with the (S,S) series, it comes as no surprise that (R,R) product is favoured over (S,S) product as (R,R) is more stable. Indeed, this corresponds with the literature value reporting 92% ee of (R,R) products over that of (S,S).

==== '''Analysis of the Transition State of Epoxidation''' ====
==== '''Shi Fructose Catalyst''' ====
For this section, I will be analyzing the the transition state of 1) styrene and 2) trans-stilbene with the Shi fructose catalyst.

===== '''(R) and (S)-styrene transition state''' =====
The transition state for the formation of (R)-styrene oxide and (S)-styrene oxide are given as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R)-styrene oxide'''
| width="150" | '''(S)-styrene oxide'''
|- align="center"
| width="150" | ''' Structure of Catalyst '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide R.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide S ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| [[File:Steric shi fructose R.png|450px|center]]
| [[File:Steric shi fructose S.png|450px|center]]
|-
|}

 

In the transition state for (R)-styrene, it was discovered that the Re face is reacting with the oxygen of the dioxirane. The phenyl ring is oriented endo with respect to the fructose catalyst. However, the (S)-styrene is reacting at the Si face and the phenyl ring is oriented exo relative to the catalyst.

The approach taken by (R)-styrene and (S)-styrene are restricted to only one due to steric interactions. Therefore, the epoxidation of both styrenes by the Shi catalyst will be stereospecific and retains all the stereochemical information of the reactant. However, whether or not (R)-styrene oxide or (S)-styrene oxide is form is dependent on the relative energies of the transition state. The more stable the transition state, the more likely the product of the transition state will be formed.

So in order to examine this, an example of transition state of both styrenes with Shi catalyst are obtained and analyzed.
 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1303.736813'''
| width="100" | '''-1303.727673'''
| width="150" | '''-0.00914'''
| width="150" | '''6.28E-05'''
| width="150" | '''99.99'''

|-
|}

 

From the above, we can see the predicted high enantiopurity of the reaction favoring the (R) product because of the lower energy of the transition states. To understand the reason, we have to turn to non-covalent interaction (NCI) analysis.

[[File:NCI shi fructose styrene.png|700px|center]]

To complement the NCI analysis, a QTAIM (Quantum Theory of Atoms in Molecules) analysis is conducted as well.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''(R)-styrene transition state'''
| width="200" | '''(S)-styrene transition state'''
|- align="center"
| width="100" | '''[[File:QTAIM R.png|400px|center]]'''
| width="100" | '''[[File:QTAIM S.png|400px|center]]'''
|- align="center"
| colspan="2" width="100" | '''Comments'''
|-
| colspan="2" width="100" | '''Unsurprisingly, QTAIM analysis has also shown that (R)-styrene/Shi catalyst has more interactions with one another. While (R)-styrene has 2 strong interactions, (S)-styrene has only one with the catalyst. Besides, the phenyl ring of (R)-styrene also confers additional positive interaction with the catalyst. QTAIM analysis has also show several interactions between the C=C geminal hydrogen of (R)-styrene intreacting with the oxygen atoms on the dioxacyclopentane ring'''
|-
|}

 

===== '''(R,R) and (S,S)-Stilbene transition state''' =====

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R,R)-Stilbene oxide'''
| width="150" | '''(S,S)-Stilbene oxide'''
|- align="center"
| width="150" | ''' Structure of Transition State '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Stilbene RR ts.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>SS stilbene oxide ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| colspan="2" | [[File:Shi fructose stilbene.png|700px|center]]

|-
|}

 

However, unlike styrene, trans-stilbene seems to approach perpendicularly to the dioxirane. This is proposed to be due to the steric interactions (marked in purple). Based on first inspection, it seems that (S,S)-Stilbene oxide has more steric interactions than (R,R)-Stilbene oxide. Although unsubstantial, it seems like my guess was correct. The (R,R)-stilbene/Shi catalyst transition state is lower in energy.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1534.687808'''
| width="100" | '''-1534.683440'''
| width="150" | '''0.004368'''
| width="150" | '''9.08E-3'''
| width="150" | '''98.20'''

|-
|}

 

NCI Analysis is also done for trans-stilbene

[[File:NCI stilbene.png|700px|center]]

==== '''Jacobsen Catalyst''' ====

For this section, cis-beta methyl styrene transition state will be analyzed.

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-3383.259559'''
| width="100" | '''-3383.251060'''
| width="150" | '''-0.008499'''
| width="150" | '''1.24E-04'''
| width="150" | '''99.98'''
|- align="center"
| width="100" | '''-3383.253442'''
| width="100" | '''-3383.250270'''
| width="150" | '''-0.003172'''
| width="150" | '''3.48E-02'''
| width="150" | '''93.27'''
|-
|}

 

As is obvious from here, the (S,R) transition state is more stable than the (R,S) transition state. Both transition states are exo with respect to the catalyst.

It is not immediately apparent just by looking at the molecule to determine which spatial groups have interactions with one another. Therefore, an NCI analysis is conducted again.

[[File:NCI Jacobsen.png|700px|center]]

Rep:Mod:Computationalreport1C

2013-11-21T23:30:26Z

Xc2611: /* The calculated NMR properties of the product */

= '''Synthesis and Computational Lab: 1C''' =
== '''Part 1: Introduction to Molecular Mechanics''' ==
=== '''Introduction to MMFF94 and MMFF94s''' ===

With the improvement of computational data and computer processing power, the usage of molecular mechanics/dynamics forcefield has become very integrated in predicting properties of chemical molecules. A molecular mechanics/dynamics forcefield should be able to predict characteristics such as molecular geometries, conformational/stereoisomeric energies, vibrational frequencies etc. to a reasonable accuracy as compared to experimental-derived values.

Building on work from Kollman et al. s’ AMBER forcefield and Allinger et al. s’ MM1, MM2, MM3 and MM4, Merck Research Laboratories have managed to optimized and improved the previous computational algorithms and produced MMFF94 (Merck Molecular Force Field 94). One of the most prominent advantages of MMFF94 over other preceeding work is its enhanced prediction accuracy. The reason lies in the fact that MMFF94’s core parameterization utilizes an unprecedently large amount of computational data obtained from ab initio calculations1.

Subsequently after the development of MMFF94, a new “static” variant of the MMFF was introduced i.e. the MMFF94s. Unlike MMFF94 that was developed for the use of molecular dynamics simulations (which can be expensive), MMFF94s was developed with the purpose of energy minimization studies in mind. Although both systems provide identical results for most systems, they differ for amides and unsaturated amines which contain resonance-delocalized trigonal nitrogen atoms2.

In this computational exercise, MMFF94s is used predominantly as oppose to the alternative Universal Force Field (UFF). Although versatile across the entire periodic table, UFF is derived from simple rules and atomic parameters such as fixed hybridization that increases the likelihood of erroneous structural and energetic predictions3.

=== '''Forms of MMFF94s''' ===

Steric energy of a molecule is the energy arise due to its geometry or conformation. Energy minimization of steric energy process ensures that the molecule is in its lowest energy conformation.

MMFF94s assumes that the total steric energy of a molecule can be found by the sum of a few specific interactions in a molecule.

ES = EBS + EAB + E SB + ET + EOOP + EVdW + EEE

'''where the bonded interactions are:'''

ES = Total Steric energy

EBS = Total Bond Stretching energy

EAB = Total Angle Bending energy

ESB = Total Stretch Bending energy

ET = Total Torsional Energy

EOOP = Total Out-Of-Plane Bending energy, and

'''where the non-bonded interactions are:'''

EVdW = Total Van der Waals Energy

EEE = Total Electrostatic Energy

{| border="1" cellspacing="1" cellpadding="10"
|-
| width="300" align="center" | '''Types of Energies'''
! width="600" align="center" | '''Explanation'''
|-
| colspan="2" style="text-align: center;" | '''Bonded Interactions'''
|-
| width="300" align="center" | '''Total Bond Stretching Energy'''
! width="600" align="left" | The total bond stretching energy is related to the vibration energy of the molecules in comparison to the equilibrium bond length. Whenever a bond deviates from the equilibrium bond length, the energy value increases.

MMFF94s uses a quartic function that has the force constant term (relate to bond strength). The quartic function term is superior to the cubic function term (used in MM2) in the sense that it avoid the “cubic stretch catastrophe” where progressive elongation of molecule bond length leads to negative infinity.
|-
| width="300" align="center" | '''Total Angle Bending Energy'''
! width="600" align="left" | Similar to Total Bond Stretching Energy, the total angle bending energy is also related to the vibration energy of the molecules about the equilibrium bond length. However, unlike EBS that measures the bond strength, EAB is associated with the stiffness of the molecules based on the Hookiean potential. Whenever bond angles deviate from the norm during vibration, this energy term increases as well.
|-
| width="300" align="center" | '''Total Stretch-Bending Energy'''
! width="600" align="left" | This energy term takes into account of the energy due to increase in bond length when bond angle between two atoms changes.
|-
| width="300" align="center" | '''Total Torsional Energy'''
! width="600" align="left" | Total torsional energy is the energy required for intermolecular rotation about the bonds. In molecule mechanics, however, this term is often used as a correction that must be added or subtracted to the total energy of the molecule to fit a quantum mechanical calculation about the dihedral angles of bonds.
|-
| width="300" align="center" | '''Total Out-Of-Plane Bending Energy'''
! width="600" align="left" | This energy term refers to the energy needed to deform the dihedral angle (zero degrees) of a planar group of atoms such as carbonyl or amide functional groups.
|-
| colspan="2" style="text-align: center;" | '''Non-Bonded Interactions'''
|-
| width="300" align="center" | '''Total Van der Waals Energy'''
! width="600" align="left" | The total Van der Waals energy term examines the intramolecular interactions such as repulsion or attraction between non-bonded atoms in the molecule. This term is crucial in determining the preferred conformation of the molecule.

MMFF94s employs the novel “Buffered-14-7”. The name is derived from a buffering constant and the 14th and 7th power dependencies of the repulsive and attractive energy in the equation.
|-
| width="300" align="center" | '''Total Electrostatic Energy'''
! width="600" align="left" | The total electrostatic energy functions take into account of the Coulombic potential and partial charge/dipole/atomic point charges interactions within the molecule.
|-

|}

 

== '''Part 2 : Conformational Analysis Using Molecular Mechanics''' ==
=== '''The Hydrogenation of Cyclopentadiene Dimer''' ===

==== '''Endo and exo adduct from the Dimerization of Cyclopentadiene''' ====
Cyclopentadiene will undergo dimerization by Diels-alder reaction to form either an endo or exo adduct.

[[File:XcwDimerization of CP.png|500px|center]]

==== '''Stereoselectivity of Dimerization of Cyclopentadiene''' ====
Although the exo adduct is thermodynamically more stable than the endo adduct, the endo adduct is form preferentially. Using the QST2 method, the transition state of the Diels Alder dimerization was found. It was discovered that due to the secondary orbital interactions in the endo transition state, the endo dimer is formed preferentially (the kinetic product). Hence, it is proven that the Diels Alder dimerization between two cyclopentadiene are kinetically controlled.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Transition State of Dimerization of Cyclopentadiene'''
| '''Imaginary Stretch Frequency (-881.25) of the Endo Transition State (click to animate)'''
| '''Secondary Orbital Interaction (Red overlapping orbitals)'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<uploadedFileContents>EndotsDCPD2.mol
</uploadedFileContents>
</jmolApplet></jmol>
| [[File:Xcwendotsimaginary.gif|300px|center]]
| [[File:XcwSecondary orbital interaction1.jpg|300px|center]]
|-
|}

 

==== '''Asynchronous Bond Formation of Dimerization of Cyclopentadiene''' ====

The initial study of the molecular orbitals of the transition states seemed a bit peculiar. Instead of getting a LUMO with symmetrical orbitals, the calculations showed a HOMO that is asymetric at the carbons where the new sigma bonds will be formed. Running an IRC further, it soon became clear that the asymmetry of the HOMO leads to an asychronous bond formation before leading to the product.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''IRC plot following the Endo Transition State '''
| '''IRC following the Endo Transition State (click to animate)'''
| '''Asymmetry of orbitals at the carbons where the new sigma bonds will be formed'''
|- align="center"
| [[File:XcwendotscyclopentadieneIRC.png|300px|center]]
| [[File:XcwendotsIRC.gif|300px|center]]
| [[File:XcwAsynchronous mo.jpg|300px|center]]
|-
|}

 

==== '''Comparison of Energies between the Endo and Exo adduct of Dicyclopentadiene''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Adduct of Dicyclopentadiene dimerization'''
| '''Exo Adduct of Dicyclopentadiene dimerization'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=19,atomno=1,atomno=2; color green;measure 19 1;measure 19 2;</script>
<uploadedFileContents>XcwEndodimer3.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>Exodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=7,atomno=17; color green;measure 17 7;</script>
<uploadedFileContents>XcwExodimer1.mol</uploadedFileContents>
</jmolApplet></jmol>
|-
|}

 

Using MMFF94s ab initio calculations, the energies for the exo dimer and the endo dimer are derived.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Exodimer'''
| '''55.374'''
| 3.543
| 30.772
| -2.041
| -2.728
| 0.015
| 12.800
| 13.014
|-
| '''Endodimer'''
| '''58.191'''
| 3.468
| 33.187
| -2.082
| -2.950
| 0.023
| 12.360
| 14.186
|-
|}

 

The MMFF94s steric energy (after minimization) for the exo dimer is lower than that of the endo dimer. This is reflected by the large difference for the EEE between the endo dimer and the exo dimer due to unfavourable steric repulsion between the two “arched down” cyclopentene rings.

==== '''Hydrogenation of Dicyclopentadiene''' ====

Hydrogenation of the endo dicyclopentadiene (DCPD) would lead to two potential products: dihydro product 1 and dihydro product 2.

[[File:XcwFormation of Dihydro products.png|500px|center]]

Using MMFF94s, the energy of the two dihydro products are calculated.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Dihydro Product 1'''
| '''50.123'''
| 3.308
| 30.864
| -1.927
| 0.060
| 0.015(2)
| 13.281
| 5.121
|-
| '''Dihydro Product 2'''
| '''41.257'''
| 2.823
| 24.685
| -1.657
| -0.379
| 0.000(2)
| 10.639
| 5.147
|-
| '''Tetrahydro Product'''
| '''39.042'''
| 2.730
| 25.151
| -1.676
| 1.287
| 0.000
| 11.551
| 0.000
|}

 

From the MMFF94s calculation, it can be seen that dihydro product 2 has a lower steric energy than dihydro product 1. Therefore, dihydro product 2 is the thermodynamic product for the hydrogenation of dicylopentadiene. And indeed, this was what was observed by Skala et al.. He observed that the first hydrogenation occur at the norborene part of the molecule (rate of hydrogenation several times faster than that in the cyclopentene ring)6. The first heat of hydrogenation at the norborene is 138.8 kJ/mol while the second hydrogenation at the cyclopentene right is 109.5 kJ/mol6.

From the above results, it is also obvious that tetrahydro product is much more stable than either dihydro product. And yet, studies have shown that the tetrahydro product will only form after prolonged hydrogenation under high temperature. However, subjecting DCPD to high temperature leads to low yield due to cracking of DCPD.

Since thermodynamically it is predicted to form favourably, the fact that it does not could only mean that the hydrogenation of DCPD to tetrahydrodicyclopentadiene (TH-DCPD) is kinetically controlled. Most possibly, the transition state of the hydrogenation of DCPD is highly unstable hence it is unlikely to form.

=== '''Atropisomerism in an Intermediate related to the Synthesis of Taxol''' ===

Atropisomerism is a type of stereoisomerism that is form as a result of hindered rotation about a single bond.

[[File:XcwAtropisomerism example.png|500px|center]]

In the case of the 6,6’-dinitro-2,2’-diphenic acid, rotation about the bonds joining the two substituted phenyl rings would have to overcome large steric interaction between the bulky substituents. The barrier of rotation is high enough for the two conformers to be isolated individually.

In the synthesis of taxol, one of the key intermediates exhibit atropisomerism.

==== '''Atropisomerism in Taxol Synthesis''' ====

For the key intermediate, rotation about the carbon-carbon bonds would lead to two types of atropisomers, each with either the carbonyl group poining upwards or downwards in relative to the bridge.

[[File:XcwIntermediate 9 and Intermediate 10.png|500px|center]]

Once again by using MMFF94s ab initio calculations, the steric energies for the two intermediates are illustrated as below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 9'''
| '''70.571'''
| 7.743
| 28.356
| -0.062
| 0.004
| 0.949
| 33.293
| 0.288
|-
| '''Intermediate 10'''
| '''60.553'''
| 7.599
| 18.838
| -0.139
| 0.199
| 0.844
| 33.269
| -0.056
|-

|}

 

Analyzing the data above, the largest energy difference between Intermediate 9 and Intermediate 10 stems from the EAB which is related to the strain of the ring. Intermediate 9 has an excess of 9.518 kcal/mol EAB as compared to Intermediate 10. This comes as a surprise as intermediate 9 is predicted to be more stable alkene.

The rationale behind the prediction of the stability of intermediate 9 stems from the fact that the through-space distance of the upward-pointing carbonyl oxygen with the carbon-carbon is further than the through space distance between the downward-pointing carbonyl oxygen with the -CH2-CH2- fragment at the norbornene part in intermediate 10.

==== '''Hyperstable Olefins''' ====

Intermediate 9 and Intermediate 10 does not react readily with other reagents during functionalization. This is due to the hyperstability effect found in hyperstable olefins.

Hyperstable olefins are alkenes that contain less strain in the ring (i.e. negative olefin strain values) compared to the parent hydrocarbon. To study this further, further MMFF94s calculation was done to compare Intermediate 10 with the parent hydrocarbon.

[[File:XcwIntermediate10andPH.png|500px|center]]

The energies that we calculated are tabulated as shown below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 10'''
| '''44.878 '''
| 5.211
| 15.488
| -0.267
| -1.655
| 0.998
| 25.014
| 0.088
|-
| '''Parent Hydrocarbon'''
| '''50.564'''
| 4.692
| 21.979
| 0.109
| -0.958
| 0.247
| 24.495
| 0.000
|-

|}

 

Scrutinizing the results, the largest energy difference between intermediate 10 and the parent hydrocarbon stems from the Total Angle Bending Energy, EAB. Since the Total Angle bending energy is related to the angle strain in the molecules, it is apparent that the parent hydrocarbon has more ring strain as compared to the bridgehead olefin.

== '''Part 3 : Spectroscopic Simulation Using Quantum Mechanics''' ==
=== '''Spectroscopy of an Intermediate Related to the Synthesis of Taxol''' ===

Molecule 17 and 18 are derivatives of intermediate 9 and 10. In this exercise, MMFF94s is used to predict the 1H and 13C NMR of molecule 17 and molecule 18.

[[File:XcwIntermediate17&18.png|500px|center]]

==== '''NMR Spectra of Molecule 17''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 17.mol
</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwHNMRMolecule 17 Chair Overall NMR.png|500px|center]]
| [[File:XcwHNMRMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.1825
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| The first three results were fairly straight forward to be deduced and correlate wit experimental data.

The hydrogen atom that is geminally attached to the carbon of the double bonds is the most deshielded due to the ring current anisotropic effect of the ring current

The second most deshielded hydrogen atom is the hydrogen atom on the methyl group on the bridge. The hydrogen atom is pointing directly to the oxygen atom of the carbonyl functional group.

The peaks with an integration height of 4 is assigned to the hydrogen atoms in the 1,3-dithiolane ring fragment.

Subsequent analysis of the 1H NMR became very complicated very quickly for two reasons:

1. Gaussian calculations showed some atoms with an integration height of 3. Comparing their file atom number and checking their chemical environment, it is not possible to find any correlation between them.

2. Some of the peaks in the literature remains unresolved and are given as multiplets or grouped together.

|- align="center"
| 52
| 3.1775
| 1
| '''2.99'''
|- align="center"
| 53,52,50,51
| 3.0867
| 4
| '''3.40-3.10'''
|- align="center"
| 42,43,39
| 2.7445
| 3
| ''' '''
|- align="center"
| 49
| 2.6187
| 1
| ''' '''
|- align="center"
| 34
| 2.4371
| 1
| ''' '''
|- align="center"
| 35
| 2.3782
| 1
| ''' '''
|- align="center"
| 40,37,26
| 2.2730
| 3
| ''' '''
|- align="center"
| 30
| 2.1566
| 1
| ''' '''
|- align="center"
| 36
| 2.1033
| 1
| ''' '''
|- align="center"
| 32,28
| 2.0259
| 2
| ''' '''
|- align="center"
| 25
| 1.8535
| 2
| ''' '''
|- align="center"
| 38,46,27
| 1.5898
| 3
| '''1.25'''
|- align="center"
| 29
| 1.4557
| 1
| ''' '''
|- align="center"
| 31
| 1.0123
| 1
| ''' '''
|- align="center"
| 44,48,45
| 0.9087
| 3
| '''1.10'''
|- align="center"
| 47
| 0.8354
| 1
| ''' '''
|- align="center"
| 33
| 0.5790
| 1
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 17 Chair Overall NMR2.png|500px|center]]
| [[File:XcwMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 216.2725
| 1
| '''218.79'''
| rowspan="10" style="text-align:center;"| [[File:XcwMolecule 17 image for CNMR.jpg|600px|center]]
|- align="center"
| 13
| 144.8626
| 1
| '''144.63'''
|- align="center"
| 14
| 124.7193
| 1
| '''125.33'''
|- align="center"
| 3
| 91.3340
| 1
| '''72.88'''
|- align="center"
| 2
| 60.9568
| 1
| '''56.19'''
|- align="center"
| 1
| 57.0811
| 1
| '''52.52'''
|- align="center"
| 10
| 52.4663
| 1
| '''48.50'''
|- align="center"
| 16
| 51.4857
| 1
| '''46.80'''
|- align="center"
| 9
| 46.9196
| 1
| '''45.76'''
|- align="center"
| 23
| 43.8647
| 1
| '''39.80'''
|- align="center"
| 22
| 41.9450
| 1
| '''38.81'''
| Comments
|- align="center"
| 4
| 41.8724
| 1
| '''35.85'''
| rowspan="9" style="text-align:left;"| The carbon bonded to the oxygen atom is the most deshielded, as is shown in the predicted values and the experimental values. There is a deviation between the values. Quite possibly, this is due to the fact that in reality, the carbonyl functional group is pointing slightly towards the equatorial position rather than a lateral position relative to the ring (as is in the input for Gaussian calculation)

Most of the 1CNMR values that was predicted by Gaussian are all within an acceptable range of deviation. However, there is carbon 3 that has significant deviation between the predicted value and experimental value.

Carbon 3 is the carbon bonded to the two sulphurs in the 1,3-dithiolane ring fragment. Such a huge deviation would possibly mean that the conformer that was given as input to Gaussian differs from the literature.

The above NMR spectra was corrected with a level of theory B3LYP/6-31G(d,p) using TMS as reference and in chloroform.

|- align="center"
| 15
| 35.4348
| 1
| '''32.66'''
|- align="center"
| 11
| 31.1964
| 1
| '''28.79'''
|- align="center"
| 6
| 28.9432
| 1
| '''28.29'''
|- align="center"
| 7
| 28.3640
| 1
| '''26.88'''
|- align="center"
| 12
| 27.3767
| 1
| '''25.66'''
|- align="center"
| 17
| 26.3311
| 1
| '''23.86'''
|- align="center"
| 15
| 24.5483
| 1
| '''20.96'''
|- align="center"
| 18
| 19.7788
| 1
| '''18.71'''
|-
|}
 

==== '''NMR Spectra of Molecule 18''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 18 Boat for Image2.mol</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"-
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 18 Chair Overall NMR.png|500px|center]]
| [[File:Molecule 18 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.2832
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| ''' '''
|- align="center"
| 50
| 3.3175
| 1
| rowspan="4" style="text-align:centre;"| '''3.00-2.70'''
|- align="center"
| 52
| 3.2153
| 1
|- align="center"
| 51,53
| 3.1161
| 2
|- align="center"
| 34,43
| 2.8606
| 2
|- align="center"
| 38
| 2.4549
| 1
| ''' '''
|- align="center"
| 42
| 2.3968
| 1
| ''' '''
|- align="center"
| 25,29,26
| 2.2796
| 3
| ''' '''
|- align="center"
| 39
| 2.0844
| 1
| ''' '''
|- align="center"
| 40,36
| 1.9699
| 2
| ''' '''
|- align="center"
| 37,24
| 1.8519
| 2
| ''' '''
|- align="center"
| 31,27
| 1.6780
| 2
| ''' '''
|- align="center"
| 28
| 1.6175
| 1
| ''' '''
|- align="center"
| 46,49
| 1.4979
| 2
| ''' '''
|- align="center"
| 35
| 1.4150
| 1
| ''' '''
|- align="center"
| 32
| 1.3531
| 1
| ''' '''
|- align="center"
| 48
| 1.1606
| 1
| ''' '''
|- align="center"
| 33,30,47
| 1.0653
| 3
| '''1.03'''
|- align="center"
| 44,45
| 0.9643
| 2
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwMolecule 18 Boat Overall NMR.png|500px|center]]
| [[File:XcwMolecule 18 Boat zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 211.8325
| 1
| '''211.49'''
| rowspan="10" style="text-align:center;"| [[File:Molecule 18 Boat for 13 CNMR.jpg|600px|center]]
|- align="center"
| 13
| 148.6673
| 1
| '''148.72'''
|- align="center"
| 14
| 118.8373
| 1
| '''120.90'''
|- align="center"
| 3
| 89.0869
| 1
| '''74.61'''
|- align="center"
| 2
| 67.8886
| 1
| '''60.53'''
|- align="center"
| 1
| 56.1133
| 1
| '''51.30'''
|- align="center"
| 10
| 55.5998
| 1
| '''50.94'''
|- align="center"
| 16
| 50.1124
| 1
| '''45.53'''
|- align="center"
| 22
| 48.2030
| 1
| '''43.28'''
|- align="center"
| 23
| 44.2222
| 1
| '''40.82'''
|- align="center"
| 4
| 42.0354
| 1
| '''38.73'''
| Comments
|- align="center"
| 9
| 37.5865
| 1
| '''36.78'''
| rowspan="9" style="text-align:left;"| ''' '''
|- align="center"
| 6
| 35.3106
| 1
| '''35.47'''
|- align="center"
| 15
| 31.0459
| 1
| '''30.84'''
|- align="center"
| 7
| 28.8476
| 1
| '''30.00'''
|- align="center"
| 12
| 28.6623
| 1
| '''25.56'''
|- align="center"
| 17
| 25.7393
| 1
| '''25.35'''
|- align="center"
| 11
| 25.2603
| 1
| '''22.21'''
|- align="center"
| 18
| 23.3944
| 1
| '''21.39'''
|- align="center"
| 5
| 21.0478
| 1
| '''19.83'''
|-
|}
 

== '''Part 4 : Analysis of the Properties of the Synthesized Alkene Epoxides''' ==
=== '''The two catalytics systems''' ===

Assymmetric epoxidation of prochiral alkenes may lead to product with different stereochemical outcome as illustrated as below. To solve this problem, different types of asymmetric epoxidation catalyst have been synthesized. In this study, we shall be focusing on Shi asymmetric fructose catalyst as well as Jacobsen asymmetric catalyst.

[[File:Asymmetric catalyst.png|400px|center]]

==== ''' The Shi Asymmetric Fructose Catalyst''' ====

Molecule 21 is the stable precursor of molecule 22, the active catalyst. Molecule 21 can be converted to molecule 22 by using either persulfuric acid or potassium peroxymonosulphate.

[[File:Molecule 21 to 23.png|400px|center]]

The transition state of the Shi epoxidation was a subject of debate for a few moments. However, recent studies have led to the conclusion that the spiro transition state is more favored than the planar transition state. The spiro transition state is the transition that has its dioxirane perpendicularly bisecting the alkene double bond. This is thought to be more favourable due to interactions between the lone pairs of the oxygen with the LUMO of the alkene.

[[File:Spiro and planar ts.png|500px|center]]

==== ''' The Jacobsen Asymmetric Catalyst''' ====

Molecule 23 is the stable precursor of molecule 24, the active catalyst. Molecule 23 can be converted to molecule 24 by using sodium perchlorate.

[[File:Salen, 23 and 24.png|400px|center]]

Jacobsen catalyst is biphasic. The first phase involves the transfer of oxygen to molecule 23. Sodium perchlorate oxidizes Mn(III) to Mn(V).

In the second step, Jacobsen catalyst acts via a radical mechanism. It is thought to be so because epoxidation of trans-alkene by Jacobsen catalyst yield cis-alkene as well. A radical mechanism will lead to the lost of stereochemical information of the molecule.

=== ''' Crystal structure of the two catalyst''' ===
==== '''Molecule 21''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 21'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 21 strucutre.png|600px|center]]'''
|-
| style="text-align:center;" width="150" | ''' Bond '''
| style="text-align:center;" width="150"| ''' Bond Lenghts (Angstrom)'''
| style="text-align:center;" | ''' Evaluation'''
|-
| style="text-align:center;"| ''' O1-C1 '''
| style="text-align:center;"| ''' 1.400'''
| rowspan="10" style="text-align:left;"| [[File:Molecule 21 2.png|300px|center]]

The normal bond length of an C-O bond is 1.430 angstrom.

The most interesting aspect here is O4 and O2. The lone pair of O4 is antiperplanar to the sigma* orbital of the carbonyl group while the lone pair of O2 is anti periplanar to the carbonyl pi* orbital. Donation of electron can occur because of the correct symmetry. Due to the mixing of the orbitals, the C2-O2 and C4-O4 has been conferred with a certain degree of double bond character.

However, due to the lone pair on oxygen being now donated to the carbonyl antibonding orbitals, the O2 and O4 is slightly “electron deficient” and electron density will be pulled away from O2 and O4. That would explain why the bond length increase for O2-C7 and O4-C10. Increase in bond length is an indicator of the weakening of the bond.
|-
| style="text-align:center;"|'''O1-C7'''
| style="text-align:center;"|'''1.413'''
|-
| style="text-align:center;"|'''O2-C7'''
| style="text-align:center;"|'''1.441'''
|-
| style="text-align:center;"|'''O2-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O4-C4'''
| style="text-align:center;"|'''1.396'''
|-
| style="text-align:center;"|'''O4-C10'''
| style="text-align:center;"|'''1.439'''
|-
| style="text-align:center;"|'''O5-C10'''
| style="text-align:center;"|'''1.409'''
|-
| style="text-align:center;"|'''O5-C5'''
| style="text-align:center;"|'''1.416'''
|-
| style="text-align:center;"|'''O6-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O6-C6'''
| style="text-align:center;"|'''1.420'''
|-
|}
 

==== '''Molecule 23''' ====

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 23'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 23 struc.png|600px|center]]'''
|-
| The most outstanding feature from this molecule is the fact that is adopt a puckered form of the square base pyramidal form. This is no surprise that the molecule is almost planar due to the electron delocalization around each side of the salen ligand.

The tery-butyl hydrogen are oriented closely to one another. Non-covalent interaction studies indicated that repulsion would occur for H---H bond length that are less than 2.1 angstrom while favourable interaction may be dominant with bond length above 2.4 angstrom. It was discovered that all 4 hydrogens have bond length more than 2.4 angstrom hence there should not be any significant repulsion between them. Instead, certain amount of attractive force will ensue and that contributes to the overall stability of the molecule

|-
|}
 

=== ''' The calculated NMR properties of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | '''
Shielding (ppm) Degeneracy
7.4891704929 4.0000
7.2988172444 1.0000
3.6627082199 1.0000
3.1170156088 1.0000
2.5382383043 1.0000 '''
| width="100" | '''
Shielding (ppm) Degeneracy
24.2569032127 4.0000
24.4474861875 1.0000
28.0829310079 1.0000
28.6310290891 1.0000
29.2122790315 1.0000
'''
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Styrene R HNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Styrene S HNMR.png|400px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | '''
Shift (ppm) Degeneracy
135.1098747604 1.0000
124.1186533632 1.0000
123.4150641684 1.0000
122.9584694331 2.0000
118.2653162569 1.0000
54.0265785300 1.0000
53.4853575062 1.0000 '''
| width="100" | '''
Shift (ppm) Degeneracy
135.1323742030 1.0000
124.1343038829 1.0000
123.4137039868 1.0000
122.9558208084 2.0000
118.2690258882 1.0000
54.0599580762 1.0000
53.4684920923 1.0000
'''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | ''' [[File:Styrene R CNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Styrene S CNMR.png|400px|center|]]'''
|-
| width="100" | ''' '''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | ''' Shift (ppm) Degeneracy
7.5705724829 2.0000
7.4791732656 8.0000
3.5390102503 2.0000
| width="100" | ''' Shift (ppm) Degeneracy
7.5705651164 2.0000
7.4791779628 8.0000
3.5374502607 2.0000
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Stilbene RR HNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|400px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | ''' Shift (ppm) Degeneracy
134.0942417727 2.0000
124.2206838184 2.0000
123.5192390024 2.0000
123.2125901307 2.0000
123.0785800542 2.0000
118.2583039589 2.0000
66.4212770637 2.0000 '''
| width="100" | ''' Shift (ppm) Degeneracy
134.0899175142 2.0000
124.2224499528 2.0000
123.5180152862 2.0000
123.2113538650 2.0000
123.0745448885 2.0000
118.2635789492 2.0000
66.4249347217 2.0000 '''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | ''' [[File:Stilbene RR CNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|400px|center|]]'''
|-
|}

 

=== ''' Assigning the absolute configuration of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''Predicted ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg'''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg '''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental conditions'''
| width="100" | '''1.00g/100ml, chloroform, 21 degree Celcisus, 589 nm wavelength '''
| width="100" | '''1.02g/100ml (99% ee), chloroform, 25 degree Celsius, 589 nm wavelength '''
| width="100" | '''1.01g/100ml, ethanol, 22 degree Celsius, 589 nm wavelength '''
| width="100" | '''0.6g/100ml, ethanol, 20 degree Celsius, 589 nm wavelength '''
|- align="left"
| width="100" | ''' Predicted VCD Spectrum'''
| width="100" | '''[[File:Styrene R VCD.png|200px|center|]] '''
| width="100" | '''[[File:Styrene S VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene RR VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene SS VCD.png|200px|center|]]'''
|-
|}

 

All the assignments given in the literature reports are correct although the predicted value differs slightly with the experimental values

=== ''' Analysis of the Transition State for Reactions''' ===
==== '''Predicting Enantiomeric Excess based on Transition State energies''' ====

One of the energy output from Gaussian calculation is the “sum of electronic and thermal free energies”. This is Gibbs Free Energy at 298.15K and 1 atm.

Using this term and invoking a variant of the Curtin-Hammett Principle, it is possible to calculate a predicted enantiomeric excess of one enantiomer over the other.

[[File:Ee and transition state energy.png|800px|center]]

Using the derivations from above and equation (4), we analyze the enantiomeric excess of beta-methyl styrene and the results are tabulated as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1343.022970'''
| width="100" | '''-1343.017942'''
| width="150" | '''-0.005028'''
| width="150" | '''4.88E-03'''
| width="150" | '''99.03'''
|- align="center"
| width="100" | '''-1343.019233'''
| width="100" | '''-1343.015603'''
| width="150" | '''-0.003630'''
| width="150" | '''2.14E-02'''
| width="150" | '''95.80'''
|- align="center"
| width="100" | '''-1343.029272'''
| width="100" | '''-1343.023766'''
| width="150" | '''-0.005506'''
| width="150" | '''2.94E-03'''
| width="150" | '''99.41'''
|- align="center"
| width="100" | '''-1343.032443'''
| width="100" | '''-1343.024742'''
| width="150" | '''-0.007701'''
| width="150" | '''2.88E-04'''
| width="150" | '''99.94'''
|-
|}

 

The above hartree units are converted to J/mol for calculation of K where 1 hartress = 4.3597E-18

Studying all the free energies of the (R,R) series and compare them with the (S,S) series, it comes as no surprise that (R,R) product is favoured over (S,S) product as (R,R) is more stable. Indeed, this corresponds with the literature value reporting 92% ee of (R,R) products over that of (S,S).

==== '''Analysis of the Transition State of Epoxidation''' ====
==== '''Shi Fructose Catalyst''' ====
For this section, I will be analyzing the the transition state of 1) styrene and 2) trans-stilbene with the Shi fructose catalyst.

===== '''(R) and (S)-styrene transition state''' =====
The transition state for the formation of (R)-styrene oxide and (S)-styrene oxide are given as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R)-styrene oxide'''
| width="150" | '''(S)-styrene oxide'''
|- align="center"
| width="150" | ''' Structure of Catalyst '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide R.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide S ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| [[File:Steric shi fructose R.png|450px|center]]
| [[File:Steric shi fructose S.png|450px|center]]
|-
|}

 

In the transition state for (R)-styrene, it was discovered that the Re face is reacting with the oxygen of the dioxirane. The phenyl ring is oriented endo with respect to the fructose catalyst. However, the (S)-styrene is reacting at the Si face and the phenyl ring is oriented exo relative to the catalyst.

The approach taken by (R)-styrene and (S)-styrene are restricted to only one due to steric interactions. Therefore, the epoxidation of both styrenes by the Shi catalyst will be stereospecific and retains all the stereochemical information of the reactant. However, whether or not (R)-styrene oxide or (S)-styrene oxide is form is dependent on the relative energies of the transition state. The more stable the transition state, the more likely the product of the transition state will be formed.

So in order to examine this, an example of transition state of both styrenes with Shi catalyst are obtained and analyzed.
 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1303.736813'''
| width="100" | '''-1303.727673'''
| width="150" | '''-0.00914'''
| width="150" | '''6.28E-05'''
| width="150" | '''99.99'''

|-
|}

 

From the above, we can see the predicted high enantiopurity of the reaction favoring the (R) product because of the lower energy of the transition states. To understand the reason, we have to turn to non-covalent interaction (NCI) analysis.

[[File:NCI shi fructose styrene.png|700px|center]]

To complement the NCI analysis, a QTAIM (Quantum Theory of Atoms in Molecules) analysis is conducted as well.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''(R)-styrene transition state'''
| width="200" | '''(S)-styrene transition state'''
|- align="center"
| width="100" | '''[[File:QTAIM R.png|400px|center]]'''
| width="100" | '''[[File:QTAIM S.png|400px|center]]'''
|- align="center"
| colspan="2" width="100" | '''Comments'''
|-
| colspan="2" width="100" | '''Unsurprisingly, QTAIM analysis has also shown that (R)-styrene/Shi catalyst has more interactions with one another. While (R)-styrene has 2 strong interactions, (S)-styrene has only one with the catalyst. Besides, the phenyl ring of (R)-styrene also confers additional positive interaction with the catalyst. QTAIM analysis has also show several interactions between the C=C geminal hydrogen of (R)-styrene intreacting with the oxygen atoms on the dioxacyclopentane ring'''
|-
|}

 

===== '''(R,R) and (S,S)-Stilbene transition state''' =====

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R,R)-Stilbene oxide'''
| width="150" | '''(S,S)-Stilbene oxide'''
|- align="center"
| width="150" | ''' Structure of Transition State '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Stilbene RR ts.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>SS stilbene oxide ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| colspan="2" | [[File:Shi fructose stilbene.png|700px|center]]

|-
|}

 

However, unlike styrene, trans-stilbene seems to approach perpendicularly to the dioxirane. This is proposed to be due to the steric interactions (marked in purple). Based on first inspection, it seems that (S,S)-Stilbene oxide has more steric interactions than (R,R)-Stilbene oxide. Although unsubstantial, it seems like my guess was correct. The (R,R)-stilbene/Shi catalyst transition state is lower in energy.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1534.687808'''
| width="100" | '''-1534.683440'''
| width="150" | '''0.004368'''
| width="150" | '''9.08E-3'''
| width="150" | '''98.20'''

|-
|}

 

NCI Analysis is also done for trans-stilbene

[[File:NCI stilbene.png|700px|center]]

==== '''Jacobsen Catalyst''' ====

For this section, cis-beta methyl styrene transition state will be analyzed.

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-3383.259559'''
| width="100" | '''-3383.251060'''
| width="150" | '''-0.008499'''
| width="150" | '''1.24E-04'''
| width="150" | '''99.98'''
|- align="center"
| width="100" | '''-3383.253442'''
| width="100" | '''-3383.250270'''
| width="150" | '''-0.003172'''
| width="150" | '''3.48E-02'''
| width="150" | '''93.27'''
|-
|}

 

As is obvious from here, the (S,R) transition state is more stable than the (R,S) transition state. Both transition states are exo with respect to the catalyst.

It is not immediately apparent just by looking at the molecule to determine which spatial groups have interactions with one another. Therefore, an NCI analysis is conducted again.

[[File:NCI Jacobsen.png|700px|center]]

Rep:Mod:Computationalreport1C

2013-11-21T23:29:58Z

Xc2611: /* The calculated NMR properties of the product */

= '''Synthesis and Computational Lab: 1C''' =
== '''Part 1: Introduction to Molecular Mechanics''' ==
=== '''Introduction to MMFF94 and MMFF94s''' ===

With the improvement of computational data and computer processing power, the usage of molecular mechanics/dynamics forcefield has become very integrated in predicting properties of chemical molecules. A molecular mechanics/dynamics forcefield should be able to predict characteristics such as molecular geometries, conformational/stereoisomeric energies, vibrational frequencies etc. to a reasonable accuracy as compared to experimental-derived values.

Building on work from Kollman et al. s’ AMBER forcefield and Allinger et al. s’ MM1, MM2, MM3 and MM4, Merck Research Laboratories have managed to optimized and improved the previous computational algorithms and produced MMFF94 (Merck Molecular Force Field 94). One of the most prominent advantages of MMFF94 over other preceeding work is its enhanced prediction accuracy. The reason lies in the fact that MMFF94’s core parameterization utilizes an unprecedently large amount of computational data obtained from ab initio calculations1.

Subsequently after the development of MMFF94, a new “static” variant of the MMFF was introduced i.e. the MMFF94s. Unlike MMFF94 that was developed for the use of molecular dynamics simulations (which can be expensive), MMFF94s was developed with the purpose of energy minimization studies in mind. Although both systems provide identical results for most systems, they differ for amides and unsaturated amines which contain resonance-delocalized trigonal nitrogen atoms2.

In this computational exercise, MMFF94s is used predominantly as oppose to the alternative Universal Force Field (UFF). Although versatile across the entire periodic table, UFF is derived from simple rules and atomic parameters such as fixed hybridization that increases the likelihood of erroneous structural and energetic predictions3.

=== '''Forms of MMFF94s''' ===

Steric energy of a molecule is the energy arise due to its geometry or conformation. Energy minimization of steric energy process ensures that the molecule is in its lowest energy conformation.

MMFF94s assumes that the total steric energy of a molecule can be found by the sum of a few specific interactions in a molecule.

ES = EBS + EAB + E SB + ET + EOOP + EVdW + EEE

'''where the bonded interactions are:'''

ES = Total Steric energy

EBS = Total Bond Stretching energy

EAB = Total Angle Bending energy

ESB = Total Stretch Bending energy

ET = Total Torsional Energy

EOOP = Total Out-Of-Plane Bending energy, and

'''where the non-bonded interactions are:'''

EVdW = Total Van der Waals Energy

EEE = Total Electrostatic Energy

{| border="1" cellspacing="1" cellpadding="10"
|-
| width="300" align="center" | '''Types of Energies'''
! width="600" align="center" | '''Explanation'''
|-
| colspan="2" style="text-align: center;" | '''Bonded Interactions'''
|-
| width="300" align="center" | '''Total Bond Stretching Energy'''
! width="600" align="left" | The total bond stretching energy is related to the vibration energy of the molecules in comparison to the equilibrium bond length. Whenever a bond deviates from the equilibrium bond length, the energy value increases.

MMFF94s uses a quartic function that has the force constant term (relate to bond strength). The quartic function term is superior to the cubic function term (used in MM2) in the sense that it avoid the “cubic stretch catastrophe” where progressive elongation of molecule bond length leads to negative infinity.
|-
| width="300" align="center" | '''Total Angle Bending Energy'''
! width="600" align="left" | Similar to Total Bond Stretching Energy, the total angle bending energy is also related to the vibration energy of the molecules about the equilibrium bond length. However, unlike EBS that measures the bond strength, EAB is associated with the stiffness of the molecules based on the Hookiean potential. Whenever bond angles deviate from the norm during vibration, this energy term increases as well.
|-
| width="300" align="center" | '''Total Stretch-Bending Energy'''
! width="600" align="left" | This energy term takes into account of the energy due to increase in bond length when bond angle between two atoms changes.
|-
| width="300" align="center" | '''Total Torsional Energy'''
! width="600" align="left" | Total torsional energy is the energy required for intermolecular rotation about the bonds. In molecule mechanics, however, this term is often used as a correction that must be added or subtracted to the total energy of the molecule to fit a quantum mechanical calculation about the dihedral angles of bonds.
|-
| width="300" align="center" | '''Total Out-Of-Plane Bending Energy'''
! width="600" align="left" | This energy term refers to the energy needed to deform the dihedral angle (zero degrees) of a planar group of atoms such as carbonyl or amide functional groups.
|-
| colspan="2" style="text-align: center;" | '''Non-Bonded Interactions'''
|-
| width="300" align="center" | '''Total Van der Waals Energy'''
! width="600" align="left" | The total Van der Waals energy term examines the intramolecular interactions such as repulsion or attraction between non-bonded atoms in the molecule. This term is crucial in determining the preferred conformation of the molecule.

MMFF94s employs the novel “Buffered-14-7”. The name is derived from a buffering constant and the 14th and 7th power dependencies of the repulsive and attractive energy in the equation.
|-
| width="300" align="center" | '''Total Electrostatic Energy'''
! width="600" align="left" | The total electrostatic energy functions take into account of the Coulombic potential and partial charge/dipole/atomic point charges interactions within the molecule.
|-

|}

 

== '''Part 2 : Conformational Analysis Using Molecular Mechanics''' ==
=== '''The Hydrogenation of Cyclopentadiene Dimer''' ===

==== '''Endo and exo adduct from the Dimerization of Cyclopentadiene''' ====
Cyclopentadiene will undergo dimerization by Diels-alder reaction to form either an endo or exo adduct.

[[File:XcwDimerization of CP.png|500px|center]]

==== '''Stereoselectivity of Dimerization of Cyclopentadiene''' ====
Although the exo adduct is thermodynamically more stable than the endo adduct, the endo adduct is form preferentially. Using the QST2 method, the transition state of the Diels Alder dimerization was found. It was discovered that due to the secondary orbital interactions in the endo transition state, the endo dimer is formed preferentially (the kinetic product). Hence, it is proven that the Diels Alder dimerization between two cyclopentadiene are kinetically controlled.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Transition State of Dimerization of Cyclopentadiene'''
| '''Imaginary Stretch Frequency (-881.25) of the Endo Transition State (click to animate)'''
| '''Secondary Orbital Interaction (Red overlapping orbitals)'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<uploadedFileContents>EndotsDCPD2.mol
</uploadedFileContents>
</jmolApplet></jmol>
| [[File:Xcwendotsimaginary.gif|300px|center]]
| [[File:XcwSecondary orbital interaction1.jpg|300px|center]]
|-
|}

 

==== '''Asynchronous Bond Formation of Dimerization of Cyclopentadiene''' ====

The initial study of the molecular orbitals of the transition states seemed a bit peculiar. Instead of getting a LUMO with symmetrical orbitals, the calculations showed a HOMO that is asymetric at the carbons where the new sigma bonds will be formed. Running an IRC further, it soon became clear that the asymmetry of the HOMO leads to an asychronous bond formation before leading to the product.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''IRC plot following the Endo Transition State '''
| '''IRC following the Endo Transition State (click to animate)'''
| '''Asymmetry of orbitals at the carbons where the new sigma bonds will be formed'''
|- align="center"
| [[File:XcwendotscyclopentadieneIRC.png|300px|center]]
| [[File:XcwendotsIRC.gif|300px|center]]
| [[File:XcwAsynchronous mo.jpg|300px|center]]
|-
|}

 

==== '''Comparison of Energies between the Endo and Exo adduct of Dicyclopentadiene''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Adduct of Dicyclopentadiene dimerization'''
| '''Exo Adduct of Dicyclopentadiene dimerization'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=19,atomno=1,atomno=2; color green;measure 19 1;measure 19 2;</script>
<uploadedFileContents>XcwEndodimer3.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>Exodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=7,atomno=17; color green;measure 17 7;</script>
<uploadedFileContents>XcwExodimer1.mol</uploadedFileContents>
</jmolApplet></jmol>
|-
|}

 

Using MMFF94s ab initio calculations, the energies for the exo dimer and the endo dimer are derived.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Exodimer'''
| '''55.374'''
| 3.543
| 30.772
| -2.041
| -2.728
| 0.015
| 12.800
| 13.014
|-
| '''Endodimer'''
| '''58.191'''
| 3.468
| 33.187
| -2.082
| -2.950
| 0.023
| 12.360
| 14.186
|-
|}

 

The MMFF94s steric energy (after minimization) for the exo dimer is lower than that of the endo dimer. This is reflected by the large difference for the EEE between the endo dimer and the exo dimer due to unfavourable steric repulsion between the two “arched down” cyclopentene rings.

==== '''Hydrogenation of Dicyclopentadiene''' ====

Hydrogenation of the endo dicyclopentadiene (DCPD) would lead to two potential products: dihydro product 1 and dihydro product 2.

[[File:XcwFormation of Dihydro products.png|500px|center]]

Using MMFF94s, the energy of the two dihydro products are calculated.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Dihydro Product 1'''
| '''50.123'''
| 3.308
| 30.864
| -1.927
| 0.060
| 0.015(2)
| 13.281
| 5.121
|-
| '''Dihydro Product 2'''
| '''41.257'''
| 2.823
| 24.685
| -1.657
| -0.379
| 0.000(2)
| 10.639
| 5.147
|-
| '''Tetrahydro Product'''
| '''39.042'''
| 2.730
| 25.151
| -1.676
| 1.287
| 0.000
| 11.551
| 0.000
|}

 

From the MMFF94s calculation, it can be seen that dihydro product 2 has a lower steric energy than dihydro product 1. Therefore, dihydro product 2 is the thermodynamic product for the hydrogenation of dicylopentadiene. And indeed, this was what was observed by Skala et al.. He observed that the first hydrogenation occur at the norborene part of the molecule (rate of hydrogenation several times faster than that in the cyclopentene ring)6. The first heat of hydrogenation at the norborene is 138.8 kJ/mol while the second hydrogenation at the cyclopentene right is 109.5 kJ/mol6.

From the above results, it is also obvious that tetrahydro product is much more stable than either dihydro product. And yet, studies have shown that the tetrahydro product will only form after prolonged hydrogenation under high temperature. However, subjecting DCPD to high temperature leads to low yield due to cracking of DCPD.

Since thermodynamically it is predicted to form favourably, the fact that it does not could only mean that the hydrogenation of DCPD to tetrahydrodicyclopentadiene (TH-DCPD) is kinetically controlled. Most possibly, the transition state of the hydrogenation of DCPD is highly unstable hence it is unlikely to form.

=== '''Atropisomerism in an Intermediate related to the Synthesis of Taxol''' ===

Atropisomerism is a type of stereoisomerism that is form as a result of hindered rotation about a single bond.

[[File:XcwAtropisomerism example.png|500px|center]]

In the case of the 6,6’-dinitro-2,2’-diphenic acid, rotation about the bonds joining the two substituted phenyl rings would have to overcome large steric interaction between the bulky substituents. The barrier of rotation is high enough for the two conformers to be isolated individually.

In the synthesis of taxol, one of the key intermediates exhibit atropisomerism.

==== '''Atropisomerism in Taxol Synthesis''' ====

For the key intermediate, rotation about the carbon-carbon bonds would lead to two types of atropisomers, each with either the carbonyl group poining upwards or downwards in relative to the bridge.

[[File:XcwIntermediate 9 and Intermediate 10.png|500px|center]]

Once again by using MMFF94s ab initio calculations, the steric energies for the two intermediates are illustrated as below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 9'''
| '''70.571'''
| 7.743
| 28.356
| -0.062
| 0.004
| 0.949
| 33.293
| 0.288
|-
| '''Intermediate 10'''
| '''60.553'''
| 7.599
| 18.838
| -0.139
| 0.199
| 0.844
| 33.269
| -0.056
|-

|}

 

Analyzing the data above, the largest energy difference between Intermediate 9 and Intermediate 10 stems from the EAB which is related to the strain of the ring. Intermediate 9 has an excess of 9.518 kcal/mol EAB as compared to Intermediate 10. This comes as a surprise as intermediate 9 is predicted to be more stable alkene.

The rationale behind the prediction of the stability of intermediate 9 stems from the fact that the through-space distance of the upward-pointing carbonyl oxygen with the carbon-carbon is further than the through space distance between the downward-pointing carbonyl oxygen with the -CH2-CH2- fragment at the norbornene part in intermediate 10.

==== '''Hyperstable Olefins''' ====

Intermediate 9 and Intermediate 10 does not react readily with other reagents during functionalization. This is due to the hyperstability effect found in hyperstable olefins.

Hyperstable olefins are alkenes that contain less strain in the ring (i.e. negative olefin strain values) compared to the parent hydrocarbon. To study this further, further MMFF94s calculation was done to compare Intermediate 10 with the parent hydrocarbon.

[[File:XcwIntermediate10andPH.png|500px|center]]

The energies that we calculated are tabulated as shown below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 10'''
| '''44.878 '''
| 5.211
| 15.488
| -0.267
| -1.655
| 0.998
| 25.014
| 0.088
|-
| '''Parent Hydrocarbon'''
| '''50.564'''
| 4.692
| 21.979
| 0.109
| -0.958
| 0.247
| 24.495
| 0.000
|-

|}

 

Scrutinizing the results, the largest energy difference between intermediate 10 and the parent hydrocarbon stems from the Total Angle Bending Energy, EAB. Since the Total Angle bending energy is related to the angle strain in the molecules, it is apparent that the parent hydrocarbon has more ring strain as compared to the bridgehead olefin.

== '''Part 3 : Spectroscopic Simulation Using Quantum Mechanics''' ==
=== '''Spectroscopy of an Intermediate Related to the Synthesis of Taxol''' ===

Molecule 17 and 18 are derivatives of intermediate 9 and 10. In this exercise, MMFF94s is used to predict the 1H and 13C NMR of molecule 17 and molecule 18.

[[File:XcwIntermediate17&18.png|500px|center]]

==== '''NMR Spectra of Molecule 17''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 17.mol
</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwHNMRMolecule 17 Chair Overall NMR.png|500px|center]]
| [[File:XcwHNMRMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.1825
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| The first three results were fairly straight forward to be deduced and correlate wit experimental data.

The hydrogen atom that is geminally attached to the carbon of the double bonds is the most deshielded due to the ring current anisotropic effect of the ring current

The second most deshielded hydrogen atom is the hydrogen atom on the methyl group on the bridge. The hydrogen atom is pointing directly to the oxygen atom of the carbonyl functional group.

The peaks with an integration height of 4 is assigned to the hydrogen atoms in the 1,3-dithiolane ring fragment.

Subsequent analysis of the 1H NMR became very complicated very quickly for two reasons:

1. Gaussian calculations showed some atoms with an integration height of 3. Comparing their file atom number and checking their chemical environment, it is not possible to find any correlation between them.

2. Some of the peaks in the literature remains unresolved and are given as multiplets or grouped together.

|- align="center"
| 52
| 3.1775
| 1
| '''2.99'''
|- align="center"
| 53,52,50,51
| 3.0867
| 4
| '''3.40-3.10'''
|- align="center"
| 42,43,39
| 2.7445
| 3
| ''' '''
|- align="center"
| 49
| 2.6187
| 1
| ''' '''
|- align="center"
| 34
| 2.4371
| 1
| ''' '''
|- align="center"
| 35
| 2.3782
| 1
| ''' '''
|- align="center"
| 40,37,26
| 2.2730
| 3
| ''' '''
|- align="center"
| 30
| 2.1566
| 1
| ''' '''
|- align="center"
| 36
| 2.1033
| 1
| ''' '''
|- align="center"
| 32,28
| 2.0259
| 2
| ''' '''
|- align="center"
| 25
| 1.8535
| 2
| ''' '''
|- align="center"
| 38,46,27
| 1.5898
| 3
| '''1.25'''
|- align="center"
| 29
| 1.4557
| 1
| ''' '''
|- align="center"
| 31
| 1.0123
| 1
| ''' '''
|- align="center"
| 44,48,45
| 0.9087
| 3
| '''1.10'''
|- align="center"
| 47
| 0.8354
| 1
| ''' '''
|- align="center"
| 33
| 0.5790
| 1
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 17 Chair Overall NMR2.png|500px|center]]
| [[File:XcwMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 216.2725
| 1
| '''218.79'''
| rowspan="10" style="text-align:center;"| [[File:XcwMolecule 17 image for CNMR.jpg|600px|center]]
|- align="center"
| 13
| 144.8626
| 1
| '''144.63'''
|- align="center"
| 14
| 124.7193
| 1
| '''125.33'''
|- align="center"
| 3
| 91.3340
| 1
| '''72.88'''
|- align="center"
| 2
| 60.9568
| 1
| '''56.19'''
|- align="center"
| 1
| 57.0811
| 1
| '''52.52'''
|- align="center"
| 10
| 52.4663
| 1
| '''48.50'''
|- align="center"
| 16
| 51.4857
| 1
| '''46.80'''
|- align="center"
| 9
| 46.9196
| 1
| '''45.76'''
|- align="center"
| 23
| 43.8647
| 1
| '''39.80'''
|- align="center"
| 22
| 41.9450
| 1
| '''38.81'''
| Comments
|- align="center"
| 4
| 41.8724
| 1
| '''35.85'''
| rowspan="9" style="text-align:left;"| The carbon bonded to the oxygen atom is the most deshielded, as is shown in the predicted values and the experimental values. There is a deviation between the values. Quite possibly, this is due to the fact that in reality, the carbonyl functional group is pointing slightly towards the equatorial position rather than a lateral position relative to the ring (as is in the input for Gaussian calculation)

Most of the 1CNMR values that was predicted by Gaussian are all within an acceptable range of deviation. However, there is carbon 3 that has significant deviation between the predicted value and experimental value.

Carbon 3 is the carbon bonded to the two sulphurs in the 1,3-dithiolane ring fragment. Such a huge deviation would possibly mean that the conformer that was given as input to Gaussian differs from the literature.

The above NMR spectra was corrected with a level of theory B3LYP/6-31G(d,p) using TMS as reference and in chloroform.

|- align="center"
| 15
| 35.4348
| 1
| '''32.66'''
|- align="center"
| 11
| 31.1964
| 1
| '''28.79'''
|- align="center"
| 6
| 28.9432
| 1
| '''28.29'''
|- align="center"
| 7
| 28.3640
| 1
| '''26.88'''
|- align="center"
| 12
| 27.3767
| 1
| '''25.66'''
|- align="center"
| 17
| 26.3311
| 1
| '''23.86'''
|- align="center"
| 15
| 24.5483
| 1
| '''20.96'''
|- align="center"
| 18
| 19.7788
| 1
| '''18.71'''
|-
|}
 

==== '''NMR Spectra of Molecule 18''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 18 Boat for Image2.mol</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"-
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 18 Chair Overall NMR.png|500px|center]]
| [[File:Molecule 18 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.2832
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| ''' '''
|- align="center"
| 50
| 3.3175
| 1
| rowspan="4" style="text-align:centre;"| '''3.00-2.70'''
|- align="center"
| 52
| 3.2153
| 1
|- align="center"
| 51,53
| 3.1161
| 2
|- align="center"
| 34,43
| 2.8606
| 2
|- align="center"
| 38
| 2.4549
| 1
| ''' '''
|- align="center"
| 42
| 2.3968
| 1
| ''' '''
|- align="center"
| 25,29,26
| 2.2796
| 3
| ''' '''
|- align="center"
| 39
| 2.0844
| 1
| ''' '''
|- align="center"
| 40,36
| 1.9699
| 2
| ''' '''
|- align="center"
| 37,24
| 1.8519
| 2
| ''' '''
|- align="center"
| 31,27
| 1.6780
| 2
| ''' '''
|- align="center"
| 28
| 1.6175
| 1
| ''' '''
|- align="center"
| 46,49
| 1.4979
| 2
| ''' '''
|- align="center"
| 35
| 1.4150
| 1
| ''' '''
|- align="center"
| 32
| 1.3531
| 1
| ''' '''
|- align="center"
| 48
| 1.1606
| 1
| ''' '''
|- align="center"
| 33,30,47
| 1.0653
| 3
| '''1.03'''
|- align="center"
| 44,45
| 0.9643
| 2
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwMolecule 18 Boat Overall NMR.png|500px|center]]
| [[File:XcwMolecule 18 Boat zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 211.8325
| 1
| '''211.49'''
| rowspan="10" style="text-align:center;"| [[File:Molecule 18 Boat for 13 CNMR.jpg|600px|center]]
|- align="center"
| 13
| 148.6673
| 1
| '''148.72'''
|- align="center"
| 14
| 118.8373
| 1
| '''120.90'''
|- align="center"
| 3
| 89.0869
| 1
| '''74.61'''
|- align="center"
| 2
| 67.8886
| 1
| '''60.53'''
|- align="center"
| 1
| 56.1133
| 1
| '''51.30'''
|- align="center"
| 10
| 55.5998
| 1
| '''50.94'''
|- align="center"
| 16
| 50.1124
| 1
| '''45.53'''
|- align="center"
| 22
| 48.2030
| 1
| '''43.28'''
|- align="center"
| 23
| 44.2222
| 1
| '''40.82'''
|- align="center"
| 4
| 42.0354
| 1
| '''38.73'''
| Comments
|- align="center"
| 9
| 37.5865
| 1
| '''36.78'''
| rowspan="9" style="text-align:left;"| ''' '''
|- align="center"
| 6
| 35.3106
| 1
| '''35.47'''
|- align="center"
| 15
| 31.0459
| 1
| '''30.84'''
|- align="center"
| 7
| 28.8476
| 1
| '''30.00'''
|- align="center"
| 12
| 28.6623
| 1
| '''25.56'''
|- align="center"
| 17
| 25.7393
| 1
| '''25.35'''
|- align="center"
| 11
| 25.2603
| 1
| '''22.21'''
|- align="center"
| 18
| 23.3944
| 1
| '''21.39'''
|- align="center"
| 5
| 21.0478
| 1
| '''19.83'''
|-
|}
 

== '''Part 4 : Analysis of the Properties of the Synthesized Alkene Epoxides''' ==
=== '''The two catalytics systems''' ===

Assymmetric epoxidation of prochiral alkenes may lead to product with different stereochemical outcome as illustrated as below. To solve this problem, different types of asymmetric epoxidation catalyst have been synthesized. In this study, we shall be focusing on Shi asymmetric fructose catalyst as well as Jacobsen asymmetric catalyst.

[[File:Asymmetric catalyst.png|400px|center]]

==== ''' The Shi Asymmetric Fructose Catalyst''' ====

Molecule 21 is the stable precursor of molecule 22, the active catalyst. Molecule 21 can be converted to molecule 22 by using either persulfuric acid or potassium peroxymonosulphate.

[[File:Molecule 21 to 23.png|400px|center]]

The transition state of the Shi epoxidation was a subject of debate for a few moments. However, recent studies have led to the conclusion that the spiro transition state is more favored than the planar transition state. The spiro transition state is the transition that has its dioxirane perpendicularly bisecting the alkene double bond. This is thought to be more favourable due to interactions between the lone pairs of the oxygen with the LUMO of the alkene.

[[File:Spiro and planar ts.png|500px|center]]

==== ''' The Jacobsen Asymmetric Catalyst''' ====

Molecule 23 is the stable precursor of molecule 24, the active catalyst. Molecule 23 can be converted to molecule 24 by using sodium perchlorate.

[[File:Salen, 23 and 24.png|400px|center]]

Jacobsen catalyst is biphasic. The first phase involves the transfer of oxygen to molecule 23. Sodium perchlorate oxidizes Mn(III) to Mn(V).

In the second step, Jacobsen catalyst acts via a radical mechanism. It is thought to be so because epoxidation of trans-alkene by Jacobsen catalyst yield cis-alkene as well. A radical mechanism will lead to the lost of stereochemical information of the molecule.

=== ''' Crystal structure of the two catalyst''' ===
==== '''Molecule 21''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 21'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 21 strucutre.png|600px|center]]'''
|-
| style="text-align:center;" width="150" | ''' Bond '''
| style="text-align:center;" width="150"| ''' Bond Lenghts (Angstrom)'''
| style="text-align:center;" | ''' Evaluation'''
|-
| style="text-align:center;"| ''' O1-C1 '''
| style="text-align:center;"| ''' 1.400'''
| rowspan="10" style="text-align:left;"| [[File:Molecule 21 2.png|300px|center]]

The normal bond length of an C-O bond is 1.430 angstrom.

The most interesting aspect here is O4 and O2. The lone pair of O4 is antiperplanar to the sigma* orbital of the carbonyl group while the lone pair of O2 is anti periplanar to the carbonyl pi* orbital. Donation of electron can occur because of the correct symmetry. Due to the mixing of the orbitals, the C2-O2 and C4-O4 has been conferred with a certain degree of double bond character.

However, due to the lone pair on oxygen being now donated to the carbonyl antibonding orbitals, the O2 and O4 is slightly “electron deficient” and electron density will be pulled away from O2 and O4. That would explain why the bond length increase for O2-C7 and O4-C10. Increase in bond length is an indicator of the weakening of the bond.
|-
| style="text-align:center;"|'''O1-C7'''
| style="text-align:center;"|'''1.413'''
|-
| style="text-align:center;"|'''O2-C7'''
| style="text-align:center;"|'''1.441'''
|-
| style="text-align:center;"|'''O2-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O4-C4'''
| style="text-align:center;"|'''1.396'''
|-
| style="text-align:center;"|'''O4-C10'''
| style="text-align:center;"|'''1.439'''
|-
| style="text-align:center;"|'''O5-C10'''
| style="text-align:center;"|'''1.409'''
|-
| style="text-align:center;"|'''O5-C5'''
| style="text-align:center;"|'''1.416'''
|-
| style="text-align:center;"|'''O6-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O6-C6'''
| style="text-align:center;"|'''1.420'''
|-
|}
 

==== '''Molecule 23''' ====

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 23'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 23 struc.png|600px|center]]'''
|-
| The most outstanding feature from this molecule is the fact that is adopt a puckered form of the square base pyramidal form. This is no surprise that the molecule is almost planar due to the electron delocalization around each side of the salen ligand.

The tery-butyl hydrogen are oriented closely to one another. Non-covalent interaction studies indicated that repulsion would occur for H---H bond length that are less than 2.1 angstrom while favourable interaction may be dominant with bond length above 2.4 angstrom. It was discovered that all 4 hydrogens have bond length more than 2.4 angstrom hence there should not be any significant repulsion between them. Instead, certain amount of attractive force will ensue and that contributes to the overall stability of the molecule

|-
|}
 

=== ''' The calculated NMR properties of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | '''
Shielding (ppm) Degeneracy
7.4891704929 4.0000
7.2988172444 1.0000
3.6627082199 1.0000
3.1170156088 1.0000
2.5382383043 1.0000 '''
| width="100" | '''
Shielding (ppm) Degeneracy
24.2569032127 4.0000
24.4474861875 1.0000
28.0829310079 1.0000
28.6310290891 1.0000
29.2122790315 1.0000
'''
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Styrene R HNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Styrene S HNMR.png|400px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | '''
Shift (ppm) Degeneracy
135.1098747604 1.0000
124.1186533632 1.0000
123.4150641684 1.0000
122.9584694331 2.0000
118.2653162569 1.0000
54.0265785300 1.0000
53.4853575062 1.0000 '''
| width="100" | '''
Shift (ppm) Degeneracy
135.1323742030 1.0000
124.1343038829 1.0000
123.4137039868 1.0000
122.9558208084 2.0000
118.2690258882 1.0000
54.0599580762 1.0000
53.4684920923 1.0000
'''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | ''' [[File:Styrene R CNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Styrene S CNMR.png|400px|center|]]'''
|-
| width="100" | ''' '''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | ''' Shift (ppm) Degeneracy
7.5705724829 2.0000
7.4791732656 8.0000
3.5390102503 2.0000
| width="100" | ''' Shift (ppm) Degeneracy
7.5705651164 2.0000
7.4791779628 8.0000
3.5374502607 2.0000
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Stilbene RR HNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|400px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | ''' Shift (ppm) Degeneracy
134.0942417727 2.0000
124.2206838184 2.0000
123.5192390024 2.0000
123.2125901307 2.0000
123.0785800542 2.0000
118.2583039589 2.0000

66.4212770637 2.0000 '''
| width="100" | ''' Shift (ppm) Degeneracy
134.0899175142 2.0000
124.2224499528 2.0000
123.5180152862 2.0000
123.2113538650 2.0000
123.0745448885 2.0000
118.2635789492 2.0000
66.4249347217 2.0000 '''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | ''' [[File:Stilbene RR CNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|400px|center|]]'''
|-
|}

 

=== ''' Assigning the absolute configuration of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''Predicted ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg'''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg '''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental conditions'''
| width="100" | '''1.00g/100ml, chloroform, 21 degree Celcisus, 589 nm wavelength '''
| width="100" | '''1.02g/100ml (99% ee), chloroform, 25 degree Celsius, 589 nm wavelength '''
| width="100" | '''1.01g/100ml, ethanol, 22 degree Celsius, 589 nm wavelength '''
| width="100" | '''0.6g/100ml, ethanol, 20 degree Celsius, 589 nm wavelength '''
|- align="left"
| width="100" | ''' Predicted VCD Spectrum'''
| width="100" | '''[[File:Styrene R VCD.png|200px|center|]] '''
| width="100" | '''[[File:Styrene S VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene RR VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene SS VCD.png|200px|center|]]'''
|-
|}

 

All the assignments given in the literature reports are correct although the predicted value differs slightly with the experimental values

=== ''' Analysis of the Transition State for Reactions''' ===
==== '''Predicting Enantiomeric Excess based on Transition State energies''' ====

One of the energy output from Gaussian calculation is the “sum of electronic and thermal free energies”. This is Gibbs Free Energy at 298.15K and 1 atm.

Using this term and invoking a variant of the Curtin-Hammett Principle, it is possible to calculate a predicted enantiomeric excess of one enantiomer over the other.

[[File:Ee and transition state energy.png|800px|center]]

Using the derivations from above and equation (4), we analyze the enantiomeric excess of beta-methyl styrene and the results are tabulated as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1343.022970'''
| width="100" | '''-1343.017942'''
| width="150" | '''-0.005028'''
| width="150" | '''4.88E-03'''
| width="150" | '''99.03'''
|- align="center"
| width="100" | '''-1343.019233'''
| width="100" | '''-1343.015603'''
| width="150" | '''-0.003630'''
| width="150" | '''2.14E-02'''
| width="150" | '''95.80'''
|- align="center"
| width="100" | '''-1343.029272'''
| width="100" | '''-1343.023766'''
| width="150" | '''-0.005506'''
| width="150" | '''2.94E-03'''
| width="150" | '''99.41'''
|- align="center"
| width="100" | '''-1343.032443'''
| width="100" | '''-1343.024742'''
| width="150" | '''-0.007701'''
| width="150" | '''2.88E-04'''
| width="150" | '''99.94'''
|-
|}

 

The above hartree units are converted to J/mol for calculation of K where 1 hartress = 4.3597E-18

Studying all the free energies of the (R,R) series and compare them with the (S,S) series, it comes as no surprise that (R,R) product is favoured over (S,S) product as (R,R) is more stable. Indeed, this corresponds with the literature value reporting 92% ee of (R,R) products over that of (S,S).

==== '''Analysis of the Transition State of Epoxidation''' ====
==== '''Shi Fructose Catalyst''' ====
For this section, I will be analyzing the the transition state of 1) styrene and 2) trans-stilbene with the Shi fructose catalyst.

===== '''(R) and (S)-styrene transition state''' =====
The transition state for the formation of (R)-styrene oxide and (S)-styrene oxide are given as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R)-styrene oxide'''
| width="150" | '''(S)-styrene oxide'''
|- align="center"
| width="150" | ''' Structure of Catalyst '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide R.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide S ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| [[File:Steric shi fructose R.png|450px|center]]
| [[File:Steric shi fructose S.png|450px|center]]
|-
|}

 

In the transition state for (R)-styrene, it was discovered that the Re face is reacting with the oxygen of the dioxirane. The phenyl ring is oriented endo with respect to the fructose catalyst. However, the (S)-styrene is reacting at the Si face and the phenyl ring is oriented exo relative to the catalyst.

The approach taken by (R)-styrene and (S)-styrene are restricted to only one due to steric interactions. Therefore, the epoxidation of both styrenes by the Shi catalyst will be stereospecific and retains all the stereochemical information of the reactant. However, whether or not (R)-styrene oxide or (S)-styrene oxide is form is dependent on the relative energies of the transition state. The more stable the transition state, the more likely the product of the transition state will be formed.

So in order to examine this, an example of transition state of both styrenes with Shi catalyst are obtained and analyzed.
 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1303.736813'''
| width="100" | '''-1303.727673'''
| width="150" | '''-0.00914'''
| width="150" | '''6.28E-05'''
| width="150" | '''99.99'''

|-
|}

 

From the above, we can see the predicted high enantiopurity of the reaction favoring the (R) product because of the lower energy of the transition states. To understand the reason, we have to turn to non-covalent interaction (NCI) analysis.

[[File:NCI shi fructose styrene.png|700px|center]]

To complement the NCI analysis, a QTAIM (Quantum Theory of Atoms in Molecules) analysis is conducted as well.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''(R)-styrene transition state'''
| width="200" | '''(S)-styrene transition state'''
|- align="center"
| width="100" | '''[[File:QTAIM R.png|400px|center]]'''
| width="100" | '''[[File:QTAIM S.png|400px|center]]'''
|- align="center"
| colspan="2" width="100" | '''Comments'''
|-
| colspan="2" width="100" | '''Unsurprisingly, QTAIM analysis has also shown that (R)-styrene/Shi catalyst has more interactions with one another. While (R)-styrene has 2 strong interactions, (S)-styrene has only one with the catalyst. Besides, the phenyl ring of (R)-styrene also confers additional positive interaction with the catalyst. QTAIM analysis has also show several interactions between the C=C geminal hydrogen of (R)-styrene intreacting with the oxygen atoms on the dioxacyclopentane ring'''
|-
|}

 

===== '''(R,R) and (S,S)-Stilbene transition state''' =====

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R,R)-Stilbene oxide'''
| width="150" | '''(S,S)-Stilbene oxide'''
|- align="center"
| width="150" | ''' Structure of Transition State '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Stilbene RR ts.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>SS stilbene oxide ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| colspan="2" | [[File:Shi fructose stilbene.png|700px|center]]

|-
|}

 

However, unlike styrene, trans-stilbene seems to approach perpendicularly to the dioxirane. This is proposed to be due to the steric interactions (marked in purple). Based on first inspection, it seems that (S,S)-Stilbene oxide has more steric interactions than (R,R)-Stilbene oxide. Although unsubstantial, it seems like my guess was correct. The (R,R)-stilbene/Shi catalyst transition state is lower in energy.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1534.687808'''
| width="100" | '''-1534.683440'''
| width="150" | '''0.004368'''
| width="150" | '''9.08E-3'''
| width="150" | '''98.20'''

|-
|}

 

NCI Analysis is also done for trans-stilbene

[[File:NCI stilbene.png|700px|center]]

==== '''Jacobsen Catalyst''' ====

For this section, cis-beta methyl styrene transition state will be analyzed.

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-3383.259559'''
| width="100" | '''-3383.251060'''
| width="150" | '''-0.008499'''
| width="150" | '''1.24E-04'''
| width="150" | '''99.98'''
|- align="center"
| width="100" | '''-3383.253442'''
| width="100" | '''-3383.250270'''
| width="150" | '''-0.003172'''
| width="150" | '''3.48E-02'''
| width="150" | '''93.27'''
|-
|}

 

As is obvious from here, the (S,R) transition state is more stable than the (R,S) transition state. Both transition states are exo with respect to the catalyst.

It is not immediately apparent just by looking at the molecule to determine which spatial groups have interactions with one another. Therefore, an NCI analysis is conducted again.

[[File:NCI Jacobsen.png|700px|center]]

Rep:Mod:Computationalreport1C

2013-11-21T23:26:22Z

Xc2611: /* The calculated NMR properties of the product */

= '''Synthesis and Computational Lab: 1C''' =
== '''Part 1: Introduction to Molecular Mechanics''' ==
=== '''Introduction to MMFF94 and MMFF94s''' ===

With the improvement of computational data and computer processing power, the usage of molecular mechanics/dynamics forcefield has become very integrated in predicting properties of chemical molecules. A molecular mechanics/dynamics forcefield should be able to predict characteristics such as molecular geometries, conformational/stereoisomeric energies, vibrational frequencies etc. to a reasonable accuracy as compared to experimental-derived values.

Building on work from Kollman et al. s’ AMBER forcefield and Allinger et al. s’ MM1, MM2, MM3 and MM4, Merck Research Laboratories have managed to optimized and improved the previous computational algorithms and produced MMFF94 (Merck Molecular Force Field 94). One of the most prominent advantages of MMFF94 over other preceeding work is its enhanced prediction accuracy. The reason lies in the fact that MMFF94’s core parameterization utilizes an unprecedently large amount of computational data obtained from ab initio calculations1.

Subsequently after the development of MMFF94, a new “static” variant of the MMFF was introduced i.e. the MMFF94s. Unlike MMFF94 that was developed for the use of molecular dynamics simulations (which can be expensive), MMFF94s was developed with the purpose of energy minimization studies in mind. Although both systems provide identical results for most systems, they differ for amides and unsaturated amines which contain resonance-delocalized trigonal nitrogen atoms2.

In this computational exercise, MMFF94s is used predominantly as oppose to the alternative Universal Force Field (UFF). Although versatile across the entire periodic table, UFF is derived from simple rules and atomic parameters such as fixed hybridization that increases the likelihood of erroneous structural and energetic predictions3.

=== '''Forms of MMFF94s''' ===

Steric energy of a molecule is the energy arise due to its geometry or conformation. Energy minimization of steric energy process ensures that the molecule is in its lowest energy conformation.

MMFF94s assumes that the total steric energy of a molecule can be found by the sum of a few specific interactions in a molecule.

ES = EBS + EAB + E SB + ET + EOOP + EVdW + EEE

'''where the bonded interactions are:'''

ES = Total Steric energy

EBS = Total Bond Stretching energy

EAB = Total Angle Bending energy

ESB = Total Stretch Bending energy

ET = Total Torsional Energy

EOOP = Total Out-Of-Plane Bending energy, and

'''where the non-bonded interactions are:'''

EVdW = Total Van der Waals Energy

EEE = Total Electrostatic Energy

{| border="1" cellspacing="1" cellpadding="10"
|-
| width="300" align="center" | '''Types of Energies'''
! width="600" align="center" | '''Explanation'''
|-
| colspan="2" style="text-align: center;" | '''Bonded Interactions'''
|-
| width="300" align="center" | '''Total Bond Stretching Energy'''
! width="600" align="left" | The total bond stretching energy is related to the vibration energy of the molecules in comparison to the equilibrium bond length. Whenever a bond deviates from the equilibrium bond length, the energy value increases.

MMFF94s uses a quartic function that has the force constant term (relate to bond strength). The quartic function term is superior to the cubic function term (used in MM2) in the sense that it avoid the “cubic stretch catastrophe” where progressive elongation of molecule bond length leads to negative infinity.
|-
| width="300" align="center" | '''Total Angle Bending Energy'''
! width="600" align="left" | Similar to Total Bond Stretching Energy, the total angle bending energy is also related to the vibration energy of the molecules about the equilibrium bond length. However, unlike EBS that measures the bond strength, EAB is associated with the stiffness of the molecules based on the Hookiean potential. Whenever bond angles deviate from the norm during vibration, this energy term increases as well.
|-
| width="300" align="center" | '''Total Stretch-Bending Energy'''
! width="600" align="left" | This energy term takes into account of the energy due to increase in bond length when bond angle between two atoms changes.
|-
| width="300" align="center" | '''Total Torsional Energy'''
! width="600" align="left" | Total torsional energy is the energy required for intermolecular rotation about the bonds. In molecule mechanics, however, this term is often used as a correction that must be added or subtracted to the total energy of the molecule to fit a quantum mechanical calculation about the dihedral angles of bonds.
|-
| width="300" align="center" | '''Total Out-Of-Plane Bending Energy'''
! width="600" align="left" | This energy term refers to the energy needed to deform the dihedral angle (zero degrees) of a planar group of atoms such as carbonyl or amide functional groups.
|-
| colspan="2" style="text-align: center;" | '''Non-Bonded Interactions'''
|-
| width="300" align="center" | '''Total Van der Waals Energy'''
! width="600" align="left" | The total Van der Waals energy term examines the intramolecular interactions such as repulsion or attraction between non-bonded atoms in the molecule. This term is crucial in determining the preferred conformation of the molecule.

MMFF94s employs the novel “Buffered-14-7”. The name is derived from a buffering constant and the 14th and 7th power dependencies of the repulsive and attractive energy in the equation.
|-
| width="300" align="center" | '''Total Electrostatic Energy'''
! width="600" align="left" | The total electrostatic energy functions take into account of the Coulombic potential and partial charge/dipole/atomic point charges interactions within the molecule.
|-

|}

 

== '''Part 2 : Conformational Analysis Using Molecular Mechanics''' ==
=== '''The Hydrogenation of Cyclopentadiene Dimer''' ===

==== '''Endo and exo adduct from the Dimerization of Cyclopentadiene''' ====
Cyclopentadiene will undergo dimerization by Diels-alder reaction to form either an endo or exo adduct.

[[File:XcwDimerization of CP.png|500px|center]]

==== '''Stereoselectivity of Dimerization of Cyclopentadiene''' ====
Although the exo adduct is thermodynamically more stable than the endo adduct, the endo adduct is form preferentially. Using the QST2 method, the transition state of the Diels Alder dimerization was found. It was discovered that due to the secondary orbital interactions in the endo transition state, the endo dimer is formed preferentially (the kinetic product). Hence, it is proven that the Diels Alder dimerization between two cyclopentadiene are kinetically controlled.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Transition State of Dimerization of Cyclopentadiene'''
| '''Imaginary Stretch Frequency (-881.25) of the Endo Transition State (click to animate)'''
| '''Secondary Orbital Interaction (Red overlapping orbitals)'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<uploadedFileContents>EndotsDCPD2.mol
</uploadedFileContents>
</jmolApplet></jmol>
| [[File:Xcwendotsimaginary.gif|300px|center]]
| [[File:XcwSecondary orbital interaction1.jpg|300px|center]]
|-
|}

 

==== '''Asynchronous Bond Formation of Dimerization of Cyclopentadiene''' ====

The initial study of the molecular orbitals of the transition states seemed a bit peculiar. Instead of getting a LUMO with symmetrical orbitals, the calculations showed a HOMO that is asymetric at the carbons where the new sigma bonds will be formed. Running an IRC further, it soon became clear that the asymmetry of the HOMO leads to an asychronous bond formation before leading to the product.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''IRC plot following the Endo Transition State '''
| '''IRC following the Endo Transition State (click to animate)'''
| '''Asymmetry of orbitals at the carbons where the new sigma bonds will be formed'''
|- align="center"
| [[File:XcwendotscyclopentadieneIRC.png|300px|center]]
| [[File:XcwendotsIRC.gif|300px|center]]
| [[File:XcwAsynchronous mo.jpg|300px|center]]
|-
|}

 

==== '''Comparison of Energies between the Endo and Exo adduct of Dicyclopentadiene''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Adduct of Dicyclopentadiene dimerization'''
| '''Exo Adduct of Dicyclopentadiene dimerization'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=19,atomno=1,atomno=2; color green;measure 19 1;measure 19 2;</script>
<uploadedFileContents>XcwEndodimer3.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>Exodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=7,atomno=17; color green;measure 17 7;</script>
<uploadedFileContents>XcwExodimer1.mol</uploadedFileContents>
</jmolApplet></jmol>
|-
|}

 

Using MMFF94s ab initio calculations, the energies for the exo dimer and the endo dimer are derived.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Exodimer'''
| '''55.374'''
| 3.543
| 30.772
| -2.041
| -2.728
| 0.015
| 12.800
| 13.014
|-
| '''Endodimer'''
| '''58.191'''
| 3.468
| 33.187
| -2.082
| -2.950
| 0.023
| 12.360
| 14.186
|-
|}

 

The MMFF94s steric energy (after minimization) for the exo dimer is lower than that of the endo dimer. This is reflected by the large difference for the EEE between the endo dimer and the exo dimer due to unfavourable steric repulsion between the two “arched down” cyclopentene rings.

==== '''Hydrogenation of Dicyclopentadiene''' ====

Hydrogenation of the endo dicyclopentadiene (DCPD) would lead to two potential products: dihydro product 1 and dihydro product 2.

[[File:XcwFormation of Dihydro products.png|500px|center]]

Using MMFF94s, the energy of the two dihydro products are calculated.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Dihydro Product 1'''
| '''50.123'''
| 3.308
| 30.864
| -1.927
| 0.060
| 0.015(2)
| 13.281
| 5.121
|-
| '''Dihydro Product 2'''
| '''41.257'''
| 2.823
| 24.685
| -1.657
| -0.379
| 0.000(2)
| 10.639
| 5.147
|-
| '''Tetrahydro Product'''
| '''39.042'''
| 2.730
| 25.151
| -1.676
| 1.287
| 0.000
| 11.551
| 0.000
|}

 

From the MMFF94s calculation, it can be seen that dihydro product 2 has a lower steric energy than dihydro product 1. Therefore, dihydro product 2 is the thermodynamic product for the hydrogenation of dicylopentadiene. And indeed, this was what was observed by Skala et al.. He observed that the first hydrogenation occur at the norborene part of the molecule (rate of hydrogenation several times faster than that in the cyclopentene ring)6. The first heat of hydrogenation at the norborene is 138.8 kJ/mol while the second hydrogenation at the cyclopentene right is 109.5 kJ/mol6.

From the above results, it is also obvious that tetrahydro product is much more stable than either dihydro product. And yet, studies have shown that the tetrahydro product will only form after prolonged hydrogenation under high temperature. However, subjecting DCPD to high temperature leads to low yield due to cracking of DCPD.

Since thermodynamically it is predicted to form favourably, the fact that it does not could only mean that the hydrogenation of DCPD to tetrahydrodicyclopentadiene (TH-DCPD) is kinetically controlled. Most possibly, the transition state of the hydrogenation of DCPD is highly unstable hence it is unlikely to form.

=== '''Atropisomerism in an Intermediate related to the Synthesis of Taxol''' ===

Atropisomerism is a type of stereoisomerism that is form as a result of hindered rotation about a single bond.

[[File:XcwAtropisomerism example.png|500px|center]]

In the case of the 6,6’-dinitro-2,2’-diphenic acid, rotation about the bonds joining the two substituted phenyl rings would have to overcome large steric interaction between the bulky substituents. The barrier of rotation is high enough for the two conformers to be isolated individually.

In the synthesis of taxol, one of the key intermediates exhibit atropisomerism.

==== '''Atropisomerism in Taxol Synthesis''' ====

For the key intermediate, rotation about the carbon-carbon bonds would lead to two types of atropisomers, each with either the carbonyl group poining upwards or downwards in relative to the bridge.

[[File:XcwIntermediate 9 and Intermediate 10.png|500px|center]]

Once again by using MMFF94s ab initio calculations, the steric energies for the two intermediates are illustrated as below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 9'''
| '''70.571'''
| 7.743
| 28.356
| -0.062
| 0.004
| 0.949
| 33.293
| 0.288
|-
| '''Intermediate 10'''
| '''60.553'''
| 7.599
| 18.838
| -0.139
| 0.199
| 0.844
| 33.269
| -0.056
|-

|}

 

Analyzing the data above, the largest energy difference between Intermediate 9 and Intermediate 10 stems from the EAB which is related to the strain of the ring. Intermediate 9 has an excess of 9.518 kcal/mol EAB as compared to Intermediate 10. This comes as a surprise as intermediate 9 is predicted to be more stable alkene.

The rationale behind the prediction of the stability of intermediate 9 stems from the fact that the through-space distance of the upward-pointing carbonyl oxygen with the carbon-carbon is further than the through space distance between the downward-pointing carbonyl oxygen with the -CH2-CH2- fragment at the norbornene part in intermediate 10.

==== '''Hyperstable Olefins''' ====

Intermediate 9 and Intermediate 10 does not react readily with other reagents during functionalization. This is due to the hyperstability effect found in hyperstable olefins.

Hyperstable olefins are alkenes that contain less strain in the ring (i.e. negative olefin strain values) compared to the parent hydrocarbon. To study this further, further MMFF94s calculation was done to compare Intermediate 10 with the parent hydrocarbon.

[[File:XcwIntermediate10andPH.png|500px|center]]

The energies that we calculated are tabulated as shown below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 10'''
| '''44.878 '''
| 5.211
| 15.488
| -0.267
| -1.655
| 0.998
| 25.014
| 0.088
|-
| '''Parent Hydrocarbon'''
| '''50.564'''
| 4.692
| 21.979
| 0.109
| -0.958
| 0.247
| 24.495
| 0.000
|-

|}

 

Scrutinizing the results, the largest energy difference between intermediate 10 and the parent hydrocarbon stems from the Total Angle Bending Energy, EAB. Since the Total Angle bending energy is related to the angle strain in the molecules, it is apparent that the parent hydrocarbon has more ring strain as compared to the bridgehead olefin.

== '''Part 3 : Spectroscopic Simulation Using Quantum Mechanics''' ==
=== '''Spectroscopy of an Intermediate Related to the Synthesis of Taxol''' ===

Molecule 17 and 18 are derivatives of intermediate 9 and 10. In this exercise, MMFF94s is used to predict the 1H and 13C NMR of molecule 17 and molecule 18.

[[File:XcwIntermediate17&18.png|500px|center]]

==== '''NMR Spectra of Molecule 17''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 17.mol
</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwHNMRMolecule 17 Chair Overall NMR.png|500px|center]]
| [[File:XcwHNMRMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.1825
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| The first three results were fairly straight forward to be deduced and correlate wit experimental data.

The hydrogen atom that is geminally attached to the carbon of the double bonds is the most deshielded due to the ring current anisotropic effect of the ring current

The second most deshielded hydrogen atom is the hydrogen atom on the methyl group on the bridge. The hydrogen atom is pointing directly to the oxygen atom of the carbonyl functional group.

The peaks with an integration height of 4 is assigned to the hydrogen atoms in the 1,3-dithiolane ring fragment.

Subsequent analysis of the 1H NMR became very complicated very quickly for two reasons:

1. Gaussian calculations showed some atoms with an integration height of 3. Comparing their file atom number and checking their chemical environment, it is not possible to find any correlation between them.

2. Some of the peaks in the literature remains unresolved and are given as multiplets or grouped together.

|- align="center"
| 52
| 3.1775
| 1
| '''2.99'''
|- align="center"
| 53,52,50,51
| 3.0867
| 4
| '''3.40-3.10'''
|- align="center"
| 42,43,39
| 2.7445
| 3
| ''' '''
|- align="center"
| 49
| 2.6187
| 1
| ''' '''
|- align="center"
| 34
| 2.4371
| 1
| ''' '''
|- align="center"
| 35
| 2.3782
| 1
| ''' '''
|- align="center"
| 40,37,26
| 2.2730
| 3
| ''' '''
|- align="center"
| 30
| 2.1566
| 1
| ''' '''
|- align="center"
| 36
| 2.1033
| 1
| ''' '''
|- align="center"
| 32,28
| 2.0259
| 2
| ''' '''
|- align="center"
| 25
| 1.8535
| 2
| ''' '''
|- align="center"
| 38,46,27
| 1.5898
| 3
| '''1.25'''
|- align="center"
| 29
| 1.4557
| 1
| ''' '''
|- align="center"
| 31
| 1.0123
| 1
| ''' '''
|- align="center"
| 44,48,45
| 0.9087
| 3
| '''1.10'''
|- align="center"
| 47
| 0.8354
| 1
| ''' '''
|- align="center"
| 33
| 0.5790
| 1
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 17 Chair Overall NMR2.png|500px|center]]
| [[File:XcwMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 216.2725
| 1
| '''218.79'''
| rowspan="10" style="text-align:center;"| [[File:XcwMolecule 17 image for CNMR.jpg|600px|center]]
|- align="center"
| 13
| 144.8626
| 1
| '''144.63'''
|- align="center"
| 14
| 124.7193
| 1
| '''125.33'''
|- align="center"
| 3
| 91.3340
| 1
| '''72.88'''
|- align="center"
| 2
| 60.9568
| 1
| '''56.19'''
|- align="center"
| 1
| 57.0811
| 1
| '''52.52'''
|- align="center"
| 10
| 52.4663
| 1
| '''48.50'''
|- align="center"
| 16
| 51.4857
| 1
| '''46.80'''
|- align="center"
| 9
| 46.9196
| 1
| '''45.76'''
|- align="center"
| 23
| 43.8647
| 1
| '''39.80'''
|- align="center"
| 22
| 41.9450
| 1
| '''38.81'''
| Comments
|- align="center"
| 4
| 41.8724
| 1
| '''35.85'''
| rowspan="9" style="text-align:left;"| The carbon bonded to the oxygen atom is the most deshielded, as is shown in the predicted values and the experimental values. There is a deviation between the values. Quite possibly, this is due to the fact that in reality, the carbonyl functional group is pointing slightly towards the equatorial position rather than a lateral position relative to the ring (as is in the input for Gaussian calculation)

Most of the 1CNMR values that was predicted by Gaussian are all within an acceptable range of deviation. However, there is carbon 3 that has significant deviation between the predicted value and experimental value.

Carbon 3 is the carbon bonded to the two sulphurs in the 1,3-dithiolane ring fragment. Such a huge deviation would possibly mean that the conformer that was given as input to Gaussian differs from the literature.

The above NMR spectra was corrected with a level of theory B3LYP/6-31G(d,p) using TMS as reference and in chloroform.

|- align="center"
| 15
| 35.4348
| 1
| '''32.66'''
|- align="center"
| 11
| 31.1964
| 1
| '''28.79'''
|- align="center"
| 6
| 28.9432
| 1
| '''28.29'''
|- align="center"
| 7
| 28.3640
| 1
| '''26.88'''
|- align="center"
| 12
| 27.3767
| 1
| '''25.66'''
|- align="center"
| 17
| 26.3311
| 1
| '''23.86'''
|- align="center"
| 15
| 24.5483
| 1
| '''20.96'''
|- align="center"
| 18
| 19.7788
| 1
| '''18.71'''
|-
|}
 

==== '''NMR Spectra of Molecule 18''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 18 Boat for Image2.mol</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"-
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 18 Chair Overall NMR.png|500px|center]]
| [[File:Molecule 18 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.2832
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| ''' '''
|- align="center"
| 50
| 3.3175
| 1
| rowspan="4" style="text-align:centre;"| '''3.00-2.70'''
|- align="center"
| 52
| 3.2153
| 1
|- align="center"
| 51,53
| 3.1161
| 2
|- align="center"
| 34,43
| 2.8606
| 2
|- align="center"
| 38
| 2.4549
| 1
| ''' '''
|- align="center"
| 42
| 2.3968
| 1
| ''' '''
|- align="center"
| 25,29,26
| 2.2796
| 3
| ''' '''
|- align="center"
| 39
| 2.0844
| 1
| ''' '''
|- align="center"
| 40,36
| 1.9699
| 2
| ''' '''
|- align="center"
| 37,24
| 1.8519
| 2
| ''' '''
|- align="center"
| 31,27
| 1.6780
| 2
| ''' '''
|- align="center"
| 28
| 1.6175
| 1
| ''' '''
|- align="center"
| 46,49
| 1.4979
| 2
| ''' '''
|- align="center"
| 35
| 1.4150
| 1
| ''' '''
|- align="center"
| 32
| 1.3531
| 1
| ''' '''
|- align="center"
| 48
| 1.1606
| 1
| ''' '''
|- align="center"
| 33,30,47
| 1.0653
| 3
| '''1.03'''
|- align="center"
| 44,45
| 0.9643
| 2
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwMolecule 18 Boat Overall NMR.png|500px|center]]
| [[File:XcwMolecule 18 Boat zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 211.8325
| 1
| '''211.49'''
| rowspan="10" style="text-align:center;"| [[File:Molecule 18 Boat for 13 CNMR.jpg|600px|center]]
|- align="center"
| 13
| 148.6673
| 1
| '''148.72'''
|- align="center"
| 14
| 118.8373
| 1
| '''120.90'''
|- align="center"
| 3
| 89.0869
| 1
| '''74.61'''
|- align="center"
| 2
| 67.8886
| 1
| '''60.53'''
|- align="center"
| 1
| 56.1133
| 1
| '''51.30'''
|- align="center"
| 10
| 55.5998
| 1
| '''50.94'''
|- align="center"
| 16
| 50.1124
| 1
| '''45.53'''
|- align="center"
| 22
| 48.2030
| 1
| '''43.28'''
|- align="center"
| 23
| 44.2222
| 1
| '''40.82'''
|- align="center"
| 4
| 42.0354
| 1
| '''38.73'''
| Comments
|- align="center"
| 9
| 37.5865
| 1
| '''36.78'''
| rowspan="9" style="text-align:left;"| ''' '''
|- align="center"
| 6
| 35.3106
| 1
| '''35.47'''
|- align="center"
| 15
| 31.0459
| 1
| '''30.84'''
|- align="center"
| 7
| 28.8476
| 1
| '''30.00'''
|- align="center"
| 12
| 28.6623
| 1
| '''25.56'''
|- align="center"
| 17
| 25.7393
| 1
| '''25.35'''
|- align="center"
| 11
| 25.2603
| 1
| '''22.21'''
|- align="center"
| 18
| 23.3944
| 1
| '''21.39'''
|- align="center"
| 5
| 21.0478
| 1
| '''19.83'''
|-
|}
 

== '''Part 4 : Analysis of the Properties of the Synthesized Alkene Epoxides''' ==
=== '''The two catalytics systems''' ===

Assymmetric epoxidation of prochiral alkenes may lead to product with different stereochemical outcome as illustrated as below. To solve this problem, different types of asymmetric epoxidation catalyst have been synthesized. In this study, we shall be focusing on Shi asymmetric fructose catalyst as well as Jacobsen asymmetric catalyst.

[[File:Asymmetric catalyst.png|400px|center]]

==== ''' The Shi Asymmetric Fructose Catalyst''' ====

Molecule 21 is the stable precursor of molecule 22, the active catalyst. Molecule 21 can be converted to molecule 22 by using either persulfuric acid or potassium peroxymonosulphate.

[[File:Molecule 21 to 23.png|400px|center]]

The transition state of the Shi epoxidation was a subject of debate for a few moments. However, recent studies have led to the conclusion that the spiro transition state is more favored than the planar transition state. The spiro transition state is the transition that has its dioxirane perpendicularly bisecting the alkene double bond. This is thought to be more favourable due to interactions between the lone pairs of the oxygen with the LUMO of the alkene.

[[File:Spiro and planar ts.png|500px|center]]

==== ''' The Jacobsen Asymmetric Catalyst''' ====

Molecule 23 is the stable precursor of molecule 24, the active catalyst. Molecule 23 can be converted to molecule 24 by using sodium perchlorate.

[[File:Salen, 23 and 24.png|400px|center]]

Jacobsen catalyst is biphasic. The first phase involves the transfer of oxygen to molecule 23. Sodium perchlorate oxidizes Mn(III) to Mn(V).

In the second step, Jacobsen catalyst acts via a radical mechanism. It is thought to be so because epoxidation of trans-alkene by Jacobsen catalyst yield cis-alkene as well. A radical mechanism will lead to the lost of stereochemical information of the molecule.

=== ''' Crystal structure of the two catalyst''' ===
==== '''Molecule 21''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 21'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 21 strucutre.png|600px|center]]'''
|-
| style="text-align:center;" width="150" | ''' Bond '''
| style="text-align:center;" width="150"| ''' Bond Lenghts (Angstrom)'''
| style="text-align:center;" | ''' Evaluation'''
|-
| style="text-align:center;"| ''' O1-C1 '''
| style="text-align:center;"| ''' 1.400'''
| rowspan="10" style="text-align:left;"| [[File:Molecule 21 2.png|300px|center]]

The normal bond length of an C-O bond is 1.430 angstrom.

The most interesting aspect here is O4 and O2. The lone pair of O4 is antiperplanar to the sigma* orbital of the carbonyl group while the lone pair of O2 is anti periplanar to the carbonyl pi* orbital. Donation of electron can occur because of the correct symmetry. Due to the mixing of the orbitals, the C2-O2 and C4-O4 has been conferred with a certain degree of double bond character.

However, due to the lone pair on oxygen being now donated to the carbonyl antibonding orbitals, the O2 and O4 is slightly “electron deficient” and electron density will be pulled away from O2 and O4. That would explain why the bond length increase for O2-C7 and O4-C10. Increase in bond length is an indicator of the weakening of the bond.
|-
| style="text-align:center;"|'''O1-C7'''
| style="text-align:center;"|'''1.413'''
|-
| style="text-align:center;"|'''O2-C7'''
| style="text-align:center;"|'''1.441'''
|-
| style="text-align:center;"|'''O2-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O4-C4'''
| style="text-align:center;"|'''1.396'''
|-
| style="text-align:center;"|'''O4-C10'''
| style="text-align:center;"|'''1.439'''
|-
| style="text-align:center;"|'''O5-C10'''
| style="text-align:center;"|'''1.409'''
|-
| style="text-align:center;"|'''O5-C5'''
| style="text-align:center;"|'''1.416'''
|-
| style="text-align:center;"|'''O6-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O6-C6'''
| style="text-align:center;"|'''1.420'''
|-
|}
 

==== '''Molecule 23''' ====

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 23'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 23 struc.png|600px|center]]'''
|-
| The most outstanding feature from this molecule is the fact that is adopt a puckered form of the square base pyramidal form. This is no surprise that the molecule is almost planar due to the electron delocalization around each side of the salen ligand.

The tery-butyl hydrogen are oriented closely to one another. Non-covalent interaction studies indicated that repulsion would occur for H---H bond length that are less than 2.1 angstrom while favourable interaction may be dominant with bond length above 2.4 angstrom. It was discovered that all 4 hydrogens have bond length more than 2.4 angstrom hence there should not be any significant repulsion between them. Instead, certain amount of attractive force will ensue and that contributes to the overall stability of the molecule

|-
|}
 

=== ''' The calculated NMR properties of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | '''
Shielding (ppm) Degeneracy
7.4891704929 4.0000
7.2988172444 1.0000
3.6627082199 1.0000
3.1170156088 1.0000
2.5382383043 1.0000 '''
| width="100" | '''
Shielding (ppm) Degeneracy
24.2569032127 4.0000
24.4474861875 1.0000
28.0829310079 1.0000
28.6310290891 1.0000
29.2122790315 1.0000
'''
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Styrene R HNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Styrene S HNMR.png|400px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | '''
Shift (ppm) Degeneracy
135.1098747604 1.0000
124.1186533632 1.0000
123.4150641684 1.0000
122.9584694331 2.0000
118.2653162569 1.0000
54.0265785300 1.0000
53.4853575062 1.0000 '''
| width="100" | '''
Shift (ppm) Degeneracy
135.1323742030 1.0000
124.1343038829 1.0000
123.4137039868 1.0000
122.9558208084 2.0000
118.2690258882 1.0000
54.0599580762 1.0000
53.4684920923 1.0000
'''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | ''' [[File:Styrene R CNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Styrene S CNMR.png|400px|center|]]'''
|-
| width="100" | ''' '''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | ''' Shift (ppm) Degeneracy
7.5705724829 2.0000
7.4791732656 8.0000
3.5390102503 2.0000
| width="100" | ''' Shift (ppm) Degeneracy
7.5705651164 2.0000
7.4791779628 8.0000
3.5374502607 2.0000
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Stilbene RR HNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|400px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | ''' Shift (ppm) Degeneracy
58.0759582273 2.0000
67.9495161816 2.0000
68.6509609976 2.0000
68.9576098693 2.0000
69.0916199458 2.0000
73.9118960411 2.0000
125.7489229363 2.0000 '''
| width="100" | ''' Shift (ppm) Degeneracy
134.0899175142 2.0000
124.2224499528 2.0000
123.5180152862 2.0000
123.2113538650 2.0000
123.0745448885 2.0000
118.2635789492 2.0000

66.4249347217 2.0000 '''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | ''' [[File:Stilbene RR CNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|400px|center|]]'''
|-
|}

 

=== ''' Assigning the absolute configuration of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''Predicted ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg'''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg '''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental conditions'''
| width="100" | '''1.00g/100ml, chloroform, 21 degree Celcisus, 589 nm wavelength '''
| width="100" | '''1.02g/100ml (99% ee), chloroform, 25 degree Celsius, 589 nm wavelength '''
| width="100" | '''1.01g/100ml, ethanol, 22 degree Celsius, 589 nm wavelength '''
| width="100" | '''0.6g/100ml, ethanol, 20 degree Celsius, 589 nm wavelength '''
|- align="left"
| width="100" | ''' Predicted VCD Spectrum'''
| width="100" | '''[[File:Styrene R VCD.png|200px|center|]] '''
| width="100" | '''[[File:Styrene S VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene RR VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene SS VCD.png|200px|center|]]'''
|-
|}

 

All the assignments given in the literature reports are correct although the predicted value differs slightly with the experimental values

=== ''' Analysis of the Transition State for Reactions''' ===
==== '''Predicting Enantiomeric Excess based on Transition State energies''' ====

One of the energy output from Gaussian calculation is the “sum of electronic and thermal free energies”. This is Gibbs Free Energy at 298.15K and 1 atm.

Using this term and invoking a variant of the Curtin-Hammett Principle, it is possible to calculate a predicted enantiomeric excess of one enantiomer over the other.

[[File:Ee and transition state energy.png|800px|center]]

Using the derivations from above and equation (4), we analyze the enantiomeric excess of beta-methyl styrene and the results are tabulated as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1343.022970'''
| width="100" | '''-1343.017942'''
| width="150" | '''-0.005028'''
| width="150" | '''4.88E-03'''
| width="150" | '''99.03'''
|- align="center"
| width="100" | '''-1343.019233'''
| width="100" | '''-1343.015603'''
| width="150" | '''-0.003630'''
| width="150" | '''2.14E-02'''
| width="150" | '''95.80'''
|- align="center"
| width="100" | '''-1343.029272'''
| width="100" | '''-1343.023766'''
| width="150" | '''-0.005506'''
| width="150" | '''2.94E-03'''
| width="150" | '''99.41'''
|- align="center"
| width="100" | '''-1343.032443'''
| width="100" | '''-1343.024742'''
| width="150" | '''-0.007701'''
| width="150" | '''2.88E-04'''
| width="150" | '''99.94'''
|-
|}

 

The above hartree units are converted to J/mol for calculation of K where 1 hartress = 4.3597E-18

Studying all the free energies of the (R,R) series and compare them with the (S,S) series, it comes as no surprise that (R,R) product is favoured over (S,S) product as (R,R) is more stable. Indeed, this corresponds with the literature value reporting 92% ee of (R,R) products over that of (S,S).

==== '''Analysis of the Transition State of Epoxidation''' ====
==== '''Shi Fructose Catalyst''' ====
For this section, I will be analyzing the the transition state of 1) styrene and 2) trans-stilbene with the Shi fructose catalyst.

===== '''(R) and (S)-styrene transition state''' =====
The transition state for the formation of (R)-styrene oxide and (S)-styrene oxide are given as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R)-styrene oxide'''
| width="150" | '''(S)-styrene oxide'''
|- align="center"
| width="150" | ''' Structure of Catalyst '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide R.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide S ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| [[File:Steric shi fructose R.png|450px|center]]
| [[File:Steric shi fructose S.png|450px|center]]
|-
|}

 

In the transition state for (R)-styrene, it was discovered that the Re face is reacting with the oxygen of the dioxirane. The phenyl ring is oriented endo with respect to the fructose catalyst. However, the (S)-styrene is reacting at the Si face and the phenyl ring is oriented exo relative to the catalyst.

The approach taken by (R)-styrene and (S)-styrene are restricted to only one due to steric interactions. Therefore, the epoxidation of both styrenes by the Shi catalyst will be stereospecific and retains all the stereochemical information of the reactant. However, whether or not (R)-styrene oxide or (S)-styrene oxide is form is dependent on the relative energies of the transition state. The more stable the transition state, the more likely the product of the transition state will be formed.

So in order to examine this, an example of transition state of both styrenes with Shi catalyst are obtained and analyzed.
 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1303.736813'''
| width="100" | '''-1303.727673'''
| width="150" | '''-0.00914'''
| width="150" | '''6.28E-05'''
| width="150" | '''99.99'''

|-
|}

 

From the above, we can see the predicted high enantiopurity of the reaction favoring the (R) product because of the lower energy of the transition states. To understand the reason, we have to turn to non-covalent interaction (NCI) analysis.

[[File:NCI shi fructose styrene.png|700px|center]]

To complement the NCI analysis, a QTAIM (Quantum Theory of Atoms in Molecules) analysis is conducted as well.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''(R)-styrene transition state'''
| width="200" | '''(S)-styrene transition state'''
|- align="center"
| width="100" | '''[[File:QTAIM R.png|400px|center]]'''
| width="100" | '''[[File:QTAIM S.png|400px|center]]'''
|- align="center"
| colspan="2" width="100" | '''Comments'''
|-
| colspan="2" width="100" | '''Unsurprisingly, QTAIM analysis has also shown that (R)-styrene/Shi catalyst has more interactions with one another. While (R)-styrene has 2 strong interactions, (S)-styrene has only one with the catalyst. Besides, the phenyl ring of (R)-styrene also confers additional positive interaction with the catalyst. QTAIM analysis has also show several interactions between the C=C geminal hydrogen of (R)-styrene intreacting with the oxygen atoms on the dioxacyclopentane ring'''
|-
|}

 

===== '''(R,R) and (S,S)-Stilbene transition state''' =====

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R,R)-Stilbene oxide'''
| width="150" | '''(S,S)-Stilbene oxide'''
|- align="center"
| width="150" | ''' Structure of Transition State '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Stilbene RR ts.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>SS stilbene oxide ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| colspan="2" | [[File:Shi fructose stilbene.png|700px|center]]

|-
|}

 

However, unlike styrene, trans-stilbene seems to approach perpendicularly to the dioxirane. This is proposed to be due to the steric interactions (marked in purple). Based on first inspection, it seems that (S,S)-Stilbene oxide has more steric interactions than (R,R)-Stilbene oxide. Although unsubstantial, it seems like my guess was correct. The (R,R)-stilbene/Shi catalyst transition state is lower in energy.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1534.687808'''
| width="100" | '''-1534.683440'''
| width="150" | '''0.004368'''
| width="150" | '''9.08E-3'''
| width="150" | '''98.20'''

|-
|}

 

NCI Analysis is also done for trans-stilbene

[[File:NCI stilbene.png|700px|center]]

==== '''Jacobsen Catalyst''' ====

For this section, cis-beta methyl styrene transition state will be analyzed.

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-3383.259559'''
| width="100" | '''-3383.251060'''
| width="150" | '''-0.008499'''
| width="150" | '''1.24E-04'''
| width="150" | '''99.98'''
|- align="center"
| width="100" | '''-3383.253442'''
| width="100" | '''-3383.250270'''
| width="150" | '''-0.003172'''
| width="150" | '''3.48E-02'''
| width="150" | '''93.27'''
|-
|}

 

As is obvious from here, the (S,R) transition state is more stable than the (R,S) transition state. Both transition states are exo with respect to the catalyst.

It is not immediately apparent just by looking at the molecule to determine which spatial groups have interactions with one another. Therefore, an NCI analysis is conducted again.

[[File:NCI Jacobsen.png|700px|center]]

Rep:Mod:Computationalreport1C

2013-11-21T23:24:00Z

Xc2611: /* The calculated NMR properties of the product */

= '''Synthesis and Computational Lab: 1C''' =
== '''Part 1: Introduction to Molecular Mechanics''' ==
=== '''Introduction to MMFF94 and MMFF94s''' ===

With the improvement of computational data and computer processing power, the usage of molecular mechanics/dynamics forcefield has become very integrated in predicting properties of chemical molecules. A molecular mechanics/dynamics forcefield should be able to predict characteristics such as molecular geometries, conformational/stereoisomeric energies, vibrational frequencies etc. to a reasonable accuracy as compared to experimental-derived values.

Building on work from Kollman et al. s’ AMBER forcefield and Allinger et al. s’ MM1, MM2, MM3 and MM4, Merck Research Laboratories have managed to optimized and improved the previous computational algorithms and produced MMFF94 (Merck Molecular Force Field 94). One of the most prominent advantages of MMFF94 over other preceeding work is its enhanced prediction accuracy. The reason lies in the fact that MMFF94’s core parameterization utilizes an unprecedently large amount of computational data obtained from ab initio calculations1.

Subsequently after the development of MMFF94, a new “static” variant of the MMFF was introduced i.e. the MMFF94s. Unlike MMFF94 that was developed for the use of molecular dynamics simulations (which can be expensive), MMFF94s was developed with the purpose of energy minimization studies in mind. Although both systems provide identical results for most systems, they differ for amides and unsaturated amines which contain resonance-delocalized trigonal nitrogen atoms2.

In this computational exercise, MMFF94s is used predominantly as oppose to the alternative Universal Force Field (UFF). Although versatile across the entire periodic table, UFF is derived from simple rules and atomic parameters such as fixed hybridization that increases the likelihood of erroneous structural and energetic predictions3.

=== '''Forms of MMFF94s''' ===

Steric energy of a molecule is the energy arise due to its geometry or conformation. Energy minimization of steric energy process ensures that the molecule is in its lowest energy conformation.

MMFF94s assumes that the total steric energy of a molecule can be found by the sum of a few specific interactions in a molecule.

ES = EBS + EAB + E SB + ET + EOOP + EVdW + EEE

'''where the bonded interactions are:'''

ES = Total Steric energy

EBS = Total Bond Stretching energy

EAB = Total Angle Bending energy

ESB = Total Stretch Bending energy

ET = Total Torsional Energy

EOOP = Total Out-Of-Plane Bending energy, and

'''where the non-bonded interactions are:'''

EVdW = Total Van der Waals Energy

EEE = Total Electrostatic Energy

{| border="1" cellspacing="1" cellpadding="10"
|-
| width="300" align="center" | '''Types of Energies'''
! width="600" align="center" | '''Explanation'''
|-
| colspan="2" style="text-align: center;" | '''Bonded Interactions'''
|-
| width="300" align="center" | '''Total Bond Stretching Energy'''
! width="600" align="left" | The total bond stretching energy is related to the vibration energy of the molecules in comparison to the equilibrium bond length. Whenever a bond deviates from the equilibrium bond length, the energy value increases.

MMFF94s uses a quartic function that has the force constant term (relate to bond strength). The quartic function term is superior to the cubic function term (used in MM2) in the sense that it avoid the “cubic stretch catastrophe” where progressive elongation of molecule bond length leads to negative infinity.
|-
| width="300" align="center" | '''Total Angle Bending Energy'''
! width="600" align="left" | Similar to Total Bond Stretching Energy, the total angle bending energy is also related to the vibration energy of the molecules about the equilibrium bond length. However, unlike EBS that measures the bond strength, EAB is associated with the stiffness of the molecules based on the Hookiean potential. Whenever bond angles deviate from the norm during vibration, this energy term increases as well.
|-
| width="300" align="center" | '''Total Stretch-Bending Energy'''
! width="600" align="left" | This energy term takes into account of the energy due to increase in bond length when bond angle between two atoms changes.
|-
| width="300" align="center" | '''Total Torsional Energy'''
! width="600" align="left" | Total torsional energy is the energy required for intermolecular rotation about the bonds. In molecule mechanics, however, this term is often used as a correction that must be added or subtracted to the total energy of the molecule to fit a quantum mechanical calculation about the dihedral angles of bonds.
|-
| width="300" align="center" | '''Total Out-Of-Plane Bending Energy'''
! width="600" align="left" | This energy term refers to the energy needed to deform the dihedral angle (zero degrees) of a planar group of atoms such as carbonyl or amide functional groups.
|-
| colspan="2" style="text-align: center;" | '''Non-Bonded Interactions'''
|-
| width="300" align="center" | '''Total Van der Waals Energy'''
! width="600" align="left" | The total Van der Waals energy term examines the intramolecular interactions such as repulsion or attraction between non-bonded atoms in the molecule. This term is crucial in determining the preferred conformation of the molecule.

MMFF94s employs the novel “Buffered-14-7”. The name is derived from a buffering constant and the 14th and 7th power dependencies of the repulsive and attractive energy in the equation.
|-
| width="300" align="center" | '''Total Electrostatic Energy'''
! width="600" align="left" | The total electrostatic energy functions take into account of the Coulombic potential and partial charge/dipole/atomic point charges interactions within the molecule.
|-

|}

 

== '''Part 2 : Conformational Analysis Using Molecular Mechanics''' ==
=== '''The Hydrogenation of Cyclopentadiene Dimer''' ===

==== '''Endo and exo adduct from the Dimerization of Cyclopentadiene''' ====
Cyclopentadiene will undergo dimerization by Diels-alder reaction to form either an endo or exo adduct.

[[File:XcwDimerization of CP.png|500px|center]]

==== '''Stereoselectivity of Dimerization of Cyclopentadiene''' ====
Although the exo adduct is thermodynamically more stable than the endo adduct, the endo adduct is form preferentially. Using the QST2 method, the transition state of the Diels Alder dimerization was found. It was discovered that due to the secondary orbital interactions in the endo transition state, the endo dimer is formed preferentially (the kinetic product). Hence, it is proven that the Diels Alder dimerization between two cyclopentadiene are kinetically controlled.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Transition State of Dimerization of Cyclopentadiene'''
| '''Imaginary Stretch Frequency (-881.25) of the Endo Transition State (click to animate)'''
| '''Secondary Orbital Interaction (Red overlapping orbitals)'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<uploadedFileContents>EndotsDCPD2.mol
</uploadedFileContents>
</jmolApplet></jmol>
| [[File:Xcwendotsimaginary.gif|300px|center]]
| [[File:XcwSecondary orbital interaction1.jpg|300px|center]]
|-
|}

 

==== '''Asynchronous Bond Formation of Dimerization of Cyclopentadiene''' ====

The initial study of the molecular orbitals of the transition states seemed a bit peculiar. Instead of getting a LUMO with symmetrical orbitals, the calculations showed a HOMO that is asymetric at the carbons where the new sigma bonds will be formed. Running an IRC further, it soon became clear that the asymmetry of the HOMO leads to an asychronous bond formation before leading to the product.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''IRC plot following the Endo Transition State '''
| '''IRC following the Endo Transition State (click to animate)'''
| '''Asymmetry of orbitals at the carbons where the new sigma bonds will be formed'''
|- align="center"
| [[File:XcwendotscyclopentadieneIRC.png|300px|center]]
| [[File:XcwendotsIRC.gif|300px|center]]
| [[File:XcwAsynchronous mo.jpg|300px|center]]
|-
|}

 

==== '''Comparison of Energies between the Endo and Exo adduct of Dicyclopentadiene''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Adduct of Dicyclopentadiene dimerization'''
| '''Exo Adduct of Dicyclopentadiene dimerization'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=19,atomno=1,atomno=2; color green;measure 19 1;measure 19 2;</script>
<uploadedFileContents>XcwEndodimer3.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>Exodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=7,atomno=17; color green;measure 17 7;</script>
<uploadedFileContents>XcwExodimer1.mol</uploadedFileContents>
</jmolApplet></jmol>
|-
|}

 

Using MMFF94s ab initio calculations, the energies for the exo dimer and the endo dimer are derived.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Exodimer'''
| '''55.374'''
| 3.543
| 30.772
| -2.041
| -2.728
| 0.015
| 12.800
| 13.014
|-
| '''Endodimer'''
| '''58.191'''
| 3.468
| 33.187
| -2.082
| -2.950
| 0.023
| 12.360
| 14.186
|-
|}

 

The MMFF94s steric energy (after minimization) for the exo dimer is lower than that of the endo dimer. This is reflected by the large difference for the EEE between the endo dimer and the exo dimer due to unfavourable steric repulsion between the two “arched down” cyclopentene rings.

==== '''Hydrogenation of Dicyclopentadiene''' ====

Hydrogenation of the endo dicyclopentadiene (DCPD) would lead to two potential products: dihydro product 1 and dihydro product 2.

[[File:XcwFormation of Dihydro products.png|500px|center]]

Using MMFF94s, the energy of the two dihydro products are calculated.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Dihydro Product 1'''
| '''50.123'''
| 3.308
| 30.864
| -1.927
| 0.060
| 0.015(2)
| 13.281
| 5.121
|-
| '''Dihydro Product 2'''
| '''41.257'''
| 2.823
| 24.685
| -1.657
| -0.379
| 0.000(2)
| 10.639
| 5.147
|-
| '''Tetrahydro Product'''
| '''39.042'''
| 2.730
| 25.151
| -1.676
| 1.287
| 0.000
| 11.551
| 0.000
|}

 

From the MMFF94s calculation, it can be seen that dihydro product 2 has a lower steric energy than dihydro product 1. Therefore, dihydro product 2 is the thermodynamic product for the hydrogenation of dicylopentadiene. And indeed, this was what was observed by Skala et al.. He observed that the first hydrogenation occur at the norborene part of the molecule (rate of hydrogenation several times faster than that in the cyclopentene ring)6. The first heat of hydrogenation at the norborene is 138.8 kJ/mol while the second hydrogenation at the cyclopentene right is 109.5 kJ/mol6.

From the above results, it is also obvious that tetrahydro product is much more stable than either dihydro product. And yet, studies have shown that the tetrahydro product will only form after prolonged hydrogenation under high temperature. However, subjecting DCPD to high temperature leads to low yield due to cracking of DCPD.

Since thermodynamically it is predicted to form favourably, the fact that it does not could only mean that the hydrogenation of DCPD to tetrahydrodicyclopentadiene (TH-DCPD) is kinetically controlled. Most possibly, the transition state of the hydrogenation of DCPD is highly unstable hence it is unlikely to form.

=== '''Atropisomerism in an Intermediate related to the Synthesis of Taxol''' ===

Atropisomerism is a type of stereoisomerism that is form as a result of hindered rotation about a single bond.

[[File:XcwAtropisomerism example.png|500px|center]]

In the case of the 6,6’-dinitro-2,2’-diphenic acid, rotation about the bonds joining the two substituted phenyl rings would have to overcome large steric interaction between the bulky substituents. The barrier of rotation is high enough for the two conformers to be isolated individually.

In the synthesis of taxol, one of the key intermediates exhibit atropisomerism.

==== '''Atropisomerism in Taxol Synthesis''' ====

For the key intermediate, rotation about the carbon-carbon bonds would lead to two types of atropisomers, each with either the carbonyl group poining upwards or downwards in relative to the bridge.

[[File:XcwIntermediate 9 and Intermediate 10.png|500px|center]]

Once again by using MMFF94s ab initio calculations, the steric energies for the two intermediates are illustrated as below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 9'''
| '''70.571'''
| 7.743
| 28.356
| -0.062
| 0.004
| 0.949
| 33.293
| 0.288
|-
| '''Intermediate 10'''
| '''60.553'''
| 7.599
| 18.838
| -0.139
| 0.199
| 0.844
| 33.269
| -0.056
|-

|}

 

Analyzing the data above, the largest energy difference between Intermediate 9 and Intermediate 10 stems from the EAB which is related to the strain of the ring. Intermediate 9 has an excess of 9.518 kcal/mol EAB as compared to Intermediate 10. This comes as a surprise as intermediate 9 is predicted to be more stable alkene.

The rationale behind the prediction of the stability of intermediate 9 stems from the fact that the through-space distance of the upward-pointing carbonyl oxygen with the carbon-carbon is further than the through space distance between the downward-pointing carbonyl oxygen with the -CH2-CH2- fragment at the norbornene part in intermediate 10.

==== '''Hyperstable Olefins''' ====

Intermediate 9 and Intermediate 10 does not react readily with other reagents during functionalization. This is due to the hyperstability effect found in hyperstable olefins.

Hyperstable olefins are alkenes that contain less strain in the ring (i.e. negative olefin strain values) compared to the parent hydrocarbon. To study this further, further MMFF94s calculation was done to compare Intermediate 10 with the parent hydrocarbon.

[[File:XcwIntermediate10andPH.png|500px|center]]

The energies that we calculated are tabulated as shown below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 10'''
| '''44.878 '''
| 5.211
| 15.488
| -0.267
| -1.655
| 0.998
| 25.014
| 0.088
|-
| '''Parent Hydrocarbon'''
| '''50.564'''
| 4.692
| 21.979
| 0.109
| -0.958
| 0.247
| 24.495
| 0.000
|-

|}

 

Scrutinizing the results, the largest energy difference between intermediate 10 and the parent hydrocarbon stems from the Total Angle Bending Energy, EAB. Since the Total Angle bending energy is related to the angle strain in the molecules, it is apparent that the parent hydrocarbon has more ring strain as compared to the bridgehead olefin.

== '''Part 3 : Spectroscopic Simulation Using Quantum Mechanics''' ==
=== '''Spectroscopy of an Intermediate Related to the Synthesis of Taxol''' ===

Molecule 17 and 18 are derivatives of intermediate 9 and 10. In this exercise, MMFF94s is used to predict the 1H and 13C NMR of molecule 17 and molecule 18.

[[File:XcwIntermediate17&18.png|500px|center]]

==== '''NMR Spectra of Molecule 17''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 17.mol
</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwHNMRMolecule 17 Chair Overall NMR.png|500px|center]]
| [[File:XcwHNMRMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.1825
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| The first three results were fairly straight forward to be deduced and correlate wit experimental data.

The hydrogen atom that is geminally attached to the carbon of the double bonds is the most deshielded due to the ring current anisotropic effect of the ring current

The second most deshielded hydrogen atom is the hydrogen atom on the methyl group on the bridge. The hydrogen atom is pointing directly to the oxygen atom of the carbonyl functional group.

The peaks with an integration height of 4 is assigned to the hydrogen atoms in the 1,3-dithiolane ring fragment.

Subsequent analysis of the 1H NMR became very complicated very quickly for two reasons:

1. Gaussian calculations showed some atoms with an integration height of 3. Comparing their file atom number and checking their chemical environment, it is not possible to find any correlation between them.

2. Some of the peaks in the literature remains unresolved and are given as multiplets or grouped together.

|- align="center"
| 52
| 3.1775
| 1
| '''2.99'''
|- align="center"
| 53,52,50,51
| 3.0867
| 4
| '''3.40-3.10'''
|- align="center"
| 42,43,39
| 2.7445
| 3
| ''' '''
|- align="center"
| 49
| 2.6187
| 1
| ''' '''
|- align="center"
| 34
| 2.4371
| 1
| ''' '''
|- align="center"
| 35
| 2.3782
| 1
| ''' '''
|- align="center"
| 40,37,26
| 2.2730
| 3
| ''' '''
|- align="center"
| 30
| 2.1566
| 1
| ''' '''
|- align="center"
| 36
| 2.1033
| 1
| ''' '''
|- align="center"
| 32,28
| 2.0259
| 2
| ''' '''
|- align="center"
| 25
| 1.8535
| 2
| ''' '''
|- align="center"
| 38,46,27
| 1.5898
| 3
| '''1.25'''
|- align="center"
| 29
| 1.4557
| 1
| ''' '''
|- align="center"
| 31
| 1.0123
| 1
| ''' '''
|- align="center"
| 44,48,45
| 0.9087
| 3
| '''1.10'''
|- align="center"
| 47
| 0.8354
| 1
| ''' '''
|- align="center"
| 33
| 0.5790
| 1
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 17 Chair Overall NMR2.png|500px|center]]
| [[File:XcwMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 216.2725
| 1
| '''218.79'''
| rowspan="10" style="text-align:center;"| [[File:XcwMolecule 17 image for CNMR.jpg|600px|center]]
|- align="center"
| 13
| 144.8626
| 1
| '''144.63'''
|- align="center"
| 14
| 124.7193
| 1
| '''125.33'''
|- align="center"
| 3
| 91.3340
| 1
| '''72.88'''
|- align="center"
| 2
| 60.9568
| 1
| '''56.19'''
|- align="center"
| 1
| 57.0811
| 1
| '''52.52'''
|- align="center"
| 10
| 52.4663
| 1
| '''48.50'''
|- align="center"
| 16
| 51.4857
| 1
| '''46.80'''
|- align="center"
| 9
| 46.9196
| 1
| '''45.76'''
|- align="center"
| 23
| 43.8647
| 1
| '''39.80'''
|- align="center"
| 22
| 41.9450
| 1
| '''38.81'''
| Comments
|- align="center"
| 4
| 41.8724
| 1
| '''35.85'''
| rowspan="9" style="text-align:left;"| The carbon bonded to the oxygen atom is the most deshielded, as is shown in the predicted values and the experimental values. There is a deviation between the values. Quite possibly, this is due to the fact that in reality, the carbonyl functional group is pointing slightly towards the equatorial position rather than a lateral position relative to the ring (as is in the input for Gaussian calculation)

Most of the 1CNMR values that was predicted by Gaussian are all within an acceptable range of deviation. However, there is carbon 3 that has significant deviation between the predicted value and experimental value.

Carbon 3 is the carbon bonded to the two sulphurs in the 1,3-dithiolane ring fragment. Such a huge deviation would possibly mean that the conformer that was given as input to Gaussian differs from the literature.

The above NMR spectra was corrected with a level of theory B3LYP/6-31G(d,p) using TMS as reference and in chloroform.

|- align="center"
| 15
| 35.4348
| 1
| '''32.66'''
|- align="center"
| 11
| 31.1964
| 1
| '''28.79'''
|- align="center"
| 6
| 28.9432
| 1
| '''28.29'''
|- align="center"
| 7
| 28.3640
| 1
| '''26.88'''
|- align="center"
| 12
| 27.3767
| 1
| '''25.66'''
|- align="center"
| 17
| 26.3311
| 1
| '''23.86'''
|- align="center"
| 15
| 24.5483
| 1
| '''20.96'''
|- align="center"
| 18
| 19.7788
| 1
| '''18.71'''
|-
|}
 

==== '''NMR Spectra of Molecule 18''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 18 Boat for Image2.mol</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"-
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 18 Chair Overall NMR.png|500px|center]]
| [[File:Molecule 18 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.2832
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| ''' '''
|- align="center"
| 50
| 3.3175
| 1
| rowspan="4" style="text-align:centre;"| '''3.00-2.70'''
|- align="center"
| 52
| 3.2153
| 1
|- align="center"
| 51,53
| 3.1161
| 2
|- align="center"
| 34,43
| 2.8606
| 2
|- align="center"
| 38
| 2.4549
| 1
| ''' '''
|- align="center"
| 42
| 2.3968
| 1
| ''' '''
|- align="center"
| 25,29,26
| 2.2796
| 3
| ''' '''
|- align="center"
| 39
| 2.0844
| 1
| ''' '''
|- align="center"
| 40,36
| 1.9699
| 2
| ''' '''
|- align="center"
| 37,24
| 1.8519
| 2
| ''' '''
|- align="center"
| 31,27
| 1.6780
| 2
| ''' '''
|- align="center"
| 28
| 1.6175
| 1
| ''' '''
|- align="center"
| 46,49
| 1.4979
| 2
| ''' '''
|- align="center"
| 35
| 1.4150
| 1
| ''' '''
|- align="center"
| 32
| 1.3531
| 1
| ''' '''
|- align="center"
| 48
| 1.1606
| 1
| ''' '''
|- align="center"
| 33,30,47
| 1.0653
| 3
| '''1.03'''
|- align="center"
| 44,45
| 0.9643
| 2
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwMolecule 18 Boat Overall NMR.png|500px|center]]
| [[File:XcwMolecule 18 Boat zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 211.8325
| 1
| '''211.49'''
| rowspan="10" style="text-align:center;"| [[File:Molecule 18 Boat for 13 CNMR.jpg|600px|center]]
|- align="center"
| 13
| 148.6673
| 1
| '''148.72'''
|- align="center"
| 14
| 118.8373
| 1
| '''120.90'''
|- align="center"
| 3
| 89.0869
| 1
| '''74.61'''
|- align="center"
| 2
| 67.8886
| 1
| '''60.53'''
|- align="center"
| 1
| 56.1133
| 1
| '''51.30'''
|- align="center"
| 10
| 55.5998
| 1
| '''50.94'''
|- align="center"
| 16
| 50.1124
| 1
| '''45.53'''
|- align="center"
| 22
| 48.2030
| 1
| '''43.28'''
|- align="center"
| 23
| 44.2222
| 1
| '''40.82'''
|- align="center"
| 4
| 42.0354
| 1
| '''38.73'''
| Comments
|- align="center"
| 9
| 37.5865
| 1
| '''36.78'''
| rowspan="9" style="text-align:left;"| ''' '''
|- align="center"
| 6
| 35.3106
| 1
| '''35.47'''
|- align="center"
| 15
| 31.0459
| 1
| '''30.84'''
|- align="center"
| 7
| 28.8476
| 1
| '''30.00'''
|- align="center"
| 12
| 28.6623
| 1
| '''25.56'''
|- align="center"
| 17
| 25.7393
| 1
| '''25.35'''
|- align="center"
| 11
| 25.2603
| 1
| '''22.21'''
|- align="center"
| 18
| 23.3944
| 1
| '''21.39'''
|- align="center"
| 5
| 21.0478
| 1
| '''19.83'''
|-
|}
 

== '''Part 4 : Analysis of the Properties of the Synthesized Alkene Epoxides''' ==
=== '''The two catalytics systems''' ===

Assymmetric epoxidation of prochiral alkenes may lead to product with different stereochemical outcome as illustrated as below. To solve this problem, different types of asymmetric epoxidation catalyst have been synthesized. In this study, we shall be focusing on Shi asymmetric fructose catalyst as well as Jacobsen asymmetric catalyst.

[[File:Asymmetric catalyst.png|400px|center]]

==== ''' The Shi Asymmetric Fructose Catalyst''' ====

Molecule 21 is the stable precursor of molecule 22, the active catalyst. Molecule 21 can be converted to molecule 22 by using either persulfuric acid or potassium peroxymonosulphate.

[[File:Molecule 21 to 23.png|400px|center]]

The transition state of the Shi epoxidation was a subject of debate for a few moments. However, recent studies have led to the conclusion that the spiro transition state is more favored than the planar transition state. The spiro transition state is the transition that has its dioxirane perpendicularly bisecting the alkene double bond. This is thought to be more favourable due to interactions between the lone pairs of the oxygen with the LUMO of the alkene.

[[File:Spiro and planar ts.png|500px|center]]

==== ''' The Jacobsen Asymmetric Catalyst''' ====

Molecule 23 is the stable precursor of molecule 24, the active catalyst. Molecule 23 can be converted to molecule 24 by using sodium perchlorate.

[[File:Salen, 23 and 24.png|400px|center]]

Jacobsen catalyst is biphasic. The first phase involves the transfer of oxygen to molecule 23. Sodium perchlorate oxidizes Mn(III) to Mn(V).

In the second step, Jacobsen catalyst acts via a radical mechanism. It is thought to be so because epoxidation of trans-alkene by Jacobsen catalyst yield cis-alkene as well. A radical mechanism will lead to the lost of stereochemical information of the molecule.

=== ''' Crystal structure of the two catalyst''' ===
==== '''Molecule 21''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 21'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 21 strucutre.png|600px|center]]'''
|-
| style="text-align:center;" width="150" | ''' Bond '''
| style="text-align:center;" width="150"| ''' Bond Lenghts (Angstrom)'''
| style="text-align:center;" | ''' Evaluation'''
|-
| style="text-align:center;"| ''' O1-C1 '''
| style="text-align:center;"| ''' 1.400'''
| rowspan="10" style="text-align:left;"| [[File:Molecule 21 2.png|300px|center]]

The normal bond length of an C-O bond is 1.430 angstrom.

The most interesting aspect here is O4 and O2. The lone pair of O4 is antiperplanar to the sigma* orbital of the carbonyl group while the lone pair of O2 is anti periplanar to the carbonyl pi* orbital. Donation of electron can occur because of the correct symmetry. Due to the mixing of the orbitals, the C2-O2 and C4-O4 has been conferred with a certain degree of double bond character.

However, due to the lone pair on oxygen being now donated to the carbonyl antibonding orbitals, the O2 and O4 is slightly “electron deficient” and electron density will be pulled away from O2 and O4. That would explain why the bond length increase for O2-C7 and O4-C10. Increase in bond length is an indicator of the weakening of the bond.
|-
| style="text-align:center;"|'''O1-C7'''
| style="text-align:center;"|'''1.413'''
|-
| style="text-align:center;"|'''O2-C7'''
| style="text-align:center;"|'''1.441'''
|-
| style="text-align:center;"|'''O2-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O4-C4'''
| style="text-align:center;"|'''1.396'''
|-
| style="text-align:center;"|'''O4-C10'''
| style="text-align:center;"|'''1.439'''
|-
| style="text-align:center;"|'''O5-C10'''
| style="text-align:center;"|'''1.409'''
|-
| style="text-align:center;"|'''O5-C5'''
| style="text-align:center;"|'''1.416'''
|-
| style="text-align:center;"|'''O6-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O6-C6'''
| style="text-align:center;"|'''1.420'''
|-
|}
 

==== '''Molecule 23''' ====

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 23'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 23 struc.png|600px|center]]'''
|-
| The most outstanding feature from this molecule is the fact that is adopt a puckered form of the square base pyramidal form. This is no surprise that the molecule is almost planar due to the electron delocalization around each side of the salen ligand.

The tery-butyl hydrogen are oriented closely to one another. Non-covalent interaction studies indicated that repulsion would occur for H---H bond length that are less than 2.1 angstrom while favourable interaction may be dominant with bond length above 2.4 angstrom. It was discovered that all 4 hydrogens have bond length more than 2.4 angstrom hence there should not be any significant repulsion between them. Instead, certain amount of attractive force will ensue and that contributes to the overall stability of the molecule

|-
|}
 

=== ''' The calculated NMR properties of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | '''
Shielding (ppm) Degeneracy
7.4891704929 4.0000
7.2988172444 1.0000
3.6627082199 1.0000
3.1170156088 1.0000
2.5382383043 1.0000 '''
| width="100" | '''
Shielding (ppm) Degeneracy
24.2569032127 4.0000
24.4474861875 1.0000
28.0829310079 1.0000
28.6310290891 1.0000
29.2122790315 1.0000
'''
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Styrene R HNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Styrene S HNMR.png|400px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | '''
Shift (ppm) Degeneracy
135.1098747604 1.0000
124.1186533632 1.0000
123.4150641684 1.0000
122.9584694331 2.0000
118.2653162569 1.0000
54.0265785300 1.0000
53.4853575062 1.0000 '''
| width="100" | '''
Shift (ppm) Degeneracy
135.1323742030 1.0000
124.1343038829 1.0000
123.4137039868 1.0000
122.9558208084 2.0000
118.2690258882 1.0000
54.0599580762 1.0000
53.4684920923 1.0000
'''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | ''' [[File:Styrene R CNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Styrene S CNMR.png|400px|center|]]'''
|-
| width="100" | ''' '''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | ''' Shift (ppm) Degeneracy
7.5705724829 2.0000
7.4791732656 8.0000
3.5390102503 2.0000
| width="100" | ''' Shift (ppm) Degeneracy
7.5705651164 2.0000
7.4791779628 8.0000
3.5374502607 2.0000
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Stilbene RR HNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|400px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | ''' '''
| width="100" | ''' '''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | ''' [[File:Stilbene RR CNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|400px|center|]]'''
|-
|}

 

=== ''' Assigning the absolute configuration of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''Predicted ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg'''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg '''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental conditions'''
| width="100" | '''1.00g/100ml, chloroform, 21 degree Celcisus, 589 nm wavelength '''
| width="100" | '''1.02g/100ml (99% ee), chloroform, 25 degree Celsius, 589 nm wavelength '''
| width="100" | '''1.01g/100ml, ethanol, 22 degree Celsius, 589 nm wavelength '''
| width="100" | '''0.6g/100ml, ethanol, 20 degree Celsius, 589 nm wavelength '''
|- align="left"
| width="100" | ''' Predicted VCD Spectrum'''
| width="100" | '''[[File:Styrene R VCD.png|200px|center|]] '''
| width="100" | '''[[File:Styrene S VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene RR VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene SS VCD.png|200px|center|]]'''
|-
|}

 

All the assignments given in the literature reports are correct although the predicted value differs slightly with the experimental values

=== ''' Analysis of the Transition State for Reactions''' ===
==== '''Predicting Enantiomeric Excess based on Transition State energies''' ====

One of the energy output from Gaussian calculation is the “sum of electronic and thermal free energies”. This is Gibbs Free Energy at 298.15K and 1 atm.

Using this term and invoking a variant of the Curtin-Hammett Principle, it is possible to calculate a predicted enantiomeric excess of one enantiomer over the other.

[[File:Ee and transition state energy.png|800px|center]]

Using the derivations from above and equation (4), we analyze the enantiomeric excess of beta-methyl styrene and the results are tabulated as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1343.022970'''
| width="100" | '''-1343.017942'''
| width="150" | '''-0.005028'''
| width="150" | '''4.88E-03'''
| width="150" | '''99.03'''
|- align="center"
| width="100" | '''-1343.019233'''
| width="100" | '''-1343.015603'''
| width="150" | '''-0.003630'''
| width="150" | '''2.14E-02'''
| width="150" | '''95.80'''
|- align="center"
| width="100" | '''-1343.029272'''
| width="100" | '''-1343.023766'''
| width="150" | '''-0.005506'''
| width="150" | '''2.94E-03'''
| width="150" | '''99.41'''
|- align="center"
| width="100" | '''-1343.032443'''
| width="100" | '''-1343.024742'''
| width="150" | '''-0.007701'''
| width="150" | '''2.88E-04'''
| width="150" | '''99.94'''
|-
|}

 

The above hartree units are converted to J/mol for calculation of K where 1 hartress = 4.3597E-18

Studying all the free energies of the (R,R) series and compare them with the (S,S) series, it comes as no surprise that (R,R) product is favoured over (S,S) product as (R,R) is more stable. Indeed, this corresponds with the literature value reporting 92% ee of (R,R) products over that of (S,S).

==== '''Analysis of the Transition State of Epoxidation''' ====
==== '''Shi Fructose Catalyst''' ====
For this section, I will be analyzing the the transition state of 1) styrene and 2) trans-stilbene with the Shi fructose catalyst.

===== '''(R) and (S)-styrene transition state''' =====
The transition state for the formation of (R)-styrene oxide and (S)-styrene oxide are given as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R)-styrene oxide'''
| width="150" | '''(S)-styrene oxide'''
|- align="center"
| width="150" | ''' Structure of Catalyst '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide R.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide S ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| [[File:Steric shi fructose R.png|450px|center]]
| [[File:Steric shi fructose S.png|450px|center]]
|-
|}

 

In the transition state for (R)-styrene, it was discovered that the Re face is reacting with the oxygen of the dioxirane. The phenyl ring is oriented endo with respect to the fructose catalyst. However, the (S)-styrene is reacting at the Si face and the phenyl ring is oriented exo relative to the catalyst.

The approach taken by (R)-styrene and (S)-styrene are restricted to only one due to steric interactions. Therefore, the epoxidation of both styrenes by the Shi catalyst will be stereospecific and retains all the stereochemical information of the reactant. However, whether or not (R)-styrene oxide or (S)-styrene oxide is form is dependent on the relative energies of the transition state. The more stable the transition state, the more likely the product of the transition state will be formed.

So in order to examine this, an example of transition state of both styrenes with Shi catalyst are obtained and analyzed.
 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1303.736813'''
| width="100" | '''-1303.727673'''
| width="150" | '''-0.00914'''
| width="150" | '''6.28E-05'''
| width="150" | '''99.99'''

|-
|}

 

From the above, we can see the predicted high enantiopurity of the reaction favoring the (R) product because of the lower energy of the transition states. To understand the reason, we have to turn to non-covalent interaction (NCI) analysis.

[[File:NCI shi fructose styrene.png|700px|center]]

To complement the NCI analysis, a QTAIM (Quantum Theory of Atoms in Molecules) analysis is conducted as well.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''(R)-styrene transition state'''
| width="200" | '''(S)-styrene transition state'''
|- align="center"
| width="100" | '''[[File:QTAIM R.png|400px|center]]'''
| width="100" | '''[[File:QTAIM S.png|400px|center]]'''
|- align="center"
| colspan="2" width="100" | '''Comments'''
|-
| colspan="2" width="100" | '''Unsurprisingly, QTAIM analysis has also shown that (R)-styrene/Shi catalyst has more interactions with one another. While (R)-styrene has 2 strong interactions, (S)-styrene has only one with the catalyst. Besides, the phenyl ring of (R)-styrene also confers additional positive interaction with the catalyst. QTAIM analysis has also show several interactions between the C=C geminal hydrogen of (R)-styrene intreacting with the oxygen atoms on the dioxacyclopentane ring'''
|-
|}

 

===== '''(R,R) and (S,S)-Stilbene transition state''' =====

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R,R)-Stilbene oxide'''
| width="150" | '''(S,S)-Stilbene oxide'''
|- align="center"
| width="150" | ''' Structure of Transition State '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Stilbene RR ts.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>SS stilbene oxide ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| colspan="2" | [[File:Shi fructose stilbene.png|700px|center]]

|-
|}

 

However, unlike styrene, trans-stilbene seems to approach perpendicularly to the dioxirane. This is proposed to be due to the steric interactions (marked in purple). Based on first inspection, it seems that (S,S)-Stilbene oxide has more steric interactions than (R,R)-Stilbene oxide. Although unsubstantial, it seems like my guess was correct. The (R,R)-stilbene/Shi catalyst transition state is lower in energy.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1534.687808'''
| width="100" | '''-1534.683440'''
| width="150" | '''0.004368'''
| width="150" | '''9.08E-3'''
| width="150" | '''98.20'''

|-
|}

 

NCI Analysis is also done for trans-stilbene

[[File:NCI stilbene.png|700px|center]]

==== '''Jacobsen Catalyst''' ====

For this section, cis-beta methyl styrene transition state will be analyzed.

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-3383.259559'''
| width="100" | '''-3383.251060'''
| width="150" | '''-0.008499'''
| width="150" | '''1.24E-04'''
| width="150" | '''99.98'''
|- align="center"
| width="100" | '''-3383.253442'''
| width="100" | '''-3383.250270'''
| width="150" | '''-0.003172'''
| width="150" | '''3.48E-02'''
| width="150" | '''93.27'''
|-
|}

 

As is obvious from here, the (S,R) transition state is more stable than the (R,S) transition state. Both transition states are exo with respect to the catalyst.

It is not immediately apparent just by looking at the molecule to determine which spatial groups have interactions with one another. Therefore, an NCI analysis is conducted again.

[[File:NCI Jacobsen.png|700px|center]]

Rep:Mod:Computationalreport1C

2013-11-21T23:22:04Z

Xc2611: /* The calculated NMR properties of the product */

= '''Synthesis and Computational Lab: 1C''' =
== '''Part 1: Introduction to Molecular Mechanics''' ==
=== '''Introduction to MMFF94 and MMFF94s''' ===

With the improvement of computational data and computer processing power, the usage of molecular mechanics/dynamics forcefield has become very integrated in predicting properties of chemical molecules. A molecular mechanics/dynamics forcefield should be able to predict characteristics such as molecular geometries, conformational/stereoisomeric energies, vibrational frequencies etc. to a reasonable accuracy as compared to experimental-derived values.

Building on work from Kollman et al. s’ AMBER forcefield and Allinger et al. s’ MM1, MM2, MM3 and MM4, Merck Research Laboratories have managed to optimized and improved the previous computational algorithms and produced MMFF94 (Merck Molecular Force Field 94). One of the most prominent advantages of MMFF94 over other preceeding work is its enhanced prediction accuracy. The reason lies in the fact that MMFF94’s core parameterization utilizes an unprecedently large amount of computational data obtained from ab initio calculations1.

Subsequently after the development of MMFF94, a new “static” variant of the MMFF was introduced i.e. the MMFF94s. Unlike MMFF94 that was developed for the use of molecular dynamics simulations (which can be expensive), MMFF94s was developed with the purpose of energy minimization studies in mind. Although both systems provide identical results for most systems, they differ for amides and unsaturated amines which contain resonance-delocalized trigonal nitrogen atoms2.

In this computational exercise, MMFF94s is used predominantly as oppose to the alternative Universal Force Field (UFF). Although versatile across the entire periodic table, UFF is derived from simple rules and atomic parameters such as fixed hybridization that increases the likelihood of erroneous structural and energetic predictions3.

=== '''Forms of MMFF94s''' ===

Steric energy of a molecule is the energy arise due to its geometry or conformation. Energy minimization of steric energy process ensures that the molecule is in its lowest energy conformation.

MMFF94s assumes that the total steric energy of a molecule can be found by the sum of a few specific interactions in a molecule.

ES = EBS + EAB + E SB + ET + EOOP + EVdW + EEE

'''where the bonded interactions are:'''

ES = Total Steric energy

EBS = Total Bond Stretching energy

EAB = Total Angle Bending energy

ESB = Total Stretch Bending energy

ET = Total Torsional Energy

EOOP = Total Out-Of-Plane Bending energy, and

'''where the non-bonded interactions are:'''

EVdW = Total Van der Waals Energy

EEE = Total Electrostatic Energy

{| border="1" cellspacing="1" cellpadding="10"
|-
| width="300" align="center" | '''Types of Energies'''
! width="600" align="center" | '''Explanation'''
|-
| colspan="2" style="text-align: center;" | '''Bonded Interactions'''
|-
| width="300" align="center" | '''Total Bond Stretching Energy'''
! width="600" align="left" | The total bond stretching energy is related to the vibration energy of the molecules in comparison to the equilibrium bond length. Whenever a bond deviates from the equilibrium bond length, the energy value increases.

MMFF94s uses a quartic function that has the force constant term (relate to bond strength). The quartic function term is superior to the cubic function term (used in MM2) in the sense that it avoid the “cubic stretch catastrophe” where progressive elongation of molecule bond length leads to negative infinity.
|-
| width="300" align="center" | '''Total Angle Bending Energy'''
! width="600" align="left" | Similar to Total Bond Stretching Energy, the total angle bending energy is also related to the vibration energy of the molecules about the equilibrium bond length. However, unlike EBS that measures the bond strength, EAB is associated with the stiffness of the molecules based on the Hookiean potential. Whenever bond angles deviate from the norm during vibration, this energy term increases as well.
|-
| width="300" align="center" | '''Total Stretch-Bending Energy'''
! width="600" align="left" | This energy term takes into account of the energy due to increase in bond length when bond angle between two atoms changes.
|-
| width="300" align="center" | '''Total Torsional Energy'''
! width="600" align="left" | Total torsional energy is the energy required for intermolecular rotation about the bonds. In molecule mechanics, however, this term is often used as a correction that must be added or subtracted to the total energy of the molecule to fit a quantum mechanical calculation about the dihedral angles of bonds.
|-
| width="300" align="center" | '''Total Out-Of-Plane Bending Energy'''
! width="600" align="left" | This energy term refers to the energy needed to deform the dihedral angle (zero degrees) of a planar group of atoms such as carbonyl or amide functional groups.
|-
| colspan="2" style="text-align: center;" | '''Non-Bonded Interactions'''
|-
| width="300" align="center" | '''Total Van der Waals Energy'''
! width="600" align="left" | The total Van der Waals energy term examines the intramolecular interactions such as repulsion or attraction between non-bonded atoms in the molecule. This term is crucial in determining the preferred conformation of the molecule.

MMFF94s employs the novel “Buffered-14-7”. The name is derived from a buffering constant and the 14th and 7th power dependencies of the repulsive and attractive energy in the equation.
|-
| width="300" align="center" | '''Total Electrostatic Energy'''
! width="600" align="left" | The total electrostatic energy functions take into account of the Coulombic potential and partial charge/dipole/atomic point charges interactions within the molecule.
|-

|}

 

== '''Part 2 : Conformational Analysis Using Molecular Mechanics''' ==
=== '''The Hydrogenation of Cyclopentadiene Dimer''' ===

==== '''Endo and exo adduct from the Dimerization of Cyclopentadiene''' ====
Cyclopentadiene will undergo dimerization by Diels-alder reaction to form either an endo or exo adduct.

[[File:XcwDimerization of CP.png|500px|center]]

==== '''Stereoselectivity of Dimerization of Cyclopentadiene''' ====
Although the exo adduct is thermodynamically more stable than the endo adduct, the endo adduct is form preferentially. Using the QST2 method, the transition state of the Diels Alder dimerization was found. It was discovered that due to the secondary orbital interactions in the endo transition state, the endo dimer is formed preferentially (the kinetic product). Hence, it is proven that the Diels Alder dimerization between two cyclopentadiene are kinetically controlled.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Transition State of Dimerization of Cyclopentadiene'''
| '''Imaginary Stretch Frequency (-881.25) of the Endo Transition State (click to animate)'''
| '''Secondary Orbital Interaction (Red overlapping orbitals)'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<uploadedFileContents>EndotsDCPD2.mol
</uploadedFileContents>
</jmolApplet></jmol>
| [[File:Xcwendotsimaginary.gif|300px|center]]
| [[File:XcwSecondary orbital interaction1.jpg|300px|center]]
|-
|}

 

==== '''Asynchronous Bond Formation of Dimerization of Cyclopentadiene''' ====

The initial study of the molecular orbitals of the transition states seemed a bit peculiar. Instead of getting a LUMO with symmetrical orbitals, the calculations showed a HOMO that is asymetric at the carbons where the new sigma bonds will be formed. Running an IRC further, it soon became clear that the asymmetry of the HOMO leads to an asychronous bond formation before leading to the product.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''IRC plot following the Endo Transition State '''
| '''IRC following the Endo Transition State (click to animate)'''
| '''Asymmetry of orbitals at the carbons where the new sigma bonds will be formed'''
|- align="center"
| [[File:XcwendotscyclopentadieneIRC.png|300px|center]]
| [[File:XcwendotsIRC.gif|300px|center]]
| [[File:XcwAsynchronous mo.jpg|300px|center]]
|-
|}

 

==== '''Comparison of Energies between the Endo and Exo adduct of Dicyclopentadiene''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Adduct of Dicyclopentadiene dimerization'''
| '''Exo Adduct of Dicyclopentadiene dimerization'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=19,atomno=1,atomno=2; color green;measure 19 1;measure 19 2;</script>
<uploadedFileContents>XcwEndodimer3.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>Exodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=7,atomno=17; color green;measure 17 7;</script>
<uploadedFileContents>XcwExodimer1.mol</uploadedFileContents>
</jmolApplet></jmol>
|-
|}

 

Using MMFF94s ab initio calculations, the energies for the exo dimer and the endo dimer are derived.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Exodimer'''
| '''55.374'''
| 3.543
| 30.772
| -2.041
| -2.728
| 0.015
| 12.800
| 13.014
|-
| '''Endodimer'''
| '''58.191'''
| 3.468
| 33.187
| -2.082
| -2.950
| 0.023
| 12.360
| 14.186
|-
|}

 

The MMFF94s steric energy (after minimization) for the exo dimer is lower than that of the endo dimer. This is reflected by the large difference for the EEE between the endo dimer and the exo dimer due to unfavourable steric repulsion between the two “arched down” cyclopentene rings.

==== '''Hydrogenation of Dicyclopentadiene''' ====

Hydrogenation of the endo dicyclopentadiene (DCPD) would lead to two potential products: dihydro product 1 and dihydro product 2.

[[File:XcwFormation of Dihydro products.png|500px|center]]

Using MMFF94s, the energy of the two dihydro products are calculated.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Dihydro Product 1'''
| '''50.123'''
| 3.308
| 30.864
| -1.927
| 0.060
| 0.015(2)
| 13.281
| 5.121
|-
| '''Dihydro Product 2'''
| '''41.257'''
| 2.823
| 24.685
| -1.657
| -0.379
| 0.000(2)
| 10.639
| 5.147
|-
| '''Tetrahydro Product'''
| '''39.042'''
| 2.730
| 25.151
| -1.676
| 1.287
| 0.000
| 11.551
| 0.000
|}

 

From the MMFF94s calculation, it can be seen that dihydro product 2 has a lower steric energy than dihydro product 1. Therefore, dihydro product 2 is the thermodynamic product for the hydrogenation of dicylopentadiene. And indeed, this was what was observed by Skala et al.. He observed that the first hydrogenation occur at the norborene part of the molecule (rate of hydrogenation several times faster than that in the cyclopentene ring)6. The first heat of hydrogenation at the norborene is 138.8 kJ/mol while the second hydrogenation at the cyclopentene right is 109.5 kJ/mol6.

From the above results, it is also obvious that tetrahydro product is much more stable than either dihydro product. And yet, studies have shown that the tetrahydro product will only form after prolonged hydrogenation under high temperature. However, subjecting DCPD to high temperature leads to low yield due to cracking of DCPD.

Since thermodynamically it is predicted to form favourably, the fact that it does not could only mean that the hydrogenation of DCPD to tetrahydrodicyclopentadiene (TH-DCPD) is kinetically controlled. Most possibly, the transition state of the hydrogenation of DCPD is highly unstable hence it is unlikely to form.

=== '''Atropisomerism in an Intermediate related to the Synthesis of Taxol''' ===

Atropisomerism is a type of stereoisomerism that is form as a result of hindered rotation about a single bond.

[[File:XcwAtropisomerism example.png|500px|center]]

In the case of the 6,6’-dinitro-2,2’-diphenic acid, rotation about the bonds joining the two substituted phenyl rings would have to overcome large steric interaction between the bulky substituents. The barrier of rotation is high enough for the two conformers to be isolated individually.

In the synthesis of taxol, one of the key intermediates exhibit atropisomerism.

==== '''Atropisomerism in Taxol Synthesis''' ====

For the key intermediate, rotation about the carbon-carbon bonds would lead to two types of atropisomers, each with either the carbonyl group poining upwards or downwards in relative to the bridge.

[[File:XcwIntermediate 9 and Intermediate 10.png|500px|center]]

Once again by using MMFF94s ab initio calculations, the steric energies for the two intermediates are illustrated as below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 9'''
| '''70.571'''
| 7.743
| 28.356
| -0.062
| 0.004
| 0.949
| 33.293
| 0.288
|-
| '''Intermediate 10'''
| '''60.553'''
| 7.599
| 18.838
| -0.139
| 0.199
| 0.844
| 33.269
| -0.056
|-

|}

 

Analyzing the data above, the largest energy difference between Intermediate 9 and Intermediate 10 stems from the EAB which is related to the strain of the ring. Intermediate 9 has an excess of 9.518 kcal/mol EAB as compared to Intermediate 10. This comes as a surprise as intermediate 9 is predicted to be more stable alkene.

The rationale behind the prediction of the stability of intermediate 9 stems from the fact that the through-space distance of the upward-pointing carbonyl oxygen with the carbon-carbon is further than the through space distance between the downward-pointing carbonyl oxygen with the -CH2-CH2- fragment at the norbornene part in intermediate 10.

==== '''Hyperstable Olefins''' ====

Intermediate 9 and Intermediate 10 does not react readily with other reagents during functionalization. This is due to the hyperstability effect found in hyperstable olefins.

Hyperstable olefins are alkenes that contain less strain in the ring (i.e. negative olefin strain values) compared to the parent hydrocarbon. To study this further, further MMFF94s calculation was done to compare Intermediate 10 with the parent hydrocarbon.

[[File:XcwIntermediate10andPH.png|500px|center]]

The energies that we calculated are tabulated as shown below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 10'''
| '''44.878 '''
| 5.211
| 15.488
| -0.267
| -1.655
| 0.998
| 25.014
| 0.088
|-
| '''Parent Hydrocarbon'''
| '''50.564'''
| 4.692
| 21.979
| 0.109
| -0.958
| 0.247
| 24.495
| 0.000
|-

|}

 

Scrutinizing the results, the largest energy difference between intermediate 10 and the parent hydrocarbon stems from the Total Angle Bending Energy, EAB. Since the Total Angle bending energy is related to the angle strain in the molecules, it is apparent that the parent hydrocarbon has more ring strain as compared to the bridgehead olefin.

== '''Part 3 : Spectroscopic Simulation Using Quantum Mechanics''' ==
=== '''Spectroscopy of an Intermediate Related to the Synthesis of Taxol''' ===

Molecule 17 and 18 are derivatives of intermediate 9 and 10. In this exercise, MMFF94s is used to predict the 1H and 13C NMR of molecule 17 and molecule 18.

[[File:XcwIntermediate17&18.png|500px|center]]

==== '''NMR Spectra of Molecule 17''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 17.mol
</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwHNMRMolecule 17 Chair Overall NMR.png|500px|center]]
| [[File:XcwHNMRMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.1825
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| The first three results were fairly straight forward to be deduced and correlate wit experimental data.

The hydrogen atom that is geminally attached to the carbon of the double bonds is the most deshielded due to the ring current anisotropic effect of the ring current

The second most deshielded hydrogen atom is the hydrogen atom on the methyl group on the bridge. The hydrogen atom is pointing directly to the oxygen atom of the carbonyl functional group.

The peaks with an integration height of 4 is assigned to the hydrogen atoms in the 1,3-dithiolane ring fragment.

Subsequent analysis of the 1H NMR became very complicated very quickly for two reasons:

1. Gaussian calculations showed some atoms with an integration height of 3. Comparing their file atom number and checking their chemical environment, it is not possible to find any correlation between them.

2. Some of the peaks in the literature remains unresolved and are given as multiplets or grouped together.

|- align="center"
| 52
| 3.1775
| 1
| '''2.99'''
|- align="center"
| 53,52,50,51
| 3.0867
| 4
| '''3.40-3.10'''
|- align="center"
| 42,43,39
| 2.7445
| 3
| ''' '''
|- align="center"
| 49
| 2.6187
| 1
| ''' '''
|- align="center"
| 34
| 2.4371
| 1
| ''' '''
|- align="center"
| 35
| 2.3782
| 1
| ''' '''
|- align="center"
| 40,37,26
| 2.2730
| 3
| ''' '''
|- align="center"
| 30
| 2.1566
| 1
| ''' '''
|- align="center"
| 36
| 2.1033
| 1
| ''' '''
|- align="center"
| 32,28
| 2.0259
| 2
| ''' '''
|- align="center"
| 25
| 1.8535
| 2
| ''' '''
|- align="center"
| 38,46,27
| 1.5898
| 3
| '''1.25'''
|- align="center"
| 29
| 1.4557
| 1
| ''' '''
|- align="center"
| 31
| 1.0123
| 1
| ''' '''
|- align="center"
| 44,48,45
| 0.9087
| 3
| '''1.10'''
|- align="center"
| 47
| 0.8354
| 1
| ''' '''
|- align="center"
| 33
| 0.5790
| 1
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 17 Chair Overall NMR2.png|500px|center]]
| [[File:XcwMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 216.2725
| 1
| '''218.79'''
| rowspan="10" style="text-align:center;"| [[File:XcwMolecule 17 image for CNMR.jpg|600px|center]]
|- align="center"
| 13
| 144.8626
| 1
| '''144.63'''
|- align="center"
| 14
| 124.7193
| 1
| '''125.33'''
|- align="center"
| 3
| 91.3340
| 1
| '''72.88'''
|- align="center"
| 2
| 60.9568
| 1
| '''56.19'''
|- align="center"
| 1
| 57.0811
| 1
| '''52.52'''
|- align="center"
| 10
| 52.4663
| 1
| '''48.50'''
|- align="center"
| 16
| 51.4857
| 1
| '''46.80'''
|- align="center"
| 9
| 46.9196
| 1
| '''45.76'''
|- align="center"
| 23
| 43.8647
| 1
| '''39.80'''
|- align="center"
| 22
| 41.9450
| 1
| '''38.81'''
| Comments
|- align="center"
| 4
| 41.8724
| 1
| '''35.85'''
| rowspan="9" style="text-align:left;"| The carbon bonded to the oxygen atom is the most deshielded, as is shown in the predicted values and the experimental values. There is a deviation between the values. Quite possibly, this is due to the fact that in reality, the carbonyl functional group is pointing slightly towards the equatorial position rather than a lateral position relative to the ring (as is in the input for Gaussian calculation)

Most of the 1CNMR values that was predicted by Gaussian are all within an acceptable range of deviation. However, there is carbon 3 that has significant deviation between the predicted value and experimental value.

Carbon 3 is the carbon bonded to the two sulphurs in the 1,3-dithiolane ring fragment. Such a huge deviation would possibly mean that the conformer that was given as input to Gaussian differs from the literature.

The above NMR spectra was corrected with a level of theory B3LYP/6-31G(d,p) using TMS as reference and in chloroform.

|- align="center"
| 15
| 35.4348
| 1
| '''32.66'''
|- align="center"
| 11
| 31.1964
| 1
| '''28.79'''
|- align="center"
| 6
| 28.9432
| 1
| '''28.29'''
|- align="center"
| 7
| 28.3640
| 1
| '''26.88'''
|- align="center"
| 12
| 27.3767
| 1
| '''25.66'''
|- align="center"
| 17
| 26.3311
| 1
| '''23.86'''
|- align="center"
| 15
| 24.5483
| 1
| '''20.96'''
|- align="center"
| 18
| 19.7788
| 1
| '''18.71'''
|-
|}
 

==== '''NMR Spectra of Molecule 18''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 18 Boat for Image2.mol</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"-
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 18 Chair Overall NMR.png|500px|center]]
| [[File:Molecule 18 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.2832
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| ''' '''
|- align="center"
| 50
| 3.3175
| 1
| rowspan="4" style="text-align:centre;"| '''3.00-2.70'''
|- align="center"
| 52
| 3.2153
| 1
|- align="center"
| 51,53
| 3.1161
| 2
|- align="center"
| 34,43
| 2.8606
| 2
|- align="center"
| 38
| 2.4549
| 1
| ''' '''
|- align="center"
| 42
| 2.3968
| 1
| ''' '''
|- align="center"
| 25,29,26
| 2.2796
| 3
| ''' '''
|- align="center"
| 39
| 2.0844
| 1
| ''' '''
|- align="center"
| 40,36
| 1.9699
| 2
| ''' '''
|- align="center"
| 37,24
| 1.8519
| 2
| ''' '''
|- align="center"
| 31,27
| 1.6780
| 2
| ''' '''
|- align="center"
| 28
| 1.6175
| 1
| ''' '''
|- align="center"
| 46,49
| 1.4979
| 2
| ''' '''
|- align="center"
| 35
| 1.4150
| 1
| ''' '''
|- align="center"
| 32
| 1.3531
| 1
| ''' '''
|- align="center"
| 48
| 1.1606
| 1
| ''' '''
|- align="center"
| 33,30,47
| 1.0653
| 3
| '''1.03'''
|- align="center"
| 44,45
| 0.9643
| 2
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwMolecule 18 Boat Overall NMR.png|500px|center]]
| [[File:XcwMolecule 18 Boat zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 211.8325
| 1
| '''211.49'''
| rowspan="10" style="text-align:center;"| [[File:Molecule 18 Boat for 13 CNMR.jpg|600px|center]]
|- align="center"
| 13
| 148.6673
| 1
| '''148.72'''
|- align="center"
| 14
| 118.8373
| 1
| '''120.90'''
|- align="center"
| 3
| 89.0869
| 1
| '''74.61'''
|- align="center"
| 2
| 67.8886
| 1
| '''60.53'''
|- align="center"
| 1
| 56.1133
| 1
| '''51.30'''
|- align="center"
| 10
| 55.5998
| 1
| '''50.94'''
|- align="center"
| 16
| 50.1124
| 1
| '''45.53'''
|- align="center"
| 22
| 48.2030
| 1
| '''43.28'''
|- align="center"
| 23
| 44.2222
| 1
| '''40.82'''
|- align="center"
| 4
| 42.0354
| 1
| '''38.73'''
| Comments
|- align="center"
| 9
| 37.5865
| 1
| '''36.78'''
| rowspan="9" style="text-align:left;"| ''' '''
|- align="center"
| 6
| 35.3106
| 1
| '''35.47'''
|- align="center"
| 15
| 31.0459
| 1
| '''30.84'''
|- align="center"
| 7
| 28.8476
| 1
| '''30.00'''
|- align="center"
| 12
| 28.6623
| 1
| '''25.56'''
|- align="center"
| 17
| 25.7393
| 1
| '''25.35'''
|- align="center"
| 11
| 25.2603
| 1
| '''22.21'''
|- align="center"
| 18
| 23.3944
| 1
| '''21.39'''
|- align="center"
| 5
| 21.0478
| 1
| '''19.83'''
|-
|}
 

== '''Part 4 : Analysis of the Properties of the Synthesized Alkene Epoxides''' ==
=== '''The two catalytics systems''' ===

Assymmetric epoxidation of prochiral alkenes may lead to product with different stereochemical outcome as illustrated as below. To solve this problem, different types of asymmetric epoxidation catalyst have been synthesized. In this study, we shall be focusing on Shi asymmetric fructose catalyst as well as Jacobsen asymmetric catalyst.

[[File:Asymmetric catalyst.png|400px|center]]

==== ''' The Shi Asymmetric Fructose Catalyst''' ====

Molecule 21 is the stable precursor of molecule 22, the active catalyst. Molecule 21 can be converted to molecule 22 by using either persulfuric acid or potassium peroxymonosulphate.

[[File:Molecule 21 to 23.png|400px|center]]

The transition state of the Shi epoxidation was a subject of debate for a few moments. However, recent studies have led to the conclusion that the spiro transition state is more favored than the planar transition state. The spiro transition state is the transition that has its dioxirane perpendicularly bisecting the alkene double bond. This is thought to be more favourable due to interactions between the lone pairs of the oxygen with the LUMO of the alkene.

[[File:Spiro and planar ts.png|500px|center]]

==== ''' The Jacobsen Asymmetric Catalyst''' ====

Molecule 23 is the stable precursor of molecule 24, the active catalyst. Molecule 23 can be converted to molecule 24 by using sodium perchlorate.

[[File:Salen, 23 and 24.png|400px|center]]

Jacobsen catalyst is biphasic. The first phase involves the transfer of oxygen to molecule 23. Sodium perchlorate oxidizes Mn(III) to Mn(V).

In the second step, Jacobsen catalyst acts via a radical mechanism. It is thought to be so because epoxidation of trans-alkene by Jacobsen catalyst yield cis-alkene as well. A radical mechanism will lead to the lost of stereochemical information of the molecule.

=== ''' Crystal structure of the two catalyst''' ===
==== '''Molecule 21''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 21'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 21 strucutre.png|600px|center]]'''
|-
| style="text-align:center;" width="150" | ''' Bond '''
| style="text-align:center;" width="150"| ''' Bond Lenghts (Angstrom)'''
| style="text-align:center;" | ''' Evaluation'''
|-
| style="text-align:center;"| ''' O1-C1 '''
| style="text-align:center;"| ''' 1.400'''
| rowspan="10" style="text-align:left;"| [[File:Molecule 21 2.png|300px|center]]

The normal bond length of an C-O bond is 1.430 angstrom.

The most interesting aspect here is O4 and O2. The lone pair of O4 is antiperplanar to the sigma* orbital of the carbonyl group while the lone pair of O2 is anti periplanar to the carbonyl pi* orbital. Donation of electron can occur because of the correct symmetry. Due to the mixing of the orbitals, the C2-O2 and C4-O4 has been conferred with a certain degree of double bond character.

However, due to the lone pair on oxygen being now donated to the carbonyl antibonding orbitals, the O2 and O4 is slightly “electron deficient” and electron density will be pulled away from O2 and O4. That would explain why the bond length increase for O2-C7 and O4-C10. Increase in bond length is an indicator of the weakening of the bond.
|-
| style="text-align:center;"|'''O1-C7'''
| style="text-align:center;"|'''1.413'''
|-
| style="text-align:center;"|'''O2-C7'''
| style="text-align:center;"|'''1.441'''
|-
| style="text-align:center;"|'''O2-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O4-C4'''
| style="text-align:center;"|'''1.396'''
|-
| style="text-align:center;"|'''O4-C10'''
| style="text-align:center;"|'''1.439'''
|-
| style="text-align:center;"|'''O5-C10'''
| style="text-align:center;"|'''1.409'''
|-
| style="text-align:center;"|'''O5-C5'''
| style="text-align:center;"|'''1.416'''
|-
| style="text-align:center;"|'''O6-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O6-C6'''
| style="text-align:center;"|'''1.420'''
|-
|}
 

==== '''Molecule 23''' ====

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 23'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 23 struc.png|600px|center]]'''
|-
| The most outstanding feature from this molecule is the fact that is adopt a puckered form of the square base pyramidal form. This is no surprise that the molecule is almost planar due to the electron delocalization around each side of the salen ligand.

The tery-butyl hydrogen are oriented closely to one another. Non-covalent interaction studies indicated that repulsion would occur for H---H bond length that are less than 2.1 angstrom while favourable interaction may be dominant with bond length above 2.4 angstrom. It was discovered that all 4 hydrogens have bond length more than 2.4 angstrom hence there should not be any significant repulsion between them. Instead, certain amount of attractive force will ensue and that contributes to the overall stability of the molecule

|-
|}
 

=== ''' The calculated NMR properties of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | '''
Shielding (ppm) Degeneracy
7.4891704929 4.0000
7.2988172444 1.0000
3.6627082199 1.0000
3.1170156088 1.0000
2.5382383043 1.0000 '''
| width="100" | '''
Shielding (ppm) Degeneracy
24.2569032127 4.0000
24.4474861875 1.0000
28.0829310079 1.0000
28.6310290891 1.0000
29.2122790315 1.0000
'''
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Styrene R HNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Styrene S HNMR.png|400px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | '''
Shift (ppm) Degeneracy
135.1098747604 1.0000
124.1186533632 1.0000
123.4150641684 1.0000
122.9584694331 2.0000
118.2653162569 1.0000
54.0265785300 1.0000
53.4853575062 1.0000 '''
| width="100" | '''
Shift (ppm) Degeneracy
135.1323742030 1.0000
124.1343038829 1.0000
123.4137039868 1.0000
122.9558208084 2.0000
118.2690258882 1.0000
54.0599580762 1.0000
53.4684920923 1.0000
'''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | ''' [[File:Styrene R CNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Styrene S CNMR.png|400px|center|]]'''
|-
| width="100" | ''' '''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | ''' '''
| width="100" | ''' '''
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Stilbene RR HNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|400px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | ''' '''
| width="100" | ''' '''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | ''' [[File:Stilbene RR CNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|400px|center|]]'''
|-
|}

 

=== ''' Assigning the absolute configuration of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''Predicted ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg'''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg '''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental conditions'''
| width="100" | '''1.00g/100ml, chloroform, 21 degree Celcisus, 589 nm wavelength '''
| width="100" | '''1.02g/100ml (99% ee), chloroform, 25 degree Celsius, 589 nm wavelength '''
| width="100" | '''1.01g/100ml, ethanol, 22 degree Celsius, 589 nm wavelength '''
| width="100" | '''0.6g/100ml, ethanol, 20 degree Celsius, 589 nm wavelength '''
|- align="left"
| width="100" | ''' Predicted VCD Spectrum'''
| width="100" | '''[[File:Styrene R VCD.png|200px|center|]] '''
| width="100" | '''[[File:Styrene S VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene RR VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene SS VCD.png|200px|center|]]'''
|-
|}

 

All the assignments given in the literature reports are correct although the predicted value differs slightly with the experimental values

=== ''' Analysis of the Transition State for Reactions''' ===
==== '''Predicting Enantiomeric Excess based on Transition State energies''' ====

One of the energy output from Gaussian calculation is the “sum of electronic and thermal free energies”. This is Gibbs Free Energy at 298.15K and 1 atm.

Using this term and invoking a variant of the Curtin-Hammett Principle, it is possible to calculate a predicted enantiomeric excess of one enantiomer over the other.

[[File:Ee and transition state energy.png|800px|center]]

Using the derivations from above and equation (4), we analyze the enantiomeric excess of beta-methyl styrene and the results are tabulated as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1343.022970'''
| width="100" | '''-1343.017942'''
| width="150" | '''-0.005028'''
| width="150" | '''4.88E-03'''
| width="150" | '''99.03'''
|- align="center"
| width="100" | '''-1343.019233'''
| width="100" | '''-1343.015603'''
| width="150" | '''-0.003630'''
| width="150" | '''2.14E-02'''
| width="150" | '''95.80'''
|- align="center"
| width="100" | '''-1343.029272'''
| width="100" | '''-1343.023766'''
| width="150" | '''-0.005506'''
| width="150" | '''2.94E-03'''
| width="150" | '''99.41'''
|- align="center"
| width="100" | '''-1343.032443'''
| width="100" | '''-1343.024742'''
| width="150" | '''-0.007701'''
| width="150" | '''2.88E-04'''
| width="150" | '''99.94'''
|-
|}

 

The above hartree units are converted to J/mol for calculation of K where 1 hartress = 4.3597E-18

Studying all the free energies of the (R,R) series and compare them with the (S,S) series, it comes as no surprise that (R,R) product is favoured over (S,S) product as (R,R) is more stable. Indeed, this corresponds with the literature value reporting 92% ee of (R,R) products over that of (S,S).

==== '''Analysis of the Transition State of Epoxidation''' ====
==== '''Shi Fructose Catalyst''' ====
For this section, I will be analyzing the the transition state of 1) styrene and 2) trans-stilbene with the Shi fructose catalyst.

===== '''(R) and (S)-styrene transition state''' =====
The transition state for the formation of (R)-styrene oxide and (S)-styrene oxide are given as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R)-styrene oxide'''
| width="150" | '''(S)-styrene oxide'''
|- align="center"
| width="150" | ''' Structure of Catalyst '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide R.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide S ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| [[File:Steric shi fructose R.png|450px|center]]
| [[File:Steric shi fructose S.png|450px|center]]
|-
|}

 

In the transition state for (R)-styrene, it was discovered that the Re face is reacting with the oxygen of the dioxirane. The phenyl ring is oriented endo with respect to the fructose catalyst. However, the (S)-styrene is reacting at the Si face and the phenyl ring is oriented exo relative to the catalyst.

The approach taken by (R)-styrene and (S)-styrene are restricted to only one due to steric interactions. Therefore, the epoxidation of both styrenes by the Shi catalyst will be stereospecific and retains all the stereochemical information of the reactant. However, whether or not (R)-styrene oxide or (S)-styrene oxide is form is dependent on the relative energies of the transition state. The more stable the transition state, the more likely the product of the transition state will be formed.

So in order to examine this, an example of transition state of both styrenes with Shi catalyst are obtained and analyzed.
 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1303.736813'''
| width="100" | '''-1303.727673'''
| width="150" | '''-0.00914'''
| width="150" | '''6.28E-05'''
| width="150" | '''99.99'''

|-
|}

 

From the above, we can see the predicted high enantiopurity of the reaction favoring the (R) product because of the lower energy of the transition states. To understand the reason, we have to turn to non-covalent interaction (NCI) analysis.

[[File:NCI shi fructose styrene.png|700px|center]]

To complement the NCI analysis, a QTAIM (Quantum Theory of Atoms in Molecules) analysis is conducted as well.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''(R)-styrene transition state'''
| width="200" | '''(S)-styrene transition state'''
|- align="center"
| width="100" | '''[[File:QTAIM R.png|400px|center]]'''
| width="100" | '''[[File:QTAIM S.png|400px|center]]'''
|- align="center"
| colspan="2" width="100" | '''Comments'''
|-
| colspan="2" width="100" | '''Unsurprisingly, QTAIM analysis has also shown that (R)-styrene/Shi catalyst has more interactions with one another. While (R)-styrene has 2 strong interactions, (S)-styrene has only one with the catalyst. Besides, the phenyl ring of (R)-styrene also confers additional positive interaction with the catalyst. QTAIM analysis has also show several interactions between the C=C geminal hydrogen of (R)-styrene intreacting with the oxygen atoms on the dioxacyclopentane ring'''
|-
|}

 

===== '''(R,R) and (S,S)-Stilbene transition state''' =====

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R,R)-Stilbene oxide'''
| width="150" | '''(S,S)-Stilbene oxide'''
|- align="center"
| width="150" | ''' Structure of Transition State '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Stilbene RR ts.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>SS stilbene oxide ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| colspan="2" | [[File:Shi fructose stilbene.png|700px|center]]

|-
|}

 

However, unlike styrene, trans-stilbene seems to approach perpendicularly to the dioxirane. This is proposed to be due to the steric interactions (marked in purple). Based on first inspection, it seems that (S,S)-Stilbene oxide has more steric interactions than (R,R)-Stilbene oxide. Although unsubstantial, it seems like my guess was correct. The (R,R)-stilbene/Shi catalyst transition state is lower in energy.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1534.687808'''
| width="100" | '''-1534.683440'''
| width="150" | '''0.004368'''
| width="150" | '''9.08E-3'''
| width="150" | '''98.20'''

|-
|}

 

NCI Analysis is also done for trans-stilbene

[[File:NCI stilbene.png|700px|center]]

==== '''Jacobsen Catalyst''' ====

For this section, cis-beta methyl styrene transition state will be analyzed.

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-3383.259559'''
| width="100" | '''-3383.251060'''
| width="150" | '''-0.008499'''
| width="150" | '''1.24E-04'''
| width="150" | '''99.98'''
|- align="center"
| width="100" | '''-3383.253442'''
| width="100" | '''-3383.250270'''
| width="150" | '''-0.003172'''
| width="150" | '''3.48E-02'''
| width="150" | '''93.27'''
|-
|}

 

As is obvious from here, the (S,R) transition state is more stable than the (R,S) transition state. Both transition states are exo with respect to the catalyst.

It is not immediately apparent just by looking at the molecule to determine which spatial groups have interactions with one another. Therefore, an NCI analysis is conducted again.

[[File:NCI Jacobsen.png|700px|center]]

Rep:Mod:Computationalreport1C

2013-11-21T23:21:27Z

Xc2611: /* The calculated NMR properties of the product */

= '''Synthesis and Computational Lab: 1C''' =
== '''Part 1: Introduction to Molecular Mechanics''' ==
=== '''Introduction to MMFF94 and MMFF94s''' ===

With the improvement of computational data and computer processing power, the usage of molecular mechanics/dynamics forcefield has become very integrated in predicting properties of chemical molecules. A molecular mechanics/dynamics forcefield should be able to predict characteristics such as molecular geometries, conformational/stereoisomeric energies, vibrational frequencies etc. to a reasonable accuracy as compared to experimental-derived values.

Building on work from Kollman et al. s’ AMBER forcefield and Allinger et al. s’ MM1, MM2, MM3 and MM4, Merck Research Laboratories have managed to optimized and improved the previous computational algorithms and produced MMFF94 (Merck Molecular Force Field 94). One of the most prominent advantages of MMFF94 over other preceeding work is its enhanced prediction accuracy. The reason lies in the fact that MMFF94’s core parameterization utilizes an unprecedently large amount of computational data obtained from ab initio calculations1.

Subsequently after the development of MMFF94, a new “static” variant of the MMFF was introduced i.e. the MMFF94s. Unlike MMFF94 that was developed for the use of molecular dynamics simulations (which can be expensive), MMFF94s was developed with the purpose of energy minimization studies in mind. Although both systems provide identical results for most systems, they differ for amides and unsaturated amines which contain resonance-delocalized trigonal nitrogen atoms2.

In this computational exercise, MMFF94s is used predominantly as oppose to the alternative Universal Force Field (UFF). Although versatile across the entire periodic table, UFF is derived from simple rules and atomic parameters such as fixed hybridization that increases the likelihood of erroneous structural and energetic predictions3.

=== '''Forms of MMFF94s''' ===

Steric energy of a molecule is the energy arise due to its geometry or conformation. Energy minimization of steric energy process ensures that the molecule is in its lowest energy conformation.

MMFF94s assumes that the total steric energy of a molecule can be found by the sum of a few specific interactions in a molecule.

ES = EBS + EAB + E SB + ET + EOOP + EVdW + EEE

'''where the bonded interactions are:'''

ES = Total Steric energy

EBS = Total Bond Stretching energy

EAB = Total Angle Bending energy

ESB = Total Stretch Bending energy

ET = Total Torsional Energy

EOOP = Total Out-Of-Plane Bending energy, and

'''where the non-bonded interactions are:'''

EVdW = Total Van der Waals Energy

EEE = Total Electrostatic Energy

{| border="1" cellspacing="1" cellpadding="10"
|-
| width="300" align="center" | '''Types of Energies'''
! width="600" align="center" | '''Explanation'''
|-
| colspan="2" style="text-align: center;" | '''Bonded Interactions'''
|-
| width="300" align="center" | '''Total Bond Stretching Energy'''
! width="600" align="left" | The total bond stretching energy is related to the vibration energy of the molecules in comparison to the equilibrium bond length. Whenever a bond deviates from the equilibrium bond length, the energy value increases.

MMFF94s uses a quartic function that has the force constant term (relate to bond strength). The quartic function term is superior to the cubic function term (used in MM2) in the sense that it avoid the “cubic stretch catastrophe” where progressive elongation of molecule bond length leads to negative infinity.
|-
| width="300" align="center" | '''Total Angle Bending Energy'''
! width="600" align="left" | Similar to Total Bond Stretching Energy, the total angle bending energy is also related to the vibration energy of the molecules about the equilibrium bond length. However, unlike EBS that measures the bond strength, EAB is associated with the stiffness of the molecules based on the Hookiean potential. Whenever bond angles deviate from the norm during vibration, this energy term increases as well.
|-
| width="300" align="center" | '''Total Stretch-Bending Energy'''
! width="600" align="left" | This energy term takes into account of the energy due to increase in bond length when bond angle between two atoms changes.
|-
| width="300" align="center" | '''Total Torsional Energy'''
! width="600" align="left" | Total torsional energy is the energy required for intermolecular rotation about the bonds. In molecule mechanics, however, this term is often used as a correction that must be added or subtracted to the total energy of the molecule to fit a quantum mechanical calculation about the dihedral angles of bonds.
|-
| width="300" align="center" | '''Total Out-Of-Plane Bending Energy'''
! width="600" align="left" | This energy term refers to the energy needed to deform the dihedral angle (zero degrees) of a planar group of atoms such as carbonyl or amide functional groups.
|-
| colspan="2" style="text-align: center;" | '''Non-Bonded Interactions'''
|-
| width="300" align="center" | '''Total Van der Waals Energy'''
! width="600" align="left" | The total Van der Waals energy term examines the intramolecular interactions such as repulsion or attraction between non-bonded atoms in the molecule. This term is crucial in determining the preferred conformation of the molecule.

MMFF94s employs the novel “Buffered-14-7”. The name is derived from a buffering constant and the 14th and 7th power dependencies of the repulsive and attractive energy in the equation.
|-
| width="300" align="center" | '''Total Electrostatic Energy'''
! width="600" align="left" | The total electrostatic energy functions take into account of the Coulombic potential and partial charge/dipole/atomic point charges interactions within the molecule.
|-

|}

 

== '''Part 2 : Conformational Analysis Using Molecular Mechanics''' ==
=== '''The Hydrogenation of Cyclopentadiene Dimer''' ===

==== '''Endo and exo adduct from the Dimerization of Cyclopentadiene''' ====
Cyclopentadiene will undergo dimerization by Diels-alder reaction to form either an endo or exo adduct.

[[File:XcwDimerization of CP.png|500px|center]]

==== '''Stereoselectivity of Dimerization of Cyclopentadiene''' ====
Although the exo adduct is thermodynamically more stable than the endo adduct, the endo adduct is form preferentially. Using the QST2 method, the transition state of the Diels Alder dimerization was found. It was discovered that due to the secondary orbital interactions in the endo transition state, the endo dimer is formed preferentially (the kinetic product). Hence, it is proven that the Diels Alder dimerization between two cyclopentadiene are kinetically controlled.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Transition State of Dimerization of Cyclopentadiene'''
| '''Imaginary Stretch Frequency (-881.25) of the Endo Transition State (click to animate)'''
| '''Secondary Orbital Interaction (Red overlapping orbitals)'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<uploadedFileContents>EndotsDCPD2.mol
</uploadedFileContents>
</jmolApplet></jmol>
| [[File:Xcwendotsimaginary.gif|300px|center]]
| [[File:XcwSecondary orbital interaction1.jpg|300px|center]]
|-
|}

 

==== '''Asynchronous Bond Formation of Dimerization of Cyclopentadiene''' ====

The initial study of the molecular orbitals of the transition states seemed a bit peculiar. Instead of getting a LUMO with symmetrical orbitals, the calculations showed a HOMO that is asymetric at the carbons where the new sigma bonds will be formed. Running an IRC further, it soon became clear that the asymmetry of the HOMO leads to an asychronous bond formation before leading to the product.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''IRC plot following the Endo Transition State '''
| '''IRC following the Endo Transition State (click to animate)'''
| '''Asymmetry of orbitals at the carbons where the new sigma bonds will be formed'''
|- align="center"
| [[File:XcwendotscyclopentadieneIRC.png|300px|center]]
| [[File:XcwendotsIRC.gif|300px|center]]
| [[File:XcwAsynchronous mo.jpg|300px|center]]
|-
|}

 

==== '''Comparison of Energies between the Endo and Exo adduct of Dicyclopentadiene''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Adduct of Dicyclopentadiene dimerization'''
| '''Exo Adduct of Dicyclopentadiene dimerization'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=19,atomno=1,atomno=2; color green;measure 19 1;measure 19 2;</script>
<uploadedFileContents>XcwEndodimer3.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>Exodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=7,atomno=17; color green;measure 17 7;</script>
<uploadedFileContents>XcwExodimer1.mol</uploadedFileContents>
</jmolApplet></jmol>
|-
|}

 

Using MMFF94s ab initio calculations, the energies for the exo dimer and the endo dimer are derived.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Exodimer'''
| '''55.374'''
| 3.543
| 30.772
| -2.041
| -2.728
| 0.015
| 12.800
| 13.014
|-
| '''Endodimer'''
| '''58.191'''
| 3.468
| 33.187
| -2.082
| -2.950
| 0.023
| 12.360
| 14.186
|-
|}

 

The MMFF94s steric energy (after minimization) for the exo dimer is lower than that of the endo dimer. This is reflected by the large difference for the EEE between the endo dimer and the exo dimer due to unfavourable steric repulsion between the two “arched down” cyclopentene rings.

==== '''Hydrogenation of Dicyclopentadiene''' ====

Hydrogenation of the endo dicyclopentadiene (DCPD) would lead to two potential products: dihydro product 1 and dihydro product 2.

[[File:XcwFormation of Dihydro products.png|500px|center]]

Using MMFF94s, the energy of the two dihydro products are calculated.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Dihydro Product 1'''
| '''50.123'''
| 3.308
| 30.864
| -1.927
| 0.060
| 0.015(2)
| 13.281
| 5.121
|-
| '''Dihydro Product 2'''
| '''41.257'''
| 2.823
| 24.685
| -1.657
| -0.379
| 0.000(2)
| 10.639
| 5.147
|-
| '''Tetrahydro Product'''
| '''39.042'''
| 2.730
| 25.151
| -1.676
| 1.287
| 0.000
| 11.551
| 0.000
|}

 

From the MMFF94s calculation, it can be seen that dihydro product 2 has a lower steric energy than dihydro product 1. Therefore, dihydro product 2 is the thermodynamic product for the hydrogenation of dicylopentadiene. And indeed, this was what was observed by Skala et al.. He observed that the first hydrogenation occur at the norborene part of the molecule (rate of hydrogenation several times faster than that in the cyclopentene ring)6. The first heat of hydrogenation at the norborene is 138.8 kJ/mol while the second hydrogenation at the cyclopentene right is 109.5 kJ/mol6.

From the above results, it is also obvious that tetrahydro product is much more stable than either dihydro product. And yet, studies have shown that the tetrahydro product will only form after prolonged hydrogenation under high temperature. However, subjecting DCPD to high temperature leads to low yield due to cracking of DCPD.

Since thermodynamically it is predicted to form favourably, the fact that it does not could only mean that the hydrogenation of DCPD to tetrahydrodicyclopentadiene (TH-DCPD) is kinetically controlled. Most possibly, the transition state of the hydrogenation of DCPD is highly unstable hence it is unlikely to form.

=== '''Atropisomerism in an Intermediate related to the Synthesis of Taxol''' ===

Atropisomerism is a type of stereoisomerism that is form as a result of hindered rotation about a single bond.

[[File:XcwAtropisomerism example.png|500px|center]]

In the case of the 6,6’-dinitro-2,2’-diphenic acid, rotation about the bonds joining the two substituted phenyl rings would have to overcome large steric interaction between the bulky substituents. The barrier of rotation is high enough for the two conformers to be isolated individually.

In the synthesis of taxol, one of the key intermediates exhibit atropisomerism.

==== '''Atropisomerism in Taxol Synthesis''' ====

For the key intermediate, rotation about the carbon-carbon bonds would lead to two types of atropisomers, each with either the carbonyl group poining upwards or downwards in relative to the bridge.

[[File:XcwIntermediate 9 and Intermediate 10.png|500px|center]]

Once again by using MMFF94s ab initio calculations, the steric energies for the two intermediates are illustrated as below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 9'''
| '''70.571'''
| 7.743
| 28.356
| -0.062
| 0.004
| 0.949
| 33.293
| 0.288
|-
| '''Intermediate 10'''
| '''60.553'''
| 7.599
| 18.838
| -0.139
| 0.199
| 0.844
| 33.269
| -0.056
|-

|}

 

Analyzing the data above, the largest energy difference between Intermediate 9 and Intermediate 10 stems from the EAB which is related to the strain of the ring. Intermediate 9 has an excess of 9.518 kcal/mol EAB as compared to Intermediate 10. This comes as a surprise as intermediate 9 is predicted to be more stable alkene.

The rationale behind the prediction of the stability of intermediate 9 stems from the fact that the through-space distance of the upward-pointing carbonyl oxygen with the carbon-carbon is further than the through space distance between the downward-pointing carbonyl oxygen with the -CH2-CH2- fragment at the norbornene part in intermediate 10.

==== '''Hyperstable Olefins''' ====

Intermediate 9 and Intermediate 10 does not react readily with other reagents during functionalization. This is due to the hyperstability effect found in hyperstable olefins.

Hyperstable olefins are alkenes that contain less strain in the ring (i.e. negative olefin strain values) compared to the parent hydrocarbon. To study this further, further MMFF94s calculation was done to compare Intermediate 10 with the parent hydrocarbon.

[[File:XcwIntermediate10andPH.png|500px|center]]

The energies that we calculated are tabulated as shown below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 10'''
| '''44.878 '''
| 5.211
| 15.488
| -0.267
| -1.655
| 0.998
| 25.014
| 0.088
|-
| '''Parent Hydrocarbon'''
| '''50.564'''
| 4.692
| 21.979
| 0.109
| -0.958
| 0.247
| 24.495
| 0.000
|-

|}

 

Scrutinizing the results, the largest energy difference between intermediate 10 and the parent hydrocarbon stems from the Total Angle Bending Energy, EAB. Since the Total Angle bending energy is related to the angle strain in the molecules, it is apparent that the parent hydrocarbon has more ring strain as compared to the bridgehead olefin.

== '''Part 3 : Spectroscopic Simulation Using Quantum Mechanics''' ==
=== '''Spectroscopy of an Intermediate Related to the Synthesis of Taxol''' ===

Molecule 17 and 18 are derivatives of intermediate 9 and 10. In this exercise, MMFF94s is used to predict the 1H and 13C NMR of molecule 17 and molecule 18.

[[File:XcwIntermediate17&18.png|500px|center]]

==== '''NMR Spectra of Molecule 17''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 17.mol
</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwHNMRMolecule 17 Chair Overall NMR.png|500px|center]]
| [[File:XcwHNMRMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.1825
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| The first three results were fairly straight forward to be deduced and correlate wit experimental data.

The hydrogen atom that is geminally attached to the carbon of the double bonds is the most deshielded due to the ring current anisotropic effect of the ring current

The second most deshielded hydrogen atom is the hydrogen atom on the methyl group on the bridge. The hydrogen atom is pointing directly to the oxygen atom of the carbonyl functional group.

The peaks with an integration height of 4 is assigned to the hydrogen atoms in the 1,3-dithiolane ring fragment.

Subsequent analysis of the 1H NMR became very complicated very quickly for two reasons:

1. Gaussian calculations showed some atoms with an integration height of 3. Comparing their file atom number and checking their chemical environment, it is not possible to find any correlation between them.

2. Some of the peaks in the literature remains unresolved and are given as multiplets or grouped together.

|- align="center"
| 52
| 3.1775
| 1
| '''2.99'''
|- align="center"
| 53,52,50,51
| 3.0867
| 4
| '''3.40-3.10'''
|- align="center"
| 42,43,39
| 2.7445
| 3
| ''' '''
|- align="center"
| 49
| 2.6187
| 1
| ''' '''
|- align="center"
| 34
| 2.4371
| 1
| ''' '''
|- align="center"
| 35
| 2.3782
| 1
| ''' '''
|- align="center"
| 40,37,26
| 2.2730
| 3
| ''' '''
|- align="center"
| 30
| 2.1566
| 1
| ''' '''
|- align="center"
| 36
| 2.1033
| 1
| ''' '''
|- align="center"
| 32,28
| 2.0259
| 2
| ''' '''
|- align="center"
| 25
| 1.8535
| 2
| ''' '''
|- align="center"
| 38,46,27
| 1.5898
| 3
| '''1.25'''
|- align="center"
| 29
| 1.4557
| 1
| ''' '''
|- align="center"
| 31
| 1.0123
| 1
| ''' '''
|- align="center"
| 44,48,45
| 0.9087
| 3
| '''1.10'''
|- align="center"
| 47
| 0.8354
| 1
| ''' '''
|- align="center"
| 33
| 0.5790
| 1
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 17 Chair Overall NMR2.png|500px|center]]
| [[File:XcwMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 216.2725
| 1
| '''218.79'''
| rowspan="10" style="text-align:center;"| [[File:XcwMolecule 17 image for CNMR.jpg|600px|center]]
|- align="center"
| 13
| 144.8626
| 1
| '''144.63'''
|- align="center"
| 14
| 124.7193
| 1
| '''125.33'''
|- align="center"
| 3
| 91.3340
| 1
| '''72.88'''
|- align="center"
| 2
| 60.9568
| 1
| '''56.19'''
|- align="center"
| 1
| 57.0811
| 1
| '''52.52'''
|- align="center"
| 10
| 52.4663
| 1
| '''48.50'''
|- align="center"
| 16
| 51.4857
| 1
| '''46.80'''
|- align="center"
| 9
| 46.9196
| 1
| '''45.76'''
|- align="center"
| 23
| 43.8647
| 1
| '''39.80'''
|- align="center"
| 22
| 41.9450
| 1
| '''38.81'''
| Comments
|- align="center"
| 4
| 41.8724
| 1
| '''35.85'''
| rowspan="9" style="text-align:left;"| The carbon bonded to the oxygen atom is the most deshielded, as is shown in the predicted values and the experimental values. There is a deviation between the values. Quite possibly, this is due to the fact that in reality, the carbonyl functional group is pointing slightly towards the equatorial position rather than a lateral position relative to the ring (as is in the input for Gaussian calculation)

Most of the 1CNMR values that was predicted by Gaussian are all within an acceptable range of deviation. However, there is carbon 3 that has significant deviation between the predicted value and experimental value.

Carbon 3 is the carbon bonded to the two sulphurs in the 1,3-dithiolane ring fragment. Such a huge deviation would possibly mean that the conformer that was given as input to Gaussian differs from the literature.

The above NMR spectra was corrected with a level of theory B3LYP/6-31G(d,p) using TMS as reference and in chloroform.

|- align="center"
| 15
| 35.4348
| 1
| '''32.66'''
|- align="center"
| 11
| 31.1964
| 1
| '''28.79'''
|- align="center"
| 6
| 28.9432
| 1
| '''28.29'''
|- align="center"
| 7
| 28.3640
| 1
| '''26.88'''
|- align="center"
| 12
| 27.3767
| 1
| '''25.66'''
|- align="center"
| 17
| 26.3311
| 1
| '''23.86'''
|- align="center"
| 15
| 24.5483
| 1
| '''20.96'''
|- align="center"
| 18
| 19.7788
| 1
| '''18.71'''
|-
|}
 

==== '''NMR Spectra of Molecule 18''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 18 Boat for Image2.mol</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"-
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 18 Chair Overall NMR.png|500px|center]]
| [[File:Molecule 18 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.2832
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| ''' '''
|- align="center"
| 50
| 3.3175
| 1
| rowspan="4" style="text-align:centre;"| '''3.00-2.70'''
|- align="center"
| 52
| 3.2153
| 1
|- align="center"
| 51,53
| 3.1161
| 2
|- align="center"
| 34,43
| 2.8606
| 2
|- align="center"
| 38
| 2.4549
| 1
| ''' '''
|- align="center"
| 42
| 2.3968
| 1
| ''' '''
|- align="center"
| 25,29,26
| 2.2796
| 3
| ''' '''
|- align="center"
| 39
| 2.0844
| 1
| ''' '''
|- align="center"
| 40,36
| 1.9699
| 2
| ''' '''
|- align="center"
| 37,24
| 1.8519
| 2
| ''' '''
|- align="center"
| 31,27
| 1.6780
| 2
| ''' '''
|- align="center"
| 28
| 1.6175
| 1
| ''' '''
|- align="center"
| 46,49
| 1.4979
| 2
| ''' '''
|- align="center"
| 35
| 1.4150
| 1
| ''' '''
|- align="center"
| 32
| 1.3531
| 1
| ''' '''
|- align="center"
| 48
| 1.1606
| 1
| ''' '''
|- align="center"
| 33,30,47
| 1.0653
| 3
| '''1.03'''
|- align="center"
| 44,45
| 0.9643
| 2
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwMolecule 18 Boat Overall NMR.png|500px|center]]
| [[File:XcwMolecule 18 Boat zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 211.8325
| 1
| '''211.49'''
| rowspan="10" style="text-align:center;"| [[File:Molecule 18 Boat for 13 CNMR.jpg|600px|center]]
|- align="center"
| 13
| 148.6673
| 1
| '''148.72'''
|- align="center"
| 14
| 118.8373
| 1
| '''120.90'''
|- align="center"
| 3
| 89.0869
| 1
| '''74.61'''
|- align="center"
| 2
| 67.8886
| 1
| '''60.53'''
|- align="center"
| 1
| 56.1133
| 1
| '''51.30'''
|- align="center"
| 10
| 55.5998
| 1
| '''50.94'''
|- align="center"
| 16
| 50.1124
| 1
| '''45.53'''
|- align="center"
| 22
| 48.2030
| 1
| '''43.28'''
|- align="center"
| 23
| 44.2222
| 1
| '''40.82'''
|- align="center"
| 4
| 42.0354
| 1
| '''38.73'''
| Comments
|- align="center"
| 9
| 37.5865
| 1
| '''36.78'''
| rowspan="9" style="text-align:left;"| ''' '''
|- align="center"
| 6
| 35.3106
| 1
| '''35.47'''
|- align="center"
| 15
| 31.0459
| 1
| '''30.84'''
|- align="center"
| 7
| 28.8476
| 1
| '''30.00'''
|- align="center"
| 12
| 28.6623
| 1
| '''25.56'''
|- align="center"
| 17
| 25.7393
| 1
| '''25.35'''
|- align="center"
| 11
| 25.2603
| 1
| '''22.21'''
|- align="center"
| 18
| 23.3944
| 1
| '''21.39'''
|- align="center"
| 5
| 21.0478
| 1
| '''19.83'''
|-
|}
 

== '''Part 4 : Analysis of the Properties of the Synthesized Alkene Epoxides''' ==
=== '''The two catalytics systems''' ===

Assymmetric epoxidation of prochiral alkenes may lead to product with different stereochemical outcome as illustrated as below. To solve this problem, different types of asymmetric epoxidation catalyst have been synthesized. In this study, we shall be focusing on Shi asymmetric fructose catalyst as well as Jacobsen asymmetric catalyst.

[[File:Asymmetric catalyst.png|400px|center]]

==== ''' The Shi Asymmetric Fructose Catalyst''' ====

Molecule 21 is the stable precursor of molecule 22, the active catalyst. Molecule 21 can be converted to molecule 22 by using either persulfuric acid or potassium peroxymonosulphate.

[[File:Molecule 21 to 23.png|400px|center]]

The transition state of the Shi epoxidation was a subject of debate for a few moments. However, recent studies have led to the conclusion that the spiro transition state is more favored than the planar transition state. The spiro transition state is the transition that has its dioxirane perpendicularly bisecting the alkene double bond. This is thought to be more favourable due to interactions between the lone pairs of the oxygen with the LUMO of the alkene.

[[File:Spiro and planar ts.png|500px|center]]

==== ''' The Jacobsen Asymmetric Catalyst''' ====

Molecule 23 is the stable precursor of molecule 24, the active catalyst. Molecule 23 can be converted to molecule 24 by using sodium perchlorate.

[[File:Salen, 23 and 24.png|400px|center]]

Jacobsen catalyst is biphasic. The first phase involves the transfer of oxygen to molecule 23. Sodium perchlorate oxidizes Mn(III) to Mn(V).

In the second step, Jacobsen catalyst acts via a radical mechanism. It is thought to be so because epoxidation of trans-alkene by Jacobsen catalyst yield cis-alkene as well. A radical mechanism will lead to the lost of stereochemical information of the molecule.

=== ''' Crystal structure of the two catalyst''' ===
==== '''Molecule 21''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 21'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 21 strucutre.png|600px|center]]'''
|-
| style="text-align:center;" width="150" | ''' Bond '''
| style="text-align:center;" width="150"| ''' Bond Lenghts (Angstrom)'''
| style="text-align:center;" | ''' Evaluation'''
|-
| style="text-align:center;"| ''' O1-C1 '''
| style="text-align:center;"| ''' 1.400'''
| rowspan="10" style="text-align:left;"| [[File:Molecule 21 2.png|300px|center]]

The normal bond length of an C-O bond is 1.430 angstrom.

The most interesting aspect here is O4 and O2. The lone pair of O4 is antiperplanar to the sigma* orbital of the carbonyl group while the lone pair of O2 is anti periplanar to the carbonyl pi* orbital. Donation of electron can occur because of the correct symmetry. Due to the mixing of the orbitals, the C2-O2 and C4-O4 has been conferred with a certain degree of double bond character.

However, due to the lone pair on oxygen being now donated to the carbonyl antibonding orbitals, the O2 and O4 is slightly “electron deficient” and electron density will be pulled away from O2 and O4. That would explain why the bond length increase for O2-C7 and O4-C10. Increase in bond length is an indicator of the weakening of the bond.
|-
| style="text-align:center;"|'''O1-C7'''
| style="text-align:center;"|'''1.413'''
|-
| style="text-align:center;"|'''O2-C7'''
| style="text-align:center;"|'''1.441'''
|-
| style="text-align:center;"|'''O2-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O4-C4'''
| style="text-align:center;"|'''1.396'''
|-
| style="text-align:center;"|'''O4-C10'''
| style="text-align:center;"|'''1.439'''
|-
| style="text-align:center;"|'''O5-C10'''
| style="text-align:center;"|'''1.409'''
|-
| style="text-align:center;"|'''O5-C5'''
| style="text-align:center;"|'''1.416'''
|-
| style="text-align:center;"|'''O6-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O6-C6'''
| style="text-align:center;"|'''1.420'''
|-
|}
 

==== '''Molecule 23''' ====

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 23'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 23 struc.png|600px|center]]'''
|-
| The most outstanding feature from this molecule is the fact that is adopt a puckered form of the square base pyramidal form. This is no surprise that the molecule is almost planar due to the electron delocalization around each side of the salen ligand.

The tery-butyl hydrogen are oriented closely to one another. Non-covalent interaction studies indicated that repulsion would occur for H---H bond length that are less than 2.1 angstrom while favourable interaction may be dominant with bond length above 2.4 angstrom. It was discovered that all 4 hydrogens have bond length more than 2.4 angstrom hence there should not be any significant repulsion between them. Instead, certain amount of attractive force will ensue and that contributes to the overall stability of the molecule

|-
|}
 

=== ''' The calculated NMR properties of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | '''
Shielding (ppm) Degeneracy
7.4891704929 4.0000
7.2988172444 1.0000
3.6627082199 1.0000
3.1170156088 1.0000
2.5382383043 1.0000 '''
| width="100" | '''
Shielding (ppm) Degeneracy
24.2569032127 4.0000
24.4474861875 1.0000
28.0829310079 1.0000
28.6310290891 1.0000
29.2122790315 1.0000
'''
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Styrene R HNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Styrene S HNMR.png|400px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | '''
Shift (ppm) Degeneracy
135.1098747604 1.0000
124.1186533632 1.0000
123.4150641684 1.0000
122.9584694331 2.0000
118.2653162569 1.0000
54.0265785300 1.0000
53.4853575062 1.0000 '''
| width="100" | '''
Shift (ppm) Degeneracy Atoms
135.1323742030 1.0000
124.1343038829 1.0000
123.4137039868 1.0000
122.9558208084 2.0000
118.2690258882 1.0000
54.0599580762 1.0000
53.4684920923 1.0000
'''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | ''' [[File:Styrene R CNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Styrene S CNMR.png|400px|center|]]'''
|-
| width="100" | ''' '''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | ''' '''
| width="100" | ''' '''
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Stilbene RR HNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|400px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | ''' '''
| width="100" | ''' '''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | ''' [[File:Stilbene RR CNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|400px|center|]]'''
|-
|}

 

=== ''' Assigning the absolute configuration of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''Predicted ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg'''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg '''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental conditions'''
| width="100" | '''1.00g/100ml, chloroform, 21 degree Celcisus, 589 nm wavelength '''
| width="100" | '''1.02g/100ml (99% ee), chloroform, 25 degree Celsius, 589 nm wavelength '''
| width="100" | '''1.01g/100ml, ethanol, 22 degree Celsius, 589 nm wavelength '''
| width="100" | '''0.6g/100ml, ethanol, 20 degree Celsius, 589 nm wavelength '''
|- align="left"
| width="100" | ''' Predicted VCD Spectrum'''
| width="100" | '''[[File:Styrene R VCD.png|200px|center|]] '''
| width="100" | '''[[File:Styrene S VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene RR VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene SS VCD.png|200px|center|]]'''
|-
|}

 

All the assignments given in the literature reports are correct although the predicted value differs slightly with the experimental values

=== ''' Analysis of the Transition State for Reactions''' ===
==== '''Predicting Enantiomeric Excess based on Transition State energies''' ====

One of the energy output from Gaussian calculation is the “sum of electronic and thermal free energies”. This is Gibbs Free Energy at 298.15K and 1 atm.

Using this term and invoking a variant of the Curtin-Hammett Principle, it is possible to calculate a predicted enantiomeric excess of one enantiomer over the other.

[[File:Ee and transition state energy.png|800px|center]]

Using the derivations from above and equation (4), we analyze the enantiomeric excess of beta-methyl styrene and the results are tabulated as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1343.022970'''
| width="100" | '''-1343.017942'''
| width="150" | '''-0.005028'''
| width="150" | '''4.88E-03'''
| width="150" | '''99.03'''
|- align="center"
| width="100" | '''-1343.019233'''
| width="100" | '''-1343.015603'''
| width="150" | '''-0.003630'''
| width="150" | '''2.14E-02'''
| width="150" | '''95.80'''
|- align="center"
| width="100" | '''-1343.029272'''
| width="100" | '''-1343.023766'''
| width="150" | '''-0.005506'''
| width="150" | '''2.94E-03'''
| width="150" | '''99.41'''
|- align="center"
| width="100" | '''-1343.032443'''
| width="100" | '''-1343.024742'''
| width="150" | '''-0.007701'''
| width="150" | '''2.88E-04'''
| width="150" | '''99.94'''
|-
|}

 

The above hartree units are converted to J/mol for calculation of K where 1 hartress = 4.3597E-18

Studying all the free energies of the (R,R) series and compare them with the (S,S) series, it comes as no surprise that (R,R) product is favoured over (S,S) product as (R,R) is more stable. Indeed, this corresponds with the literature value reporting 92% ee of (R,R) products over that of (S,S).

==== '''Analysis of the Transition State of Epoxidation''' ====
==== '''Shi Fructose Catalyst''' ====
For this section, I will be analyzing the the transition state of 1) styrene and 2) trans-stilbene with the Shi fructose catalyst.

===== '''(R) and (S)-styrene transition state''' =====
The transition state for the formation of (R)-styrene oxide and (S)-styrene oxide are given as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R)-styrene oxide'''
| width="150" | '''(S)-styrene oxide'''
|- align="center"
| width="150" | ''' Structure of Catalyst '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide R.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide S ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| [[File:Steric shi fructose R.png|450px|center]]
| [[File:Steric shi fructose S.png|450px|center]]
|-
|}

 

In the transition state for (R)-styrene, it was discovered that the Re face is reacting with the oxygen of the dioxirane. The phenyl ring is oriented endo with respect to the fructose catalyst. However, the (S)-styrene is reacting at the Si face and the phenyl ring is oriented exo relative to the catalyst.

The approach taken by (R)-styrene and (S)-styrene are restricted to only one due to steric interactions. Therefore, the epoxidation of both styrenes by the Shi catalyst will be stereospecific and retains all the stereochemical information of the reactant. However, whether or not (R)-styrene oxide or (S)-styrene oxide is form is dependent on the relative energies of the transition state. The more stable the transition state, the more likely the product of the transition state will be formed.

So in order to examine this, an example of transition state of both styrenes with Shi catalyst are obtained and analyzed.
 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1303.736813'''
| width="100" | '''-1303.727673'''
| width="150" | '''-0.00914'''
| width="150" | '''6.28E-05'''
| width="150" | '''99.99'''

|-
|}

 

From the above, we can see the predicted high enantiopurity of the reaction favoring the (R) product because of the lower energy of the transition states. To understand the reason, we have to turn to non-covalent interaction (NCI) analysis.

[[File:NCI shi fructose styrene.png|700px|center]]

To complement the NCI analysis, a QTAIM (Quantum Theory of Atoms in Molecules) analysis is conducted as well.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''(R)-styrene transition state'''
| width="200" | '''(S)-styrene transition state'''
|- align="center"
| width="100" | '''[[File:QTAIM R.png|400px|center]]'''
| width="100" | '''[[File:QTAIM S.png|400px|center]]'''
|- align="center"
| colspan="2" width="100" | '''Comments'''
|-
| colspan="2" width="100" | '''Unsurprisingly, QTAIM analysis has also shown that (R)-styrene/Shi catalyst has more interactions with one another. While (R)-styrene has 2 strong interactions, (S)-styrene has only one with the catalyst. Besides, the phenyl ring of (R)-styrene also confers additional positive interaction with the catalyst. QTAIM analysis has also show several interactions between the C=C geminal hydrogen of (R)-styrene intreacting with the oxygen atoms on the dioxacyclopentane ring'''
|-
|}

 

===== '''(R,R) and (S,S)-Stilbene transition state''' =====

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R,R)-Stilbene oxide'''
| width="150" | '''(S,S)-Stilbene oxide'''
|- align="center"
| width="150" | ''' Structure of Transition State '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Stilbene RR ts.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>SS stilbene oxide ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| colspan="2" | [[File:Shi fructose stilbene.png|700px|center]]

|-
|}

 

However, unlike styrene, trans-stilbene seems to approach perpendicularly to the dioxirane. This is proposed to be due to the steric interactions (marked in purple). Based on first inspection, it seems that (S,S)-Stilbene oxide has more steric interactions than (R,R)-Stilbene oxide. Although unsubstantial, it seems like my guess was correct. The (R,R)-stilbene/Shi catalyst transition state is lower in energy.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1534.687808'''
| width="100" | '''-1534.683440'''
| width="150" | '''0.004368'''
| width="150" | '''9.08E-3'''
| width="150" | '''98.20'''

|-
|}

 

NCI Analysis is also done for trans-stilbene

[[File:NCI stilbene.png|700px|center]]

==== '''Jacobsen Catalyst''' ====

For this section, cis-beta methyl styrene transition state will be analyzed.

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-3383.259559'''
| width="100" | '''-3383.251060'''
| width="150" | '''-0.008499'''
| width="150" | '''1.24E-04'''
| width="150" | '''99.98'''
|- align="center"
| width="100" | '''-3383.253442'''
| width="100" | '''-3383.250270'''
| width="150" | '''-0.003172'''
| width="150" | '''3.48E-02'''
| width="150" | '''93.27'''
|-
|}

 

As is obvious from here, the (S,R) transition state is more stable than the (R,S) transition state. Both transition states are exo with respect to the catalyst.

It is not immediately apparent just by looking at the molecule to determine which spatial groups have interactions with one another. Therefore, an NCI analysis is conducted again.

[[File:NCI Jacobsen.png|700px|center]]

Rep:Mod:Computationalreport1C

2013-11-21T23:18:28Z

Xc2611: /* The calculated NMR properties of the product */

= '''Synthesis and Computational Lab: 1C''' =
== '''Part 1: Introduction to Molecular Mechanics''' ==
=== '''Introduction to MMFF94 and MMFF94s''' ===

With the improvement of computational data and computer processing power, the usage of molecular mechanics/dynamics forcefield has become very integrated in predicting properties of chemical molecules. A molecular mechanics/dynamics forcefield should be able to predict characteristics such as molecular geometries, conformational/stereoisomeric energies, vibrational frequencies etc. to a reasonable accuracy as compared to experimental-derived values.

Building on work from Kollman et al. s’ AMBER forcefield and Allinger et al. s’ MM1, MM2, MM3 and MM4, Merck Research Laboratories have managed to optimized and improved the previous computational algorithms and produced MMFF94 (Merck Molecular Force Field 94). One of the most prominent advantages of MMFF94 over other preceeding work is its enhanced prediction accuracy. The reason lies in the fact that MMFF94’s core parameterization utilizes an unprecedently large amount of computational data obtained from ab initio calculations1.

Subsequently after the development of MMFF94, a new “static” variant of the MMFF was introduced i.e. the MMFF94s. Unlike MMFF94 that was developed for the use of molecular dynamics simulations (which can be expensive), MMFF94s was developed with the purpose of energy minimization studies in mind. Although both systems provide identical results for most systems, they differ for amides and unsaturated amines which contain resonance-delocalized trigonal nitrogen atoms2.

In this computational exercise, MMFF94s is used predominantly as oppose to the alternative Universal Force Field (UFF). Although versatile across the entire periodic table, UFF is derived from simple rules and atomic parameters such as fixed hybridization that increases the likelihood of erroneous structural and energetic predictions3.

=== '''Forms of MMFF94s''' ===

Steric energy of a molecule is the energy arise due to its geometry or conformation. Energy minimization of steric energy process ensures that the molecule is in its lowest energy conformation.

MMFF94s assumes that the total steric energy of a molecule can be found by the sum of a few specific interactions in a molecule.

ES = EBS + EAB + E SB + ET + EOOP + EVdW + EEE

'''where the bonded interactions are:'''

ES = Total Steric energy

EBS = Total Bond Stretching energy

EAB = Total Angle Bending energy

ESB = Total Stretch Bending energy

ET = Total Torsional Energy

EOOP = Total Out-Of-Plane Bending energy, and

'''where the non-bonded interactions are:'''

EVdW = Total Van der Waals Energy

EEE = Total Electrostatic Energy

{| border="1" cellspacing="1" cellpadding="10"
|-
| width="300" align="center" | '''Types of Energies'''
! width="600" align="center" | '''Explanation'''
|-
| colspan="2" style="text-align: center;" | '''Bonded Interactions'''
|-
| width="300" align="center" | '''Total Bond Stretching Energy'''
! width="600" align="left" | The total bond stretching energy is related to the vibration energy of the molecules in comparison to the equilibrium bond length. Whenever a bond deviates from the equilibrium bond length, the energy value increases.

MMFF94s uses a quartic function that has the force constant term (relate to bond strength). The quartic function term is superior to the cubic function term (used in MM2) in the sense that it avoid the “cubic stretch catastrophe” where progressive elongation of molecule bond length leads to negative infinity.
|-
| width="300" align="center" | '''Total Angle Bending Energy'''
! width="600" align="left" | Similar to Total Bond Stretching Energy, the total angle bending energy is also related to the vibration energy of the molecules about the equilibrium bond length. However, unlike EBS that measures the bond strength, EAB is associated with the stiffness of the molecules based on the Hookiean potential. Whenever bond angles deviate from the norm during vibration, this energy term increases as well.
|-
| width="300" align="center" | '''Total Stretch-Bending Energy'''
! width="600" align="left" | This energy term takes into account of the energy due to increase in bond length when bond angle between two atoms changes.
|-
| width="300" align="center" | '''Total Torsional Energy'''
! width="600" align="left" | Total torsional energy is the energy required for intermolecular rotation about the bonds. In molecule mechanics, however, this term is often used as a correction that must be added or subtracted to the total energy of the molecule to fit a quantum mechanical calculation about the dihedral angles of bonds.
|-
| width="300" align="center" | '''Total Out-Of-Plane Bending Energy'''
! width="600" align="left" | This energy term refers to the energy needed to deform the dihedral angle (zero degrees) of a planar group of atoms such as carbonyl or amide functional groups.
|-
| colspan="2" style="text-align: center;" | '''Non-Bonded Interactions'''
|-
| width="300" align="center" | '''Total Van der Waals Energy'''
! width="600" align="left" | The total Van der Waals energy term examines the intramolecular interactions such as repulsion or attraction between non-bonded atoms in the molecule. This term is crucial in determining the preferred conformation of the molecule.

MMFF94s employs the novel “Buffered-14-7”. The name is derived from a buffering constant and the 14th and 7th power dependencies of the repulsive and attractive energy in the equation.
|-
| width="300" align="center" | '''Total Electrostatic Energy'''
! width="600" align="left" | The total electrostatic energy functions take into account of the Coulombic potential and partial charge/dipole/atomic point charges interactions within the molecule.
|-

|}

 

== '''Part 2 : Conformational Analysis Using Molecular Mechanics''' ==
=== '''The Hydrogenation of Cyclopentadiene Dimer''' ===

==== '''Endo and exo adduct from the Dimerization of Cyclopentadiene''' ====
Cyclopentadiene will undergo dimerization by Diels-alder reaction to form either an endo or exo adduct.

[[File:XcwDimerization of CP.png|500px|center]]

==== '''Stereoselectivity of Dimerization of Cyclopentadiene''' ====
Although the exo adduct is thermodynamically more stable than the endo adduct, the endo adduct is form preferentially. Using the QST2 method, the transition state of the Diels Alder dimerization was found. It was discovered that due to the secondary orbital interactions in the endo transition state, the endo dimer is formed preferentially (the kinetic product). Hence, it is proven that the Diels Alder dimerization between two cyclopentadiene are kinetically controlled.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Transition State of Dimerization of Cyclopentadiene'''
| '''Imaginary Stretch Frequency (-881.25) of the Endo Transition State (click to animate)'''
| '''Secondary Orbital Interaction (Red overlapping orbitals)'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<uploadedFileContents>EndotsDCPD2.mol
</uploadedFileContents>
</jmolApplet></jmol>
| [[File:Xcwendotsimaginary.gif|300px|center]]
| [[File:XcwSecondary orbital interaction1.jpg|300px|center]]
|-
|}

 

==== '''Asynchronous Bond Formation of Dimerization of Cyclopentadiene''' ====

The initial study of the molecular orbitals of the transition states seemed a bit peculiar. Instead of getting a LUMO with symmetrical orbitals, the calculations showed a HOMO that is asymetric at the carbons where the new sigma bonds will be formed. Running an IRC further, it soon became clear that the asymmetry of the HOMO leads to an asychronous bond formation before leading to the product.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''IRC plot following the Endo Transition State '''
| '''IRC following the Endo Transition State (click to animate)'''
| '''Asymmetry of orbitals at the carbons where the new sigma bonds will be formed'''
|- align="center"
| [[File:XcwendotscyclopentadieneIRC.png|300px|center]]
| [[File:XcwendotsIRC.gif|300px|center]]
| [[File:XcwAsynchronous mo.jpg|300px|center]]
|-
|}

 

==== '''Comparison of Energies between the Endo and Exo adduct of Dicyclopentadiene''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Adduct of Dicyclopentadiene dimerization'''
| '''Exo Adduct of Dicyclopentadiene dimerization'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=19,atomno=1,atomno=2; color green;measure 19 1;measure 19 2;</script>
<uploadedFileContents>XcwEndodimer3.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>Exodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=7,atomno=17; color green;measure 17 7;</script>
<uploadedFileContents>XcwExodimer1.mol</uploadedFileContents>
</jmolApplet></jmol>
|-
|}

 

Using MMFF94s ab initio calculations, the energies for the exo dimer and the endo dimer are derived.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Exodimer'''
| '''55.374'''
| 3.543
| 30.772
| -2.041
| -2.728
| 0.015
| 12.800
| 13.014
|-
| '''Endodimer'''
| '''58.191'''
| 3.468
| 33.187
| -2.082
| -2.950
| 0.023
| 12.360
| 14.186
|-
|}

 

The MMFF94s steric energy (after minimization) for the exo dimer is lower than that of the endo dimer. This is reflected by the large difference for the EEE between the endo dimer and the exo dimer due to unfavourable steric repulsion between the two “arched down” cyclopentene rings.

==== '''Hydrogenation of Dicyclopentadiene''' ====

Hydrogenation of the endo dicyclopentadiene (DCPD) would lead to two potential products: dihydro product 1 and dihydro product 2.

[[File:XcwFormation of Dihydro products.png|500px|center]]

Using MMFF94s, the energy of the two dihydro products are calculated.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Dihydro Product 1'''
| '''50.123'''
| 3.308
| 30.864
| -1.927
| 0.060
| 0.015(2)
| 13.281
| 5.121
|-
| '''Dihydro Product 2'''
| '''41.257'''
| 2.823
| 24.685
| -1.657
| -0.379
| 0.000(2)
| 10.639
| 5.147
|-
| '''Tetrahydro Product'''
| '''39.042'''
| 2.730
| 25.151
| -1.676
| 1.287
| 0.000
| 11.551
| 0.000
|}

 

From the MMFF94s calculation, it can be seen that dihydro product 2 has a lower steric energy than dihydro product 1. Therefore, dihydro product 2 is the thermodynamic product for the hydrogenation of dicylopentadiene. And indeed, this was what was observed by Skala et al.. He observed that the first hydrogenation occur at the norborene part of the molecule (rate of hydrogenation several times faster than that in the cyclopentene ring)6. The first heat of hydrogenation at the norborene is 138.8 kJ/mol while the second hydrogenation at the cyclopentene right is 109.5 kJ/mol6.

From the above results, it is also obvious that tetrahydro product is much more stable than either dihydro product. And yet, studies have shown that the tetrahydro product will only form after prolonged hydrogenation under high temperature. However, subjecting DCPD to high temperature leads to low yield due to cracking of DCPD.

Since thermodynamically it is predicted to form favourably, the fact that it does not could only mean that the hydrogenation of DCPD to tetrahydrodicyclopentadiene (TH-DCPD) is kinetically controlled. Most possibly, the transition state of the hydrogenation of DCPD is highly unstable hence it is unlikely to form.

=== '''Atropisomerism in an Intermediate related to the Synthesis of Taxol''' ===

Atropisomerism is a type of stereoisomerism that is form as a result of hindered rotation about a single bond.

[[File:XcwAtropisomerism example.png|500px|center]]

In the case of the 6,6’-dinitro-2,2’-diphenic acid, rotation about the bonds joining the two substituted phenyl rings would have to overcome large steric interaction between the bulky substituents. The barrier of rotation is high enough for the two conformers to be isolated individually.

In the synthesis of taxol, one of the key intermediates exhibit atropisomerism.

==== '''Atropisomerism in Taxol Synthesis''' ====

For the key intermediate, rotation about the carbon-carbon bonds would lead to two types of atropisomers, each with either the carbonyl group poining upwards or downwards in relative to the bridge.

[[File:XcwIntermediate 9 and Intermediate 10.png|500px|center]]

Once again by using MMFF94s ab initio calculations, the steric energies for the two intermediates are illustrated as below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 9'''
| '''70.571'''
| 7.743
| 28.356
| -0.062
| 0.004
| 0.949
| 33.293
| 0.288
|-
| '''Intermediate 10'''
| '''60.553'''
| 7.599
| 18.838
| -0.139
| 0.199
| 0.844
| 33.269
| -0.056
|-

|}

 

Analyzing the data above, the largest energy difference between Intermediate 9 and Intermediate 10 stems from the EAB which is related to the strain of the ring. Intermediate 9 has an excess of 9.518 kcal/mol EAB as compared to Intermediate 10. This comes as a surprise as intermediate 9 is predicted to be more stable alkene.

The rationale behind the prediction of the stability of intermediate 9 stems from the fact that the through-space distance of the upward-pointing carbonyl oxygen with the carbon-carbon is further than the through space distance between the downward-pointing carbonyl oxygen with the -CH2-CH2- fragment at the norbornene part in intermediate 10.

==== '''Hyperstable Olefins''' ====

Intermediate 9 and Intermediate 10 does not react readily with other reagents during functionalization. This is due to the hyperstability effect found in hyperstable olefins.

Hyperstable olefins are alkenes that contain less strain in the ring (i.e. negative olefin strain values) compared to the parent hydrocarbon. To study this further, further MMFF94s calculation was done to compare Intermediate 10 with the parent hydrocarbon.

[[File:XcwIntermediate10andPH.png|500px|center]]

The energies that we calculated are tabulated as shown below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 10'''
| '''44.878 '''
| 5.211
| 15.488
| -0.267
| -1.655
| 0.998
| 25.014
| 0.088
|-
| '''Parent Hydrocarbon'''
| '''50.564'''
| 4.692
| 21.979
| 0.109
| -0.958
| 0.247
| 24.495
| 0.000
|-

|}

 

Scrutinizing the results, the largest energy difference between intermediate 10 and the parent hydrocarbon stems from the Total Angle Bending Energy, EAB. Since the Total Angle bending energy is related to the angle strain in the molecules, it is apparent that the parent hydrocarbon has more ring strain as compared to the bridgehead olefin.

== '''Part 3 : Spectroscopic Simulation Using Quantum Mechanics''' ==
=== '''Spectroscopy of an Intermediate Related to the Synthesis of Taxol''' ===

Molecule 17 and 18 are derivatives of intermediate 9 and 10. In this exercise, MMFF94s is used to predict the 1H and 13C NMR of molecule 17 and molecule 18.

[[File:XcwIntermediate17&18.png|500px|center]]

==== '''NMR Spectra of Molecule 17''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 17.mol
</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwHNMRMolecule 17 Chair Overall NMR.png|500px|center]]
| [[File:XcwHNMRMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.1825
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| The first three results were fairly straight forward to be deduced and correlate wit experimental data.

The hydrogen atom that is geminally attached to the carbon of the double bonds is the most deshielded due to the ring current anisotropic effect of the ring current

The second most deshielded hydrogen atom is the hydrogen atom on the methyl group on the bridge. The hydrogen atom is pointing directly to the oxygen atom of the carbonyl functional group.

The peaks with an integration height of 4 is assigned to the hydrogen atoms in the 1,3-dithiolane ring fragment.

Subsequent analysis of the 1H NMR became very complicated very quickly for two reasons:

1. Gaussian calculations showed some atoms with an integration height of 3. Comparing their file atom number and checking their chemical environment, it is not possible to find any correlation between them.

2. Some of the peaks in the literature remains unresolved and are given as multiplets or grouped together.

|- align="center"
| 52
| 3.1775
| 1
| '''2.99'''
|- align="center"
| 53,52,50,51
| 3.0867
| 4
| '''3.40-3.10'''
|- align="center"
| 42,43,39
| 2.7445
| 3
| ''' '''
|- align="center"
| 49
| 2.6187
| 1
| ''' '''
|- align="center"
| 34
| 2.4371
| 1
| ''' '''
|- align="center"
| 35
| 2.3782
| 1
| ''' '''
|- align="center"
| 40,37,26
| 2.2730
| 3
| ''' '''
|- align="center"
| 30
| 2.1566
| 1
| ''' '''
|- align="center"
| 36
| 2.1033
| 1
| ''' '''
|- align="center"
| 32,28
| 2.0259
| 2
| ''' '''
|- align="center"
| 25
| 1.8535
| 2
| ''' '''
|- align="center"
| 38,46,27
| 1.5898
| 3
| '''1.25'''
|- align="center"
| 29
| 1.4557
| 1
| ''' '''
|- align="center"
| 31
| 1.0123
| 1
| ''' '''
|- align="center"
| 44,48,45
| 0.9087
| 3
| '''1.10'''
|- align="center"
| 47
| 0.8354
| 1
| ''' '''
|- align="center"
| 33
| 0.5790
| 1
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 17 Chair Overall NMR2.png|500px|center]]
| [[File:XcwMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 216.2725
| 1
| '''218.79'''
| rowspan="10" style="text-align:center;"| [[File:XcwMolecule 17 image for CNMR.jpg|600px|center]]
|- align="center"
| 13
| 144.8626
| 1
| '''144.63'''
|- align="center"
| 14
| 124.7193
| 1
| '''125.33'''
|- align="center"
| 3
| 91.3340
| 1
| '''72.88'''
|- align="center"
| 2
| 60.9568
| 1
| '''56.19'''
|- align="center"
| 1
| 57.0811
| 1
| '''52.52'''
|- align="center"
| 10
| 52.4663
| 1
| '''48.50'''
|- align="center"
| 16
| 51.4857
| 1
| '''46.80'''
|- align="center"
| 9
| 46.9196
| 1
| '''45.76'''
|- align="center"
| 23
| 43.8647
| 1
| '''39.80'''
|- align="center"
| 22
| 41.9450
| 1
| '''38.81'''
| Comments
|- align="center"
| 4
| 41.8724
| 1
| '''35.85'''
| rowspan="9" style="text-align:left;"| The carbon bonded to the oxygen atom is the most deshielded, as is shown in the predicted values and the experimental values. There is a deviation between the values. Quite possibly, this is due to the fact that in reality, the carbonyl functional group is pointing slightly towards the equatorial position rather than a lateral position relative to the ring (as is in the input for Gaussian calculation)

Most of the 1CNMR values that was predicted by Gaussian are all within an acceptable range of deviation. However, there is carbon 3 that has significant deviation between the predicted value and experimental value.

Carbon 3 is the carbon bonded to the two sulphurs in the 1,3-dithiolane ring fragment. Such a huge deviation would possibly mean that the conformer that was given as input to Gaussian differs from the literature.

The above NMR spectra was corrected with a level of theory B3LYP/6-31G(d,p) using TMS as reference and in chloroform.

|- align="center"
| 15
| 35.4348
| 1
| '''32.66'''
|- align="center"
| 11
| 31.1964
| 1
| '''28.79'''
|- align="center"
| 6
| 28.9432
| 1
| '''28.29'''
|- align="center"
| 7
| 28.3640
| 1
| '''26.88'''
|- align="center"
| 12
| 27.3767
| 1
| '''25.66'''
|- align="center"
| 17
| 26.3311
| 1
| '''23.86'''
|- align="center"
| 15
| 24.5483
| 1
| '''20.96'''
|- align="center"
| 18
| 19.7788
| 1
| '''18.71'''
|-
|}
 

==== '''NMR Spectra of Molecule 18''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 18 Boat for Image2.mol</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"-
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 18 Chair Overall NMR.png|500px|center]]
| [[File:Molecule 18 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.2832
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| ''' '''
|- align="center"
| 50
| 3.3175
| 1
| rowspan="4" style="text-align:centre;"| '''3.00-2.70'''
|- align="center"
| 52
| 3.2153
| 1
|- align="center"
| 51,53
| 3.1161
| 2
|- align="center"
| 34,43
| 2.8606
| 2
|- align="center"
| 38
| 2.4549
| 1
| ''' '''
|- align="center"
| 42
| 2.3968
| 1
| ''' '''
|- align="center"
| 25,29,26
| 2.2796
| 3
| ''' '''
|- align="center"
| 39
| 2.0844
| 1
| ''' '''
|- align="center"
| 40,36
| 1.9699
| 2
| ''' '''
|- align="center"
| 37,24
| 1.8519
| 2
| ''' '''
|- align="center"
| 31,27
| 1.6780
| 2
| ''' '''
|- align="center"
| 28
| 1.6175
| 1
| ''' '''
|- align="center"
| 46,49
| 1.4979
| 2
| ''' '''
|- align="center"
| 35
| 1.4150
| 1
| ''' '''
|- align="center"
| 32
| 1.3531
| 1
| ''' '''
|- align="center"
| 48
| 1.1606
| 1
| ''' '''
|- align="center"
| 33,30,47
| 1.0653
| 3
| '''1.03'''
|- align="center"
| 44,45
| 0.9643
| 2
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwMolecule 18 Boat Overall NMR.png|500px|center]]
| [[File:XcwMolecule 18 Boat zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 211.8325
| 1
| '''211.49'''
| rowspan="10" style="text-align:center;"| [[File:Molecule 18 Boat for 13 CNMR.jpg|600px|center]]
|- align="center"
| 13
| 148.6673
| 1
| '''148.72'''
|- align="center"
| 14
| 118.8373
| 1
| '''120.90'''
|- align="center"
| 3
| 89.0869
| 1
| '''74.61'''
|- align="center"
| 2
| 67.8886
| 1
| '''60.53'''
|- align="center"
| 1
| 56.1133
| 1
| '''51.30'''
|- align="center"
| 10
| 55.5998
| 1
| '''50.94'''
|- align="center"
| 16
| 50.1124
| 1
| '''45.53'''
|- align="center"
| 22
| 48.2030
| 1
| '''43.28'''
|- align="center"
| 23
| 44.2222
| 1
| '''40.82'''
|- align="center"
| 4
| 42.0354
| 1
| '''38.73'''
| Comments
|- align="center"
| 9
| 37.5865
| 1
| '''36.78'''
| rowspan="9" style="text-align:left;"| ''' '''
|- align="center"
| 6
| 35.3106
| 1
| '''35.47'''
|- align="center"
| 15
| 31.0459
| 1
| '''30.84'''
|- align="center"
| 7
| 28.8476
| 1
| '''30.00'''
|- align="center"
| 12
| 28.6623
| 1
| '''25.56'''
|- align="center"
| 17
| 25.7393
| 1
| '''25.35'''
|- align="center"
| 11
| 25.2603
| 1
| '''22.21'''
|- align="center"
| 18
| 23.3944
| 1
| '''21.39'''
|- align="center"
| 5
| 21.0478
| 1
| '''19.83'''
|-
|}
 

== '''Part 4 : Analysis of the Properties of the Synthesized Alkene Epoxides''' ==
=== '''The two catalytics systems''' ===

Assymmetric epoxidation of prochiral alkenes may lead to product with different stereochemical outcome as illustrated as below. To solve this problem, different types of asymmetric epoxidation catalyst have been synthesized. In this study, we shall be focusing on Shi asymmetric fructose catalyst as well as Jacobsen asymmetric catalyst.

[[File:Asymmetric catalyst.png|400px|center]]

==== ''' The Shi Asymmetric Fructose Catalyst''' ====

Molecule 21 is the stable precursor of molecule 22, the active catalyst. Molecule 21 can be converted to molecule 22 by using either persulfuric acid or potassium peroxymonosulphate.

[[File:Molecule 21 to 23.png|400px|center]]

The transition state of the Shi epoxidation was a subject of debate for a few moments. However, recent studies have led to the conclusion that the spiro transition state is more favored than the planar transition state. The spiro transition state is the transition that has its dioxirane perpendicularly bisecting the alkene double bond. This is thought to be more favourable due to interactions between the lone pairs of the oxygen with the LUMO of the alkene.

[[File:Spiro and planar ts.png|500px|center]]

==== ''' The Jacobsen Asymmetric Catalyst''' ====

Molecule 23 is the stable precursor of molecule 24, the active catalyst. Molecule 23 can be converted to molecule 24 by using sodium perchlorate.

[[File:Salen, 23 and 24.png|400px|center]]

Jacobsen catalyst is biphasic. The first phase involves the transfer of oxygen to molecule 23. Sodium perchlorate oxidizes Mn(III) to Mn(V).

In the second step, Jacobsen catalyst acts via a radical mechanism. It is thought to be so because epoxidation of trans-alkene by Jacobsen catalyst yield cis-alkene as well. A radical mechanism will lead to the lost of stereochemical information of the molecule.

=== ''' Crystal structure of the two catalyst''' ===
==== '''Molecule 21''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 21'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 21 strucutre.png|600px|center]]'''
|-
| style="text-align:center;" width="150" | ''' Bond '''
| style="text-align:center;" width="150"| ''' Bond Lenghts (Angstrom)'''
| style="text-align:center;" | ''' Evaluation'''
|-
| style="text-align:center;"| ''' O1-C1 '''
| style="text-align:center;"| ''' 1.400'''
| rowspan="10" style="text-align:left;"| [[File:Molecule 21 2.png|300px|center]]

The normal bond length of an C-O bond is 1.430 angstrom.

The most interesting aspect here is O4 and O2. The lone pair of O4 is antiperplanar to the sigma* orbital of the carbonyl group while the lone pair of O2 is anti periplanar to the carbonyl pi* orbital. Donation of electron can occur because of the correct symmetry. Due to the mixing of the orbitals, the C2-O2 and C4-O4 has been conferred with a certain degree of double bond character.

However, due to the lone pair on oxygen being now donated to the carbonyl antibonding orbitals, the O2 and O4 is slightly “electron deficient” and electron density will be pulled away from O2 and O4. That would explain why the bond length increase for O2-C7 and O4-C10. Increase in bond length is an indicator of the weakening of the bond.
|-
| style="text-align:center;"|'''O1-C7'''
| style="text-align:center;"|'''1.413'''
|-
| style="text-align:center;"|'''O2-C7'''
| style="text-align:center;"|'''1.441'''
|-
| style="text-align:center;"|'''O2-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O4-C4'''
| style="text-align:center;"|'''1.396'''
|-
| style="text-align:center;"|'''O4-C10'''
| style="text-align:center;"|'''1.439'''
|-
| style="text-align:center;"|'''O5-C10'''
| style="text-align:center;"|'''1.409'''
|-
| style="text-align:center;"|'''O5-C5'''
| style="text-align:center;"|'''1.416'''
|-
| style="text-align:center;"|'''O6-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O6-C6'''
| style="text-align:center;"|'''1.420'''
|-
|}
 

==== '''Molecule 23''' ====

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 23'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 23 struc.png|600px|center]]'''
|-
| The most outstanding feature from this molecule is the fact that is adopt a puckered form of the square base pyramidal form. This is no surprise that the molecule is almost planar due to the electron delocalization around each side of the salen ligand.

The tery-butyl hydrogen are oriented closely to one another. Non-covalent interaction studies indicated that repulsion would occur for H---H bond length that are less than 2.1 angstrom while favourable interaction may be dominant with bond length above 2.4 angstrom. It was discovered that all 4 hydrogens have bond length more than 2.4 angstrom hence there should not be any significant repulsion between them. Instead, certain amount of attractive force will ensue and that contributes to the overall stability of the molecule

|-
|}
 

=== ''' The calculated NMR properties of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | '''
Shielding (ppm) Degeneracy
7.4891704929 4.0000
7.2988172444 1.0000
3.6627082199 1.0000
3.1170156088 1.0000
2.5382383043 1.0000 '''
| width="100" | '''
Shielding (ppm) Degeneracy
24.2569032127 4.0000
24.4474861875 1.0000
28.0829310079 1.0000
28.6310290891 1.0000
29.2122790315 1.0000
'''
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Styrene R HNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Styrene S HNMR.png|400px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | '''
Shift (ppm) Degeneracy Atoms
135.1098747604 1.0000 3
124.1186533632 1.0000 8
123.4150641684 1.0000 6
122.9584694331 2.0000 5,7
118.2653162569 1.0000 9
54.0265785300 1.0000 1
53.4853575062 1.0000 2'''
| width="100" | '''
Shift (ppm) Degeneracy Atoms
135.1323742030 1.0000 3
124.1343038829 1.0000 7
123.4137039868 1.0000 5
122.9558208084 2.0000 4,6
118.2690258882 1.0000 8
54.0599580762 1.0000 1
53.4684920923 1.0000 2
'''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | ''' [[File:Styrene R CNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Styrene S CNMR.png|400px|center|]]'''
|-
| width="100" | ''' '''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | ''' '''
| width="100" | ''' '''
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Stilbene RR HNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|400px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | ''' '''
| width="100" | ''' '''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | ''' [[File:Stilbene RR CNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|400px|center|]]'''
|-
|}

 

=== ''' Assigning the absolute configuration of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''Predicted ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg'''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg '''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental conditions'''
| width="100" | '''1.00g/100ml, chloroform, 21 degree Celcisus, 589 nm wavelength '''
| width="100" | '''1.02g/100ml (99% ee), chloroform, 25 degree Celsius, 589 nm wavelength '''
| width="100" | '''1.01g/100ml, ethanol, 22 degree Celsius, 589 nm wavelength '''
| width="100" | '''0.6g/100ml, ethanol, 20 degree Celsius, 589 nm wavelength '''
|- align="left"
| width="100" | ''' Predicted VCD Spectrum'''
| width="100" | '''[[File:Styrene R VCD.png|200px|center|]] '''
| width="100" | '''[[File:Styrene S VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene RR VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene SS VCD.png|200px|center|]]'''
|-
|}

 

All the assignments given in the literature reports are correct although the predicted value differs slightly with the experimental values

=== ''' Analysis of the Transition State for Reactions''' ===
==== '''Predicting Enantiomeric Excess based on Transition State energies''' ====

One of the energy output from Gaussian calculation is the “sum of electronic and thermal free energies”. This is Gibbs Free Energy at 298.15K and 1 atm.

Using this term and invoking a variant of the Curtin-Hammett Principle, it is possible to calculate a predicted enantiomeric excess of one enantiomer over the other.

[[File:Ee and transition state energy.png|800px|center]]

Using the derivations from above and equation (4), we analyze the enantiomeric excess of beta-methyl styrene and the results are tabulated as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1343.022970'''
| width="100" | '''-1343.017942'''
| width="150" | '''-0.005028'''
| width="150" | '''4.88E-03'''
| width="150" | '''99.03'''
|- align="center"
| width="100" | '''-1343.019233'''
| width="100" | '''-1343.015603'''
| width="150" | '''-0.003630'''
| width="150" | '''2.14E-02'''
| width="150" | '''95.80'''
|- align="center"
| width="100" | '''-1343.029272'''
| width="100" | '''-1343.023766'''
| width="150" | '''-0.005506'''
| width="150" | '''2.94E-03'''
| width="150" | '''99.41'''
|- align="center"
| width="100" | '''-1343.032443'''
| width="100" | '''-1343.024742'''
| width="150" | '''-0.007701'''
| width="150" | '''2.88E-04'''
| width="150" | '''99.94'''
|-
|}

 

The above hartree units are converted to J/mol for calculation of K where 1 hartress = 4.3597E-18

Studying all the free energies of the (R,R) series and compare them with the (S,S) series, it comes as no surprise that (R,R) product is favoured over (S,S) product as (R,R) is more stable. Indeed, this corresponds with the literature value reporting 92% ee of (R,R) products over that of (S,S).

==== '''Analysis of the Transition State of Epoxidation''' ====
==== '''Shi Fructose Catalyst''' ====
For this section, I will be analyzing the the transition state of 1) styrene and 2) trans-stilbene with the Shi fructose catalyst.

===== '''(R) and (S)-styrene transition state''' =====
The transition state for the formation of (R)-styrene oxide and (S)-styrene oxide are given as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R)-styrene oxide'''
| width="150" | '''(S)-styrene oxide'''
|- align="center"
| width="150" | ''' Structure of Catalyst '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide R.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide S ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| [[File:Steric shi fructose R.png|450px|center]]
| [[File:Steric shi fructose S.png|450px|center]]
|-
|}

 

In the transition state for (R)-styrene, it was discovered that the Re face is reacting with the oxygen of the dioxirane. The phenyl ring is oriented endo with respect to the fructose catalyst. However, the (S)-styrene is reacting at the Si face and the phenyl ring is oriented exo relative to the catalyst.

The approach taken by (R)-styrene and (S)-styrene are restricted to only one due to steric interactions. Therefore, the epoxidation of both styrenes by the Shi catalyst will be stereospecific and retains all the stereochemical information of the reactant. However, whether or not (R)-styrene oxide or (S)-styrene oxide is form is dependent on the relative energies of the transition state. The more stable the transition state, the more likely the product of the transition state will be formed.

So in order to examine this, an example of transition state of both styrenes with Shi catalyst are obtained and analyzed.
 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1303.736813'''
| width="100" | '''-1303.727673'''
| width="150" | '''-0.00914'''
| width="150" | '''6.28E-05'''
| width="150" | '''99.99'''

|-
|}

 

From the above, we can see the predicted high enantiopurity of the reaction favoring the (R) product because of the lower energy of the transition states. To understand the reason, we have to turn to non-covalent interaction (NCI) analysis.

[[File:NCI shi fructose styrene.png|700px|center]]

To complement the NCI analysis, a QTAIM (Quantum Theory of Atoms in Molecules) analysis is conducted as well.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''(R)-styrene transition state'''
| width="200" | '''(S)-styrene transition state'''
|- align="center"
| width="100" | '''[[File:QTAIM R.png|400px|center]]'''
| width="100" | '''[[File:QTAIM S.png|400px|center]]'''
|- align="center"
| colspan="2" width="100" | '''Comments'''
|-
| colspan="2" width="100" | '''Unsurprisingly, QTAIM analysis has also shown that (R)-styrene/Shi catalyst has more interactions with one another. While (R)-styrene has 2 strong interactions, (S)-styrene has only one with the catalyst. Besides, the phenyl ring of (R)-styrene also confers additional positive interaction with the catalyst. QTAIM analysis has also show several interactions between the C=C geminal hydrogen of (R)-styrene intreacting with the oxygen atoms on the dioxacyclopentane ring'''
|-
|}

 

===== '''(R,R) and (S,S)-Stilbene transition state''' =====

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R,R)-Stilbene oxide'''
| width="150" | '''(S,S)-Stilbene oxide'''
|- align="center"
| width="150" | ''' Structure of Transition State '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Stilbene RR ts.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>SS stilbene oxide ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| colspan="2" | [[File:Shi fructose stilbene.png|700px|center]]

|-
|}

 

However, unlike styrene, trans-stilbene seems to approach perpendicularly to the dioxirane. This is proposed to be due to the steric interactions (marked in purple). Based on first inspection, it seems that (S,S)-Stilbene oxide has more steric interactions than (R,R)-Stilbene oxide. Although unsubstantial, it seems like my guess was correct. The (R,R)-stilbene/Shi catalyst transition state is lower in energy.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1534.687808'''
| width="100" | '''-1534.683440'''
| width="150" | '''0.004368'''
| width="150" | '''9.08E-3'''
| width="150" | '''98.20'''

|-
|}

 

NCI Analysis is also done for trans-stilbene

[[File:NCI stilbene.png|700px|center]]

==== '''Jacobsen Catalyst''' ====

For this section, cis-beta methyl styrene transition state will be analyzed.

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-3383.259559'''
| width="100" | '''-3383.251060'''
| width="150" | '''-0.008499'''
| width="150" | '''1.24E-04'''
| width="150" | '''99.98'''
|- align="center"
| width="100" | '''-3383.253442'''
| width="100" | '''-3383.250270'''
| width="150" | '''-0.003172'''
| width="150" | '''3.48E-02'''
| width="150" | '''93.27'''
|-
|}

 

As is obvious from here, the (S,R) transition state is more stable than the (R,S) transition state. Both transition states are exo with respect to the catalyst.

It is not immediately apparent just by looking at the molecule to determine which spatial groups have interactions with one another. Therefore, an NCI analysis is conducted again.

[[File:NCI Jacobsen.png|700px|center]]

Rep:Mod:Computationalreport1C

2013-11-21T22:48:32Z

Xc2611: /* The calculated NMR properties of the product */

= '''Synthesis and Computational Lab: 1C''' =
== '''Part 1: Introduction to Molecular Mechanics''' ==
=== '''Introduction to MMFF94 and MMFF94s''' ===

With the improvement of computational data and computer processing power, the usage of molecular mechanics/dynamics forcefield has become very integrated in predicting properties of chemical molecules. A molecular mechanics/dynamics forcefield should be able to predict characteristics such as molecular geometries, conformational/stereoisomeric energies, vibrational frequencies etc. to a reasonable accuracy as compared to experimental-derived values.

Building on work from Kollman et al. s’ AMBER forcefield and Allinger et al. s’ MM1, MM2, MM3 and MM4, Merck Research Laboratories have managed to optimized and improved the previous computational algorithms and produced MMFF94 (Merck Molecular Force Field 94). One of the most prominent advantages of MMFF94 over other preceeding work is its enhanced prediction accuracy. The reason lies in the fact that MMFF94’s core parameterization utilizes an unprecedently large amount of computational data obtained from ab initio calculations1.

Subsequently after the development of MMFF94, a new “static” variant of the MMFF was introduced i.e. the MMFF94s. Unlike MMFF94 that was developed for the use of molecular dynamics simulations (which can be expensive), MMFF94s was developed with the purpose of energy minimization studies in mind. Although both systems provide identical results for most systems, they differ for amides and unsaturated amines which contain resonance-delocalized trigonal nitrogen atoms2.

In this computational exercise, MMFF94s is used predominantly as oppose to the alternative Universal Force Field (UFF). Although versatile across the entire periodic table, UFF is derived from simple rules and atomic parameters such as fixed hybridization that increases the likelihood of erroneous structural and energetic predictions3.

=== '''Forms of MMFF94s''' ===

Steric energy of a molecule is the energy arise due to its geometry or conformation. Energy minimization of steric energy process ensures that the molecule is in its lowest energy conformation.

MMFF94s assumes that the total steric energy of a molecule can be found by the sum of a few specific interactions in a molecule.

ES = EBS + EAB + E SB + ET + EOOP + EVdW + EEE

'''where the bonded interactions are:'''

ES = Total Steric energy

EBS = Total Bond Stretching energy

EAB = Total Angle Bending energy

ESB = Total Stretch Bending energy

ET = Total Torsional Energy

EOOP = Total Out-Of-Plane Bending energy, and

'''where the non-bonded interactions are:'''

EVdW = Total Van der Waals Energy

EEE = Total Electrostatic Energy

{| border="1" cellspacing="1" cellpadding="10"
|-
| width="300" align="center" | '''Types of Energies'''
! width="600" align="center" | '''Explanation'''
|-
| colspan="2" style="text-align: center;" | '''Bonded Interactions'''
|-
| width="300" align="center" | '''Total Bond Stretching Energy'''
! width="600" align="left" | The total bond stretching energy is related to the vibration energy of the molecules in comparison to the equilibrium bond length. Whenever a bond deviates from the equilibrium bond length, the energy value increases.

MMFF94s uses a quartic function that has the force constant term (relate to bond strength). The quartic function term is superior to the cubic function term (used in MM2) in the sense that it avoid the “cubic stretch catastrophe” where progressive elongation of molecule bond length leads to negative infinity.
|-
| width="300" align="center" | '''Total Angle Bending Energy'''
! width="600" align="left" | Similar to Total Bond Stretching Energy, the total angle bending energy is also related to the vibration energy of the molecules about the equilibrium bond length. However, unlike EBS that measures the bond strength, EAB is associated with the stiffness of the molecules based on the Hookiean potential. Whenever bond angles deviate from the norm during vibration, this energy term increases as well.
|-
| width="300" align="center" | '''Total Stretch-Bending Energy'''
! width="600" align="left" | This energy term takes into account of the energy due to increase in bond length when bond angle between two atoms changes.
|-
| width="300" align="center" | '''Total Torsional Energy'''
! width="600" align="left" | Total torsional energy is the energy required for intermolecular rotation about the bonds. In molecule mechanics, however, this term is often used as a correction that must be added or subtracted to the total energy of the molecule to fit a quantum mechanical calculation about the dihedral angles of bonds.
|-
| width="300" align="center" | '''Total Out-Of-Plane Bending Energy'''
! width="600" align="left" | This energy term refers to the energy needed to deform the dihedral angle (zero degrees) of a planar group of atoms such as carbonyl or amide functional groups.
|-
| colspan="2" style="text-align: center;" | '''Non-Bonded Interactions'''
|-
| width="300" align="center" | '''Total Van der Waals Energy'''
! width="600" align="left" | The total Van der Waals energy term examines the intramolecular interactions such as repulsion or attraction between non-bonded atoms in the molecule. This term is crucial in determining the preferred conformation of the molecule.

MMFF94s employs the novel “Buffered-14-7”. The name is derived from a buffering constant and the 14th and 7th power dependencies of the repulsive and attractive energy in the equation.
|-
| width="300" align="center" | '''Total Electrostatic Energy'''
! width="600" align="left" | The total electrostatic energy functions take into account of the Coulombic potential and partial charge/dipole/atomic point charges interactions within the molecule.
|-

|}

 

== '''Part 2 : Conformational Analysis Using Molecular Mechanics''' ==
=== '''The Hydrogenation of Cyclopentadiene Dimer''' ===

==== '''Endo and exo adduct from the Dimerization of Cyclopentadiene''' ====
Cyclopentadiene will undergo dimerization by Diels-alder reaction to form either an endo or exo adduct.

[[File:XcwDimerization of CP.png|500px|center]]

==== '''Stereoselectivity of Dimerization of Cyclopentadiene''' ====
Although the exo adduct is thermodynamically more stable than the endo adduct, the endo adduct is form preferentially. Using the QST2 method, the transition state of the Diels Alder dimerization was found. It was discovered that due to the secondary orbital interactions in the endo transition state, the endo dimer is formed preferentially (the kinetic product). Hence, it is proven that the Diels Alder dimerization between two cyclopentadiene are kinetically controlled.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Transition State of Dimerization of Cyclopentadiene'''
| '''Imaginary Stretch Frequency (-881.25) of the Endo Transition State (click to animate)'''
| '''Secondary Orbital Interaction (Red overlapping orbitals)'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<uploadedFileContents>EndotsDCPD2.mol
</uploadedFileContents>
</jmolApplet></jmol>
| [[File:Xcwendotsimaginary.gif|300px|center]]
| [[File:XcwSecondary orbital interaction1.jpg|300px|center]]
|-
|}

 

==== '''Asynchronous Bond Formation of Dimerization of Cyclopentadiene''' ====

The initial study of the molecular orbitals of the transition states seemed a bit peculiar. Instead of getting a LUMO with symmetrical orbitals, the calculations showed a HOMO that is asymetric at the carbons where the new sigma bonds will be formed. Running an IRC further, it soon became clear that the asymmetry of the HOMO leads to an asychronous bond formation before leading to the product.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''IRC plot following the Endo Transition State '''
| '''IRC following the Endo Transition State (click to animate)'''
| '''Asymmetry of orbitals at the carbons where the new sigma bonds will be formed'''
|- align="center"
| [[File:XcwendotscyclopentadieneIRC.png|300px|center]]
| [[File:XcwendotsIRC.gif|300px|center]]
| [[File:XcwAsynchronous mo.jpg|300px|center]]
|-
|}

 

==== '''Comparison of Energies between the Endo and Exo adduct of Dicyclopentadiene''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Adduct of Dicyclopentadiene dimerization'''
| '''Exo Adduct of Dicyclopentadiene dimerization'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=19,atomno=1,atomno=2; color green;measure 19 1;measure 19 2;</script>
<uploadedFileContents>XcwEndodimer3.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>Exodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=7,atomno=17; color green;measure 17 7;</script>
<uploadedFileContents>XcwExodimer1.mol</uploadedFileContents>
</jmolApplet></jmol>
|-
|}

 

Using MMFF94s ab initio calculations, the energies for the exo dimer and the endo dimer are derived.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Exodimer'''
| '''55.374'''
| 3.543
| 30.772
| -2.041
| -2.728
| 0.015
| 12.800
| 13.014
|-
| '''Endodimer'''
| '''58.191'''
| 3.468
| 33.187
| -2.082
| -2.950
| 0.023
| 12.360
| 14.186
|-
|}

 

The MMFF94s steric energy (after minimization) for the exo dimer is lower than that of the endo dimer. This is reflected by the large difference for the EEE between the endo dimer and the exo dimer due to unfavourable steric repulsion between the two “arched down” cyclopentene rings.

==== '''Hydrogenation of Dicyclopentadiene''' ====

Hydrogenation of the endo dicyclopentadiene (DCPD) would lead to two potential products: dihydro product 1 and dihydro product 2.

[[File:XcwFormation of Dihydro products.png|500px|center]]

Using MMFF94s, the energy of the two dihydro products are calculated.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Dihydro Product 1'''
| '''50.123'''
| 3.308
| 30.864
| -1.927
| 0.060
| 0.015(2)
| 13.281
| 5.121
|-
| '''Dihydro Product 2'''
| '''41.257'''
| 2.823
| 24.685
| -1.657
| -0.379
| 0.000(2)
| 10.639
| 5.147
|-
| '''Tetrahydro Product'''
| '''39.042'''
| 2.730
| 25.151
| -1.676
| 1.287
| 0.000
| 11.551
| 0.000
|}

 

From the MMFF94s calculation, it can be seen that dihydro product 2 has a lower steric energy than dihydro product 1. Therefore, dihydro product 2 is the thermodynamic product for the hydrogenation of dicylopentadiene. And indeed, this was what was observed by Skala et al.. He observed that the first hydrogenation occur at the norborene part of the molecule (rate of hydrogenation several times faster than that in the cyclopentene ring)6. The first heat of hydrogenation at the norborene is 138.8 kJ/mol while the second hydrogenation at the cyclopentene right is 109.5 kJ/mol6.

From the above results, it is also obvious that tetrahydro product is much more stable than either dihydro product. And yet, studies have shown that the tetrahydro product will only form after prolonged hydrogenation under high temperature. However, subjecting DCPD to high temperature leads to low yield due to cracking of DCPD.

Since thermodynamically it is predicted to form favourably, the fact that it does not could only mean that the hydrogenation of DCPD to tetrahydrodicyclopentadiene (TH-DCPD) is kinetically controlled. Most possibly, the transition state of the hydrogenation of DCPD is highly unstable hence it is unlikely to form.

=== '''Atropisomerism in an Intermediate related to the Synthesis of Taxol''' ===

Atropisomerism is a type of stereoisomerism that is form as a result of hindered rotation about a single bond.

[[File:XcwAtropisomerism example.png|500px|center]]

In the case of the 6,6’-dinitro-2,2’-diphenic acid, rotation about the bonds joining the two substituted phenyl rings would have to overcome large steric interaction between the bulky substituents. The barrier of rotation is high enough for the two conformers to be isolated individually.

In the synthesis of taxol, one of the key intermediates exhibit atropisomerism.

==== '''Atropisomerism in Taxol Synthesis''' ====

For the key intermediate, rotation about the carbon-carbon bonds would lead to two types of atropisomers, each with either the carbonyl group poining upwards or downwards in relative to the bridge.

[[File:XcwIntermediate 9 and Intermediate 10.png|500px|center]]

Once again by using MMFF94s ab initio calculations, the steric energies for the two intermediates are illustrated as below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 9'''
| '''70.571'''
| 7.743
| 28.356
| -0.062
| 0.004
| 0.949
| 33.293
| 0.288
|-
| '''Intermediate 10'''
| '''60.553'''
| 7.599
| 18.838
| -0.139
| 0.199
| 0.844
| 33.269
| -0.056
|-

|}

 

Analyzing the data above, the largest energy difference between Intermediate 9 and Intermediate 10 stems from the EAB which is related to the strain of the ring. Intermediate 9 has an excess of 9.518 kcal/mol EAB as compared to Intermediate 10. This comes as a surprise as intermediate 9 is predicted to be more stable alkene.

The rationale behind the prediction of the stability of intermediate 9 stems from the fact that the through-space distance of the upward-pointing carbonyl oxygen with the carbon-carbon is further than the through space distance between the downward-pointing carbonyl oxygen with the -CH2-CH2- fragment at the norbornene part in intermediate 10.

==== '''Hyperstable Olefins''' ====

Intermediate 9 and Intermediate 10 does not react readily with other reagents during functionalization. This is due to the hyperstability effect found in hyperstable olefins.

Hyperstable olefins are alkenes that contain less strain in the ring (i.e. negative olefin strain values) compared to the parent hydrocarbon. To study this further, further MMFF94s calculation was done to compare Intermediate 10 with the parent hydrocarbon.

[[File:XcwIntermediate10andPH.png|500px|center]]

The energies that we calculated are tabulated as shown below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 10'''
| '''44.878 '''
| 5.211
| 15.488
| -0.267
| -1.655
| 0.998
| 25.014
| 0.088
|-
| '''Parent Hydrocarbon'''
| '''50.564'''
| 4.692
| 21.979
| 0.109
| -0.958
| 0.247
| 24.495
| 0.000
|-

|}

 

Scrutinizing the results, the largest energy difference between intermediate 10 and the parent hydrocarbon stems from the Total Angle Bending Energy, EAB. Since the Total Angle bending energy is related to the angle strain in the molecules, it is apparent that the parent hydrocarbon has more ring strain as compared to the bridgehead olefin.

== '''Part 3 : Spectroscopic Simulation Using Quantum Mechanics''' ==
=== '''Spectroscopy of an Intermediate Related to the Synthesis of Taxol''' ===

Molecule 17 and 18 are derivatives of intermediate 9 and 10. In this exercise, MMFF94s is used to predict the 1H and 13C NMR of molecule 17 and molecule 18.

[[File:XcwIntermediate17&18.png|500px|center]]

==== '''NMR Spectra of Molecule 17''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 17.mol
</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwHNMRMolecule 17 Chair Overall NMR.png|500px|center]]
| [[File:XcwHNMRMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.1825
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| The first three results were fairly straight forward to be deduced and correlate wit experimental data.

The hydrogen atom that is geminally attached to the carbon of the double bonds is the most deshielded due to the ring current anisotropic effect of the ring current

The second most deshielded hydrogen atom is the hydrogen atom on the methyl group on the bridge. The hydrogen atom is pointing directly to the oxygen atom of the carbonyl functional group.

The peaks with an integration height of 4 is assigned to the hydrogen atoms in the 1,3-dithiolane ring fragment.

Subsequent analysis of the 1H NMR became very complicated very quickly for two reasons:

1. Gaussian calculations showed some atoms with an integration height of 3. Comparing their file atom number and checking their chemical environment, it is not possible to find any correlation between them.

2. Some of the peaks in the literature remains unresolved and are given as multiplets or grouped together.

|- align="center"
| 52
| 3.1775
| 1
| '''2.99'''
|- align="center"
| 53,52,50,51
| 3.0867
| 4
| '''3.40-3.10'''
|- align="center"
| 42,43,39
| 2.7445
| 3
| ''' '''
|- align="center"
| 49
| 2.6187
| 1
| ''' '''
|- align="center"
| 34
| 2.4371
| 1
| ''' '''
|- align="center"
| 35
| 2.3782
| 1
| ''' '''
|- align="center"
| 40,37,26
| 2.2730
| 3
| ''' '''
|- align="center"
| 30
| 2.1566
| 1
| ''' '''
|- align="center"
| 36
| 2.1033
| 1
| ''' '''
|- align="center"
| 32,28
| 2.0259
| 2
| ''' '''
|- align="center"
| 25
| 1.8535
| 2
| ''' '''
|- align="center"
| 38,46,27
| 1.5898
| 3
| '''1.25'''
|- align="center"
| 29
| 1.4557
| 1
| ''' '''
|- align="center"
| 31
| 1.0123
| 1
| ''' '''
|- align="center"
| 44,48,45
| 0.9087
| 3
| '''1.10'''
|- align="center"
| 47
| 0.8354
| 1
| ''' '''
|- align="center"
| 33
| 0.5790
| 1
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 17 Chair Overall NMR2.png|500px|center]]
| [[File:XcwMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 216.2725
| 1
| '''218.79'''
| rowspan="10" style="text-align:center;"| [[File:XcwMolecule 17 image for CNMR.jpg|600px|center]]
|- align="center"
| 13
| 144.8626
| 1
| '''144.63'''
|- align="center"
| 14
| 124.7193
| 1
| '''125.33'''
|- align="center"
| 3
| 91.3340
| 1
| '''72.88'''
|- align="center"
| 2
| 60.9568
| 1
| '''56.19'''
|- align="center"
| 1
| 57.0811
| 1
| '''52.52'''
|- align="center"
| 10
| 52.4663
| 1
| '''48.50'''
|- align="center"
| 16
| 51.4857
| 1
| '''46.80'''
|- align="center"
| 9
| 46.9196
| 1
| '''45.76'''
|- align="center"
| 23
| 43.8647
| 1
| '''39.80'''
|- align="center"
| 22
| 41.9450
| 1
| '''38.81'''
| Comments
|- align="center"
| 4
| 41.8724
| 1
| '''35.85'''
| rowspan="9" style="text-align:left;"| The carbon bonded to the oxygen atom is the most deshielded, as is shown in the predicted values and the experimental values. There is a deviation between the values. Quite possibly, this is due to the fact that in reality, the carbonyl functional group is pointing slightly towards the equatorial position rather than a lateral position relative to the ring (as is in the input for Gaussian calculation)

Most of the 1CNMR values that was predicted by Gaussian are all within an acceptable range of deviation. However, there is carbon 3 that has significant deviation between the predicted value and experimental value.

Carbon 3 is the carbon bonded to the two sulphurs in the 1,3-dithiolane ring fragment. Such a huge deviation would possibly mean that the conformer that was given as input to Gaussian differs from the literature.

The above NMR spectra was corrected with a level of theory B3LYP/6-31G(d,p) using TMS as reference and in chloroform.

|- align="center"
| 15
| 35.4348
| 1
| '''32.66'''
|- align="center"
| 11
| 31.1964
| 1
| '''28.79'''
|- align="center"
| 6
| 28.9432
| 1
| '''28.29'''
|- align="center"
| 7
| 28.3640
| 1
| '''26.88'''
|- align="center"
| 12
| 27.3767
| 1
| '''25.66'''
|- align="center"
| 17
| 26.3311
| 1
| '''23.86'''
|- align="center"
| 15
| 24.5483
| 1
| '''20.96'''
|- align="center"
| 18
| 19.7788
| 1
| '''18.71'''
|-
|}
 

==== '''NMR Spectra of Molecule 18''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 18 Boat for Image2.mol</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"-
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 18 Chair Overall NMR.png|500px|center]]
| [[File:Molecule 18 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.2832
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| ''' '''
|- align="center"
| 50
| 3.3175
| 1
| rowspan="4" style="text-align:centre;"| '''3.00-2.70'''
|- align="center"
| 52
| 3.2153
| 1
|- align="center"
| 51,53
| 3.1161
| 2
|- align="center"
| 34,43
| 2.8606
| 2
|- align="center"
| 38
| 2.4549
| 1
| ''' '''
|- align="center"
| 42
| 2.3968
| 1
| ''' '''
|- align="center"
| 25,29,26
| 2.2796
| 3
| ''' '''
|- align="center"
| 39
| 2.0844
| 1
| ''' '''
|- align="center"
| 40,36
| 1.9699
| 2
| ''' '''
|- align="center"
| 37,24
| 1.8519
| 2
| ''' '''
|- align="center"
| 31,27
| 1.6780
| 2
| ''' '''
|- align="center"
| 28
| 1.6175
| 1
| ''' '''
|- align="center"
| 46,49
| 1.4979
| 2
| ''' '''
|- align="center"
| 35
| 1.4150
| 1
| ''' '''
|- align="center"
| 32
| 1.3531
| 1
| ''' '''
|- align="center"
| 48
| 1.1606
| 1
| ''' '''
|- align="center"
| 33,30,47
| 1.0653
| 3
| '''1.03'''
|- align="center"
| 44,45
| 0.9643
| 2
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwMolecule 18 Boat Overall NMR.png|500px|center]]
| [[File:XcwMolecule 18 Boat zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 211.8325
| 1
| '''211.49'''
| rowspan="10" style="text-align:center;"| [[File:Molecule 18 Boat for 13 CNMR.jpg|600px|center]]
|- align="center"
| 13
| 148.6673
| 1
| '''148.72'''
|- align="center"
| 14
| 118.8373
| 1
| '''120.90'''
|- align="center"
| 3
| 89.0869
| 1
| '''74.61'''
|- align="center"
| 2
| 67.8886
| 1
| '''60.53'''
|- align="center"
| 1
| 56.1133
| 1
| '''51.30'''
|- align="center"
| 10
| 55.5998
| 1
| '''50.94'''
|- align="center"
| 16
| 50.1124
| 1
| '''45.53'''
|- align="center"
| 22
| 48.2030
| 1
| '''43.28'''
|- align="center"
| 23
| 44.2222
| 1
| '''40.82'''
|- align="center"
| 4
| 42.0354
| 1
| '''38.73'''
| Comments
|- align="center"
| 9
| 37.5865
| 1
| '''36.78'''
| rowspan="9" style="text-align:left;"| ''' '''
|- align="center"
| 6
| 35.3106
| 1
| '''35.47'''
|- align="center"
| 15
| 31.0459
| 1
| '''30.84'''
|- align="center"
| 7
| 28.8476
| 1
| '''30.00'''
|- align="center"
| 12
| 28.6623
| 1
| '''25.56'''
|- align="center"
| 17
| 25.7393
| 1
| '''25.35'''
|- align="center"
| 11
| 25.2603
| 1
| '''22.21'''
|- align="center"
| 18
| 23.3944
| 1
| '''21.39'''
|- align="center"
| 5
| 21.0478
| 1
| '''19.83'''
|-
|}
 

== '''Part 4 : Analysis of the Properties of the Synthesized Alkene Epoxides''' ==
=== '''The two catalytics systems''' ===

Assymmetric epoxidation of prochiral alkenes may lead to product with different stereochemical outcome as illustrated as below. To solve this problem, different types of asymmetric epoxidation catalyst have been synthesized. In this study, we shall be focusing on Shi asymmetric fructose catalyst as well as Jacobsen asymmetric catalyst.

[[File:Asymmetric catalyst.png|400px|center]]

==== ''' The Shi Asymmetric Fructose Catalyst''' ====

Molecule 21 is the stable precursor of molecule 22, the active catalyst. Molecule 21 can be converted to molecule 22 by using either persulfuric acid or potassium peroxymonosulphate.

[[File:Molecule 21 to 23.png|400px|center]]

The transition state of the Shi epoxidation was a subject of debate for a few moments. However, recent studies have led to the conclusion that the spiro transition state is more favored than the planar transition state. The spiro transition state is the transition that has its dioxirane perpendicularly bisecting the alkene double bond. This is thought to be more favourable due to interactions between the lone pairs of the oxygen with the LUMO of the alkene.

[[File:Spiro and planar ts.png|500px|center]]

==== ''' The Jacobsen Asymmetric Catalyst''' ====

Molecule 23 is the stable precursor of molecule 24, the active catalyst. Molecule 23 can be converted to molecule 24 by using sodium perchlorate.

[[File:Salen, 23 and 24.png|400px|center]]

Jacobsen catalyst is biphasic. The first phase involves the transfer of oxygen to molecule 23. Sodium perchlorate oxidizes Mn(III) to Mn(V).

In the second step, Jacobsen catalyst acts via a radical mechanism. It is thought to be so because epoxidation of trans-alkene by Jacobsen catalyst yield cis-alkene as well. A radical mechanism will lead to the lost of stereochemical information of the molecule.

=== ''' Crystal structure of the two catalyst''' ===
==== '''Molecule 21''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 21'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 21 strucutre.png|600px|center]]'''
|-
| style="text-align:center;" width="150" | ''' Bond '''
| style="text-align:center;" width="150"| ''' Bond Lenghts (Angstrom)'''
| style="text-align:center;" | ''' Evaluation'''
|-
| style="text-align:center;"| ''' O1-C1 '''
| style="text-align:center;"| ''' 1.400'''
| rowspan="10" style="text-align:left;"| [[File:Molecule 21 2.png|300px|center]]

The normal bond length of an C-O bond is 1.430 angstrom.

The most interesting aspect here is O4 and O2. The lone pair of O4 is antiperplanar to the sigma* orbital of the carbonyl group while the lone pair of O2 is anti periplanar to the carbonyl pi* orbital. Donation of electron can occur because of the correct symmetry. Due to the mixing of the orbitals, the C2-O2 and C4-O4 has been conferred with a certain degree of double bond character.

However, due to the lone pair on oxygen being now donated to the carbonyl antibonding orbitals, the O2 and O4 is slightly “electron deficient” and electron density will be pulled away from O2 and O4. That would explain why the bond length increase for O2-C7 and O4-C10. Increase in bond length is an indicator of the weakening of the bond.
|-
| style="text-align:center;"|'''O1-C7'''
| style="text-align:center;"|'''1.413'''
|-
| style="text-align:center;"|'''O2-C7'''
| style="text-align:center;"|'''1.441'''
|-
| style="text-align:center;"|'''O2-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O4-C4'''
| style="text-align:center;"|'''1.396'''
|-
| style="text-align:center;"|'''O4-C10'''
| style="text-align:center;"|'''1.439'''
|-
| style="text-align:center;"|'''O5-C10'''
| style="text-align:center;"|'''1.409'''
|-
| style="text-align:center;"|'''O5-C5'''
| style="text-align:center;"|'''1.416'''
|-
| style="text-align:center;"|'''O6-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O6-C6'''
| style="text-align:center;"|'''1.420'''
|-
|}
 

==== '''Molecule 23''' ====

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 23'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 23 struc.png|600px|center]]'''
|-
| The most outstanding feature from this molecule is the fact that is adopt a puckered form of the square base pyramidal form. This is no surprise that the molecule is almost planar due to the electron delocalization around each side of the salen ligand.

The tery-butyl hydrogen are oriented closely to one another. Non-covalent interaction studies indicated that repulsion would occur for H---H bond length that are less than 2.1 angstrom while favourable interaction may be dominant with bond length above 2.4 angstrom. It was discovered that all 4 hydrogens have bond length more than 2.4 angstrom hence there should not be any significant repulsion between them. Instead, certain amount of attractive force will ensue and that contributes to the overall stability of the molecule

|-
|}
 

=== ''' The calculated NMR properties of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | ''' '''
| width="100" | ''' '''
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Styrene R HNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Styrene S HNMR.png|400px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | ''' '''
| width="100" | ''' '''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | ''' [[File:Styrene R CNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Styrene S CNMR.png|400px|center|]]'''
|-
| width="100" | ''' '''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | ''' '''
| width="100" | ''' '''
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Stilbene RR HNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|400px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | ''' '''
| width="100" | ''' '''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | ''' [[File:Stilbene RR CNMR.png|400px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|400px|center|]]'''
|-
|}

 

=== ''' Assigning the absolute configuration of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''Predicted ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg'''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg '''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental conditions'''
| width="100" | '''1.00g/100ml, chloroform, 21 degree Celcisus, 589 nm wavelength '''
| width="100" | '''1.02g/100ml (99% ee), chloroform, 25 degree Celsius, 589 nm wavelength '''
| width="100" | '''1.01g/100ml, ethanol, 22 degree Celsius, 589 nm wavelength '''
| width="100" | '''0.6g/100ml, ethanol, 20 degree Celsius, 589 nm wavelength '''
|- align="left"
| width="100" | ''' Predicted VCD Spectrum'''
| width="100" | '''[[File:Styrene R VCD.png|200px|center|]] '''
| width="100" | '''[[File:Styrene S VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene RR VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene SS VCD.png|200px|center|]]'''
|-
|}

 

All the assignments given in the literature reports are correct although the predicted value differs slightly with the experimental values

=== ''' Analysis of the Transition State for Reactions''' ===
==== '''Predicting Enantiomeric Excess based on Transition State energies''' ====

One of the energy output from Gaussian calculation is the “sum of electronic and thermal free energies”. This is Gibbs Free Energy at 298.15K and 1 atm.

Using this term and invoking a variant of the Curtin-Hammett Principle, it is possible to calculate a predicted enantiomeric excess of one enantiomer over the other.

[[File:Ee and transition state energy.png|800px|center]]

Using the derivations from above and equation (4), we analyze the enantiomeric excess of beta-methyl styrene and the results are tabulated as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1343.022970'''
| width="100" | '''-1343.017942'''
| width="150" | '''-0.005028'''
| width="150" | '''4.88E-03'''
| width="150" | '''99.03'''
|- align="center"
| width="100" | '''-1343.019233'''
| width="100" | '''-1343.015603'''
| width="150" | '''-0.003630'''
| width="150" | '''2.14E-02'''
| width="150" | '''95.80'''
|- align="center"
| width="100" | '''-1343.029272'''
| width="100" | '''-1343.023766'''
| width="150" | '''-0.005506'''
| width="150" | '''2.94E-03'''
| width="150" | '''99.41'''
|- align="center"
| width="100" | '''-1343.032443'''
| width="100" | '''-1343.024742'''
| width="150" | '''-0.007701'''
| width="150" | '''2.88E-04'''
| width="150" | '''99.94'''
|-
|}

 

The above hartree units are converted to J/mol for calculation of K where 1 hartress = 4.3597E-18

Studying all the free energies of the (R,R) series and compare them with the (S,S) series, it comes as no surprise that (R,R) product is favoured over (S,S) product as (R,R) is more stable. Indeed, this corresponds with the literature value reporting 92% ee of (R,R) products over that of (S,S).

==== '''Analysis of the Transition State of Epoxidation''' ====
==== '''Shi Fructose Catalyst''' ====
For this section, I will be analyzing the the transition state of 1) styrene and 2) trans-stilbene with the Shi fructose catalyst.

===== '''(R) and (S)-styrene transition state''' =====
The transition state for the formation of (R)-styrene oxide and (S)-styrene oxide are given as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R)-styrene oxide'''
| width="150" | '''(S)-styrene oxide'''
|- align="center"
| width="150" | ''' Structure of Catalyst '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide R.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide S ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| [[File:Steric shi fructose R.png|450px|center]]
| [[File:Steric shi fructose S.png|450px|center]]
|-
|}

 

In the transition state for (R)-styrene, it was discovered that the Re face is reacting with the oxygen of the dioxirane. The phenyl ring is oriented endo with respect to the fructose catalyst. However, the (S)-styrene is reacting at the Si face and the phenyl ring is oriented exo relative to the catalyst.

The approach taken by (R)-styrene and (S)-styrene are restricted to only one due to steric interactions. Therefore, the epoxidation of both styrenes by the Shi catalyst will be stereospecific and retains all the stereochemical information of the reactant. However, whether or not (R)-styrene oxide or (S)-styrene oxide is form is dependent on the relative energies of the transition state. The more stable the transition state, the more likely the product of the transition state will be formed.

So in order to examine this, an example of transition state of both styrenes with Shi catalyst are obtained and analyzed.
 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1303.736813'''
| width="100" | '''-1303.727673'''
| width="150" | '''-0.00914'''
| width="150" | '''6.28E-05'''
| width="150" | '''99.99'''

|-
|}

 

From the above, we can see the predicted high enantiopurity of the reaction favoring the (R) product because of the lower energy of the transition states. To understand the reason, we have to turn to non-covalent interaction (NCI) analysis.

[[File:NCI shi fructose styrene.png|700px|center]]

To complement the NCI analysis, a QTAIM (Quantum Theory of Atoms in Molecules) analysis is conducted as well.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''(R)-styrene transition state'''
| width="200" | '''(S)-styrene transition state'''
|- align="center"
| width="100" | '''[[File:QTAIM R.png|400px|center]]'''
| width="100" | '''[[File:QTAIM S.png|400px|center]]'''
|- align="center"
| colspan="2" width="100" | '''Comments'''
|-
| colspan="2" width="100" | '''Unsurprisingly, QTAIM analysis has also shown that (R)-styrene/Shi catalyst has more interactions with one another. While (R)-styrene has 2 strong interactions, (S)-styrene has only one with the catalyst. Besides, the phenyl ring of (R)-styrene also confers additional positive interaction with the catalyst. QTAIM analysis has also show several interactions between the C=C geminal hydrogen of (R)-styrene intreacting with the oxygen atoms on the dioxacyclopentane ring'''
|-
|}

 

===== '''(R,R) and (S,S)-Stilbene transition state''' =====

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R,R)-Stilbene oxide'''
| width="150" | '''(S,S)-Stilbene oxide'''
|- align="center"
| width="150" | ''' Structure of Transition State '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Stilbene RR ts.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>SS stilbene oxide ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| colspan="2" | [[File:Shi fructose stilbene.png|700px|center]]

|-
|}

 

However, unlike styrene, trans-stilbene seems to approach perpendicularly to the dioxirane. This is proposed to be due to the steric interactions (marked in purple). Based on first inspection, it seems that (S,S)-Stilbene oxide has more steric interactions than (R,R)-Stilbene oxide. Although unsubstantial, it seems like my guess was correct. The (R,R)-stilbene/Shi catalyst transition state is lower in energy.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1534.687808'''
| width="100" | '''-1534.683440'''
| width="150" | '''0.004368'''
| width="150" | '''9.08E-3'''
| width="150" | '''98.20'''

|-
|}

 

NCI Analysis is also done for trans-stilbene

[[File:NCI stilbene.png|700px|center]]

==== '''Jacobsen Catalyst''' ====

For this section, cis-beta methyl styrene transition state will be analyzed.

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-3383.259559'''
| width="100" | '''-3383.251060'''
| width="150" | '''-0.008499'''
| width="150" | '''1.24E-04'''
| width="150" | '''99.98'''
|- align="center"
| width="100" | '''-3383.253442'''
| width="100" | '''-3383.250270'''
| width="150" | '''-0.003172'''
| width="150" | '''3.48E-02'''
| width="150" | '''93.27'''
|-
|}

 

As is obvious from here, the (S,R) transition state is more stable than the (R,S) transition state. Both transition states are exo with respect to the catalyst.

It is not immediately apparent just by looking at the molecule to determine which spatial groups have interactions with one another. Therefore, an NCI analysis is conducted again.

[[File:NCI Jacobsen.png|700px|center]]

Rep:Mod:Computationalreport1C

2013-11-21T22:47:14Z

Xc2611: /* The calculated NMR properties of the product */

= '''Synthesis and Computational Lab: 1C''' =
== '''Part 1: Introduction to Molecular Mechanics''' ==
=== '''Introduction to MMFF94 and MMFF94s''' ===

With the improvement of computational data and computer processing power, the usage of molecular mechanics/dynamics forcefield has become very integrated in predicting properties of chemical molecules. A molecular mechanics/dynamics forcefield should be able to predict characteristics such as molecular geometries, conformational/stereoisomeric energies, vibrational frequencies etc. to a reasonable accuracy as compared to experimental-derived values.

Building on work from Kollman et al. s’ AMBER forcefield and Allinger et al. s’ MM1, MM2, MM3 and MM4, Merck Research Laboratories have managed to optimized and improved the previous computational algorithms and produced MMFF94 (Merck Molecular Force Field 94). One of the most prominent advantages of MMFF94 over other preceeding work is its enhanced prediction accuracy. The reason lies in the fact that MMFF94’s core parameterization utilizes an unprecedently large amount of computational data obtained from ab initio calculations1.

Subsequently after the development of MMFF94, a new “static” variant of the MMFF was introduced i.e. the MMFF94s. Unlike MMFF94 that was developed for the use of molecular dynamics simulations (which can be expensive), MMFF94s was developed with the purpose of energy minimization studies in mind. Although both systems provide identical results for most systems, they differ for amides and unsaturated amines which contain resonance-delocalized trigonal nitrogen atoms2.

In this computational exercise, MMFF94s is used predominantly as oppose to the alternative Universal Force Field (UFF). Although versatile across the entire periodic table, UFF is derived from simple rules and atomic parameters such as fixed hybridization that increases the likelihood of erroneous structural and energetic predictions3.

=== '''Forms of MMFF94s''' ===

Steric energy of a molecule is the energy arise due to its geometry or conformation. Energy minimization of steric energy process ensures that the molecule is in its lowest energy conformation.

MMFF94s assumes that the total steric energy of a molecule can be found by the sum of a few specific interactions in a molecule.

ES = EBS + EAB + E SB + ET + EOOP + EVdW + EEE

'''where the bonded interactions are:'''

ES = Total Steric energy

EBS = Total Bond Stretching energy

EAB = Total Angle Bending energy

ESB = Total Stretch Bending energy

ET = Total Torsional Energy

EOOP = Total Out-Of-Plane Bending energy, and

'''where the non-bonded interactions are:'''

EVdW = Total Van der Waals Energy

EEE = Total Electrostatic Energy

{| border="1" cellspacing="1" cellpadding="10"
|-
| width="300" align="center" | '''Types of Energies'''
! width="600" align="center" | '''Explanation'''
|-
| colspan="2" style="text-align: center;" | '''Bonded Interactions'''
|-
| width="300" align="center" | '''Total Bond Stretching Energy'''
! width="600" align="left" | The total bond stretching energy is related to the vibration energy of the molecules in comparison to the equilibrium bond length. Whenever a bond deviates from the equilibrium bond length, the energy value increases.

MMFF94s uses a quartic function that has the force constant term (relate to bond strength). The quartic function term is superior to the cubic function term (used in MM2) in the sense that it avoid the “cubic stretch catastrophe” where progressive elongation of molecule bond length leads to negative infinity.
|-
| width="300" align="center" | '''Total Angle Bending Energy'''
! width="600" align="left" | Similar to Total Bond Stretching Energy, the total angle bending energy is also related to the vibration energy of the molecules about the equilibrium bond length. However, unlike EBS that measures the bond strength, EAB is associated with the stiffness of the molecules based on the Hookiean potential. Whenever bond angles deviate from the norm during vibration, this energy term increases as well.
|-
| width="300" align="center" | '''Total Stretch-Bending Energy'''
! width="600" align="left" | This energy term takes into account of the energy due to increase in bond length when bond angle between two atoms changes.
|-
| width="300" align="center" | '''Total Torsional Energy'''
! width="600" align="left" | Total torsional energy is the energy required for intermolecular rotation about the bonds. In molecule mechanics, however, this term is often used as a correction that must be added or subtracted to the total energy of the molecule to fit a quantum mechanical calculation about the dihedral angles of bonds.
|-
| width="300" align="center" | '''Total Out-Of-Plane Bending Energy'''
! width="600" align="left" | This energy term refers to the energy needed to deform the dihedral angle (zero degrees) of a planar group of atoms such as carbonyl or amide functional groups.
|-
| colspan="2" style="text-align: center;" | '''Non-Bonded Interactions'''
|-
| width="300" align="center" | '''Total Van der Waals Energy'''
! width="600" align="left" | The total Van der Waals energy term examines the intramolecular interactions such as repulsion or attraction between non-bonded atoms in the molecule. This term is crucial in determining the preferred conformation of the molecule.

MMFF94s employs the novel “Buffered-14-7”. The name is derived from a buffering constant and the 14th and 7th power dependencies of the repulsive and attractive energy in the equation.
|-
| width="300" align="center" | '''Total Electrostatic Energy'''
! width="600" align="left" | The total electrostatic energy functions take into account of the Coulombic potential and partial charge/dipole/atomic point charges interactions within the molecule.
|-

|}

 

== '''Part 2 : Conformational Analysis Using Molecular Mechanics''' ==
=== '''The Hydrogenation of Cyclopentadiene Dimer''' ===

==== '''Endo and exo adduct from the Dimerization of Cyclopentadiene''' ====
Cyclopentadiene will undergo dimerization by Diels-alder reaction to form either an endo or exo adduct.

[[File:XcwDimerization of CP.png|500px|center]]

==== '''Stereoselectivity of Dimerization of Cyclopentadiene''' ====
Although the exo adduct is thermodynamically more stable than the endo adduct, the endo adduct is form preferentially. Using the QST2 method, the transition state of the Diels Alder dimerization was found. It was discovered that due to the secondary orbital interactions in the endo transition state, the endo dimer is formed preferentially (the kinetic product). Hence, it is proven that the Diels Alder dimerization between two cyclopentadiene are kinetically controlled.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Transition State of Dimerization of Cyclopentadiene'''
| '''Imaginary Stretch Frequency (-881.25) of the Endo Transition State (click to animate)'''
| '''Secondary Orbital Interaction (Red overlapping orbitals)'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<uploadedFileContents>EndotsDCPD2.mol
</uploadedFileContents>
</jmolApplet></jmol>
| [[File:Xcwendotsimaginary.gif|300px|center]]
| [[File:XcwSecondary orbital interaction1.jpg|300px|center]]
|-
|}

 

==== '''Asynchronous Bond Formation of Dimerization of Cyclopentadiene''' ====

The initial study of the molecular orbitals of the transition states seemed a bit peculiar. Instead of getting a LUMO with symmetrical orbitals, the calculations showed a HOMO that is asymetric at the carbons where the new sigma bonds will be formed. Running an IRC further, it soon became clear that the asymmetry of the HOMO leads to an asychronous bond formation before leading to the product.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''IRC plot following the Endo Transition State '''
| '''IRC following the Endo Transition State (click to animate)'''
| '''Asymmetry of orbitals at the carbons where the new sigma bonds will be formed'''
|- align="center"
| [[File:XcwendotscyclopentadieneIRC.png|300px|center]]
| [[File:XcwendotsIRC.gif|300px|center]]
| [[File:XcwAsynchronous mo.jpg|300px|center]]
|-
|}

 

==== '''Comparison of Energies between the Endo and Exo adduct of Dicyclopentadiene''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Adduct of Dicyclopentadiene dimerization'''
| '''Exo Adduct of Dicyclopentadiene dimerization'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=19,atomno=1,atomno=2; color green;measure 19 1;measure 19 2;</script>
<uploadedFileContents>XcwEndodimer3.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>Exodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=7,atomno=17; color green;measure 17 7;</script>
<uploadedFileContents>XcwExodimer1.mol</uploadedFileContents>
</jmolApplet></jmol>
|-
|}

 

Using MMFF94s ab initio calculations, the energies for the exo dimer and the endo dimer are derived.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Exodimer'''
| '''55.374'''
| 3.543
| 30.772
| -2.041
| -2.728
| 0.015
| 12.800
| 13.014
|-
| '''Endodimer'''
| '''58.191'''
| 3.468
| 33.187
| -2.082
| -2.950
| 0.023
| 12.360
| 14.186
|-
|}

 

The MMFF94s steric energy (after minimization) for the exo dimer is lower than that of the endo dimer. This is reflected by the large difference for the EEE between the endo dimer and the exo dimer due to unfavourable steric repulsion between the two “arched down” cyclopentene rings.

==== '''Hydrogenation of Dicyclopentadiene''' ====

Hydrogenation of the endo dicyclopentadiene (DCPD) would lead to two potential products: dihydro product 1 and dihydro product 2.

[[File:XcwFormation of Dihydro products.png|500px|center]]

Using MMFF94s, the energy of the two dihydro products are calculated.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Dihydro Product 1'''
| '''50.123'''
| 3.308
| 30.864
| -1.927
| 0.060
| 0.015(2)
| 13.281
| 5.121
|-
| '''Dihydro Product 2'''
| '''41.257'''
| 2.823
| 24.685
| -1.657
| -0.379
| 0.000(2)
| 10.639
| 5.147
|-
| '''Tetrahydro Product'''
| '''39.042'''
| 2.730
| 25.151
| -1.676
| 1.287
| 0.000
| 11.551
| 0.000
|}

 

From the MMFF94s calculation, it can be seen that dihydro product 2 has a lower steric energy than dihydro product 1. Therefore, dihydro product 2 is the thermodynamic product for the hydrogenation of dicylopentadiene. And indeed, this was what was observed by Skala et al.. He observed that the first hydrogenation occur at the norborene part of the molecule (rate of hydrogenation several times faster than that in the cyclopentene ring)6. The first heat of hydrogenation at the norborene is 138.8 kJ/mol while the second hydrogenation at the cyclopentene right is 109.5 kJ/mol6.

From the above results, it is also obvious that tetrahydro product is much more stable than either dihydro product. And yet, studies have shown that the tetrahydro product will only form after prolonged hydrogenation under high temperature. However, subjecting DCPD to high temperature leads to low yield due to cracking of DCPD.

Since thermodynamically it is predicted to form favourably, the fact that it does not could only mean that the hydrogenation of DCPD to tetrahydrodicyclopentadiene (TH-DCPD) is kinetically controlled. Most possibly, the transition state of the hydrogenation of DCPD is highly unstable hence it is unlikely to form.

=== '''Atropisomerism in an Intermediate related to the Synthesis of Taxol''' ===

Atropisomerism is a type of stereoisomerism that is form as a result of hindered rotation about a single bond.

[[File:XcwAtropisomerism example.png|500px|center]]

In the case of the 6,6’-dinitro-2,2’-diphenic acid, rotation about the bonds joining the two substituted phenyl rings would have to overcome large steric interaction between the bulky substituents. The barrier of rotation is high enough for the two conformers to be isolated individually.

In the synthesis of taxol, one of the key intermediates exhibit atropisomerism.

==== '''Atropisomerism in Taxol Synthesis''' ====

For the key intermediate, rotation about the carbon-carbon bonds would lead to two types of atropisomers, each with either the carbonyl group poining upwards or downwards in relative to the bridge.

[[File:XcwIntermediate 9 and Intermediate 10.png|500px|center]]

Once again by using MMFF94s ab initio calculations, the steric energies for the two intermediates are illustrated as below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 9'''
| '''70.571'''
| 7.743
| 28.356
| -0.062
| 0.004
| 0.949
| 33.293
| 0.288
|-
| '''Intermediate 10'''
| '''60.553'''
| 7.599
| 18.838
| -0.139
| 0.199
| 0.844
| 33.269
| -0.056
|-

|}

 

Analyzing the data above, the largest energy difference between Intermediate 9 and Intermediate 10 stems from the EAB which is related to the strain of the ring. Intermediate 9 has an excess of 9.518 kcal/mol EAB as compared to Intermediate 10. This comes as a surprise as intermediate 9 is predicted to be more stable alkene.

The rationale behind the prediction of the stability of intermediate 9 stems from the fact that the through-space distance of the upward-pointing carbonyl oxygen with the carbon-carbon is further than the through space distance between the downward-pointing carbonyl oxygen with the -CH2-CH2- fragment at the norbornene part in intermediate 10.

==== '''Hyperstable Olefins''' ====

Intermediate 9 and Intermediate 10 does not react readily with other reagents during functionalization. This is due to the hyperstability effect found in hyperstable olefins.

Hyperstable olefins are alkenes that contain less strain in the ring (i.e. negative olefin strain values) compared to the parent hydrocarbon. To study this further, further MMFF94s calculation was done to compare Intermediate 10 with the parent hydrocarbon.

[[File:XcwIntermediate10andPH.png|500px|center]]

The energies that we calculated are tabulated as shown below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 10'''
| '''44.878 '''
| 5.211
| 15.488
| -0.267
| -1.655
| 0.998
| 25.014
| 0.088
|-
| '''Parent Hydrocarbon'''
| '''50.564'''
| 4.692
| 21.979
| 0.109
| -0.958
| 0.247
| 24.495
| 0.000
|-

|}

 

Scrutinizing the results, the largest energy difference between intermediate 10 and the parent hydrocarbon stems from the Total Angle Bending Energy, EAB. Since the Total Angle bending energy is related to the angle strain in the molecules, it is apparent that the parent hydrocarbon has more ring strain as compared to the bridgehead olefin.

== '''Part 3 : Spectroscopic Simulation Using Quantum Mechanics''' ==
=== '''Spectroscopy of an Intermediate Related to the Synthesis of Taxol''' ===

Molecule 17 and 18 are derivatives of intermediate 9 and 10. In this exercise, MMFF94s is used to predict the 1H and 13C NMR of molecule 17 and molecule 18.

[[File:XcwIntermediate17&18.png|500px|center]]

==== '''NMR Spectra of Molecule 17''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 17.mol
</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwHNMRMolecule 17 Chair Overall NMR.png|500px|center]]
| [[File:XcwHNMRMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.1825
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| The first three results were fairly straight forward to be deduced and correlate wit experimental data.

The hydrogen atom that is geminally attached to the carbon of the double bonds is the most deshielded due to the ring current anisotropic effect of the ring current

The second most deshielded hydrogen atom is the hydrogen atom on the methyl group on the bridge. The hydrogen atom is pointing directly to the oxygen atom of the carbonyl functional group.

The peaks with an integration height of 4 is assigned to the hydrogen atoms in the 1,3-dithiolane ring fragment.

Subsequent analysis of the 1H NMR became very complicated very quickly for two reasons:

1. Gaussian calculations showed some atoms with an integration height of 3. Comparing their file atom number and checking their chemical environment, it is not possible to find any correlation between them.

2. Some of the peaks in the literature remains unresolved and are given as multiplets or grouped together.

|- align="center"
| 52
| 3.1775
| 1
| '''2.99'''
|- align="center"
| 53,52,50,51
| 3.0867
| 4
| '''3.40-3.10'''
|- align="center"
| 42,43,39
| 2.7445
| 3
| ''' '''
|- align="center"
| 49
| 2.6187
| 1
| ''' '''
|- align="center"
| 34
| 2.4371
| 1
| ''' '''
|- align="center"
| 35
| 2.3782
| 1
| ''' '''
|- align="center"
| 40,37,26
| 2.2730
| 3
| ''' '''
|- align="center"
| 30
| 2.1566
| 1
| ''' '''
|- align="center"
| 36
| 2.1033
| 1
| ''' '''
|- align="center"
| 32,28
| 2.0259
| 2
| ''' '''
|- align="center"
| 25
| 1.8535
| 2
| ''' '''
|- align="center"
| 38,46,27
| 1.5898
| 3
| '''1.25'''
|- align="center"
| 29
| 1.4557
| 1
| ''' '''
|- align="center"
| 31
| 1.0123
| 1
| ''' '''
|- align="center"
| 44,48,45
| 0.9087
| 3
| '''1.10'''
|- align="center"
| 47
| 0.8354
| 1
| ''' '''
|- align="center"
| 33
| 0.5790
| 1
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 17 Chair Overall NMR2.png|500px|center]]
| [[File:XcwMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 216.2725
| 1
| '''218.79'''
| rowspan="10" style="text-align:center;"| [[File:XcwMolecule 17 image for CNMR.jpg|600px|center]]
|- align="center"
| 13
| 144.8626
| 1
| '''144.63'''
|- align="center"
| 14
| 124.7193
| 1
| '''125.33'''
|- align="center"
| 3
| 91.3340
| 1
| '''72.88'''
|- align="center"
| 2
| 60.9568
| 1
| '''56.19'''
|- align="center"
| 1
| 57.0811
| 1
| '''52.52'''
|- align="center"
| 10
| 52.4663
| 1
| '''48.50'''
|- align="center"
| 16
| 51.4857
| 1
| '''46.80'''
|- align="center"
| 9
| 46.9196
| 1
| '''45.76'''
|- align="center"
| 23
| 43.8647
| 1
| '''39.80'''
|- align="center"
| 22
| 41.9450
| 1
| '''38.81'''
| Comments
|- align="center"
| 4
| 41.8724
| 1
| '''35.85'''
| rowspan="9" style="text-align:left;"| The carbon bonded to the oxygen atom is the most deshielded, as is shown in the predicted values and the experimental values. There is a deviation between the values. Quite possibly, this is due to the fact that in reality, the carbonyl functional group is pointing slightly towards the equatorial position rather than a lateral position relative to the ring (as is in the input for Gaussian calculation)

Most of the 1CNMR values that was predicted by Gaussian are all within an acceptable range of deviation. However, there is carbon 3 that has significant deviation between the predicted value and experimental value.

Carbon 3 is the carbon bonded to the two sulphurs in the 1,3-dithiolane ring fragment. Such a huge deviation would possibly mean that the conformer that was given as input to Gaussian differs from the literature.

The above NMR spectra was corrected with a level of theory B3LYP/6-31G(d,p) using TMS as reference and in chloroform.

|- align="center"
| 15
| 35.4348
| 1
| '''32.66'''
|- align="center"
| 11
| 31.1964
| 1
| '''28.79'''
|- align="center"
| 6
| 28.9432
| 1
| '''28.29'''
|- align="center"
| 7
| 28.3640
| 1
| '''26.88'''
|- align="center"
| 12
| 27.3767
| 1
| '''25.66'''
|- align="center"
| 17
| 26.3311
| 1
| '''23.86'''
|- align="center"
| 15
| 24.5483
| 1
| '''20.96'''
|- align="center"
| 18
| 19.7788
| 1
| '''18.71'''
|-
|}
 

==== '''NMR Spectra of Molecule 18''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 18 Boat for Image2.mol</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"-
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 18 Chair Overall NMR.png|500px|center]]
| [[File:Molecule 18 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.2832
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| ''' '''
|- align="center"
| 50
| 3.3175
| 1
| rowspan="4" style="text-align:centre;"| '''3.00-2.70'''
|- align="center"
| 52
| 3.2153
| 1
|- align="center"
| 51,53
| 3.1161
| 2
|- align="center"
| 34,43
| 2.8606
| 2
|- align="center"
| 38
| 2.4549
| 1
| ''' '''
|- align="center"
| 42
| 2.3968
| 1
| ''' '''
|- align="center"
| 25,29,26
| 2.2796
| 3
| ''' '''
|- align="center"
| 39
| 2.0844
| 1
| ''' '''
|- align="center"
| 40,36
| 1.9699
| 2
| ''' '''
|- align="center"
| 37,24
| 1.8519
| 2
| ''' '''
|- align="center"
| 31,27
| 1.6780
| 2
| ''' '''
|- align="center"
| 28
| 1.6175
| 1
| ''' '''
|- align="center"
| 46,49
| 1.4979
| 2
| ''' '''
|- align="center"
| 35
| 1.4150
| 1
| ''' '''
|- align="center"
| 32
| 1.3531
| 1
| ''' '''
|- align="center"
| 48
| 1.1606
| 1
| ''' '''
|- align="center"
| 33,30,47
| 1.0653
| 3
| '''1.03'''
|- align="center"
| 44,45
| 0.9643
| 2
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwMolecule 18 Boat Overall NMR.png|500px|center]]
| [[File:XcwMolecule 18 Boat zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 211.8325
| 1
| '''211.49'''
| rowspan="10" style="text-align:center;"| [[File:Molecule 18 Boat for 13 CNMR.jpg|600px|center]]
|- align="center"
| 13
| 148.6673
| 1
| '''148.72'''
|- align="center"
| 14
| 118.8373
| 1
| '''120.90'''
|- align="center"
| 3
| 89.0869
| 1
| '''74.61'''
|- align="center"
| 2
| 67.8886
| 1
| '''60.53'''
|- align="center"
| 1
| 56.1133
| 1
| '''51.30'''
|- align="center"
| 10
| 55.5998
| 1
| '''50.94'''
|- align="center"
| 16
| 50.1124
| 1
| '''45.53'''
|- align="center"
| 22
| 48.2030
| 1
| '''43.28'''
|- align="center"
| 23
| 44.2222
| 1
| '''40.82'''
|- align="center"
| 4
| 42.0354
| 1
| '''38.73'''
| Comments
|- align="center"
| 9
| 37.5865
| 1
| '''36.78'''
| rowspan="9" style="text-align:left;"| ''' '''
|- align="center"
| 6
| 35.3106
| 1
| '''35.47'''
|- align="center"
| 15
| 31.0459
| 1
| '''30.84'''
|- align="center"
| 7
| 28.8476
| 1
| '''30.00'''
|- align="center"
| 12
| 28.6623
| 1
| '''25.56'''
|- align="center"
| 17
| 25.7393
| 1
| '''25.35'''
|- align="center"
| 11
| 25.2603
| 1
| '''22.21'''
|- align="center"
| 18
| 23.3944
| 1
| '''21.39'''
|- align="center"
| 5
| 21.0478
| 1
| '''19.83'''
|-
|}
 

== '''Part 4 : Analysis of the Properties of the Synthesized Alkene Epoxides''' ==
=== '''The two catalytics systems''' ===

Assymmetric epoxidation of prochiral alkenes may lead to product with different stereochemical outcome as illustrated as below. To solve this problem, different types of asymmetric epoxidation catalyst have been synthesized. In this study, we shall be focusing on Shi asymmetric fructose catalyst as well as Jacobsen asymmetric catalyst.

[[File:Asymmetric catalyst.png|400px|center]]

==== ''' The Shi Asymmetric Fructose Catalyst''' ====

Molecule 21 is the stable precursor of molecule 22, the active catalyst. Molecule 21 can be converted to molecule 22 by using either persulfuric acid or potassium peroxymonosulphate.

[[File:Molecule 21 to 23.png|400px|center]]

The transition state of the Shi epoxidation was a subject of debate for a few moments. However, recent studies have led to the conclusion that the spiro transition state is more favored than the planar transition state. The spiro transition state is the transition that has its dioxirane perpendicularly bisecting the alkene double bond. This is thought to be more favourable due to interactions between the lone pairs of the oxygen with the LUMO of the alkene.

[[File:Spiro and planar ts.png|500px|center]]

==== ''' The Jacobsen Asymmetric Catalyst''' ====

Molecule 23 is the stable precursor of molecule 24, the active catalyst. Molecule 23 can be converted to molecule 24 by using sodium perchlorate.

[[File:Salen, 23 and 24.png|400px|center]]

Jacobsen catalyst is biphasic. The first phase involves the transfer of oxygen to molecule 23. Sodium perchlorate oxidizes Mn(III) to Mn(V).

In the second step, Jacobsen catalyst acts via a radical mechanism. It is thought to be so because epoxidation of trans-alkene by Jacobsen catalyst yield cis-alkene as well. A radical mechanism will lead to the lost of stereochemical information of the molecule.

=== ''' Crystal structure of the two catalyst''' ===
==== '''Molecule 21''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 21'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 21 strucutre.png|600px|center]]'''
|-
| style="text-align:center;" width="150" | ''' Bond '''
| style="text-align:center;" width="150"| ''' Bond Lenghts (Angstrom)'''
| style="text-align:center;" | ''' Evaluation'''
|-
| style="text-align:center;"| ''' O1-C1 '''
| style="text-align:center;"| ''' 1.400'''
| rowspan="10" style="text-align:left;"| [[File:Molecule 21 2.png|300px|center]]

The normal bond length of an C-O bond is 1.430 angstrom.

The most interesting aspect here is O4 and O2. The lone pair of O4 is antiperplanar to the sigma* orbital of the carbonyl group while the lone pair of O2 is anti periplanar to the carbonyl pi* orbital. Donation of electron can occur because of the correct symmetry. Due to the mixing of the orbitals, the C2-O2 and C4-O4 has been conferred with a certain degree of double bond character.

However, due to the lone pair on oxygen being now donated to the carbonyl antibonding orbitals, the O2 and O4 is slightly “electron deficient” and electron density will be pulled away from O2 and O4. That would explain why the bond length increase for O2-C7 and O4-C10. Increase in bond length is an indicator of the weakening of the bond.
|-
| style="text-align:center;"|'''O1-C7'''
| style="text-align:center;"|'''1.413'''
|-
| style="text-align:center;"|'''O2-C7'''
| style="text-align:center;"|'''1.441'''
|-
| style="text-align:center;"|'''O2-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O4-C4'''
| style="text-align:center;"|'''1.396'''
|-
| style="text-align:center;"|'''O4-C10'''
| style="text-align:center;"|'''1.439'''
|-
| style="text-align:center;"|'''O5-C10'''
| style="text-align:center;"|'''1.409'''
|-
| style="text-align:center;"|'''O5-C5'''
| style="text-align:center;"|'''1.416'''
|-
| style="text-align:center;"|'''O6-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O6-C6'''
| style="text-align:center;"|'''1.420'''
|-
|}
 

==== '''Molecule 23''' ====

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 23'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 23 struc.png|600px|center]]'''
|-
| The most outstanding feature from this molecule is the fact that is adopt a puckered form of the square base pyramidal form. This is no surprise that the molecule is almost planar due to the electron delocalization around each side of the salen ligand.

The tery-butyl hydrogen are oriented closely to one another. Non-covalent interaction studies indicated that repulsion would occur for H---H bond length that are less than 2.1 angstrom while favourable interaction may be dominant with bond length above 2.4 angstrom. It was discovered that all 4 hydrogens have bond length more than 2.4 angstrom hence there should not be any significant repulsion between them. Instead, certain amount of attractive force will ensue and that contributes to the overall stability of the molecule

|-
|}
 

=== ''' The calculated NMR properties of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | ''' '''
| width="100" | ''' '''
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Styrene R HNMR.png|200px|center|]]'''
| width="100" | ''' [[File:Styrene S HNMR.png|200px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | ''' '''
| width="100" | ''' '''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | ''' [[File:Styrene R CNMR.png|200px|center|]]'''
| width="100" | ''' [[File:Styrene S CNMR.png|200px|center|]]'''
|-
| width="100" | ''' '''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | ''' '''
| width="100" | ''' '''
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Stilbene RR HNMR.png|200px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|200px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | ''' '''
| width="100" | ''' '''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | ''' [[File:Stilbene RR CNMR.png|200px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|200px|center|]]'''
|-
|}

 

=== ''' Assigning the absolute configuration of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''Predicted ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg'''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg '''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental conditions'''
| width="100" | '''1.00g/100ml, chloroform, 21 degree Celcisus, 589 nm wavelength '''
| width="100" | '''1.02g/100ml (99% ee), chloroform, 25 degree Celsius, 589 nm wavelength '''
| width="100" | '''1.01g/100ml, ethanol, 22 degree Celsius, 589 nm wavelength '''
| width="100" | '''0.6g/100ml, ethanol, 20 degree Celsius, 589 nm wavelength '''
|- align="left"
| width="100" | ''' Predicted VCD Spectrum'''
| width="100" | '''[[File:Styrene R VCD.png|200px|center|]] '''
| width="100" | '''[[File:Styrene S VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene RR VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene SS VCD.png|200px|center|]]'''
|-
|}

 

All the assignments given in the literature reports are correct although the predicted value differs slightly with the experimental values

=== ''' Analysis of the Transition State for Reactions''' ===
==== '''Predicting Enantiomeric Excess based on Transition State energies''' ====

One of the energy output from Gaussian calculation is the “sum of electronic and thermal free energies”. This is Gibbs Free Energy at 298.15K and 1 atm.

Using this term and invoking a variant of the Curtin-Hammett Principle, it is possible to calculate a predicted enantiomeric excess of one enantiomer over the other.

[[File:Ee and transition state energy.png|800px|center]]

Using the derivations from above and equation (4), we analyze the enantiomeric excess of beta-methyl styrene and the results are tabulated as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1343.022970'''
| width="100" | '''-1343.017942'''
| width="150" | '''-0.005028'''
| width="150" | '''4.88E-03'''
| width="150" | '''99.03'''
|- align="center"
| width="100" | '''-1343.019233'''
| width="100" | '''-1343.015603'''
| width="150" | '''-0.003630'''
| width="150" | '''2.14E-02'''
| width="150" | '''95.80'''
|- align="center"
| width="100" | '''-1343.029272'''
| width="100" | '''-1343.023766'''
| width="150" | '''-0.005506'''
| width="150" | '''2.94E-03'''
| width="150" | '''99.41'''
|- align="center"
| width="100" | '''-1343.032443'''
| width="100" | '''-1343.024742'''
| width="150" | '''-0.007701'''
| width="150" | '''2.88E-04'''
| width="150" | '''99.94'''
|-
|}

 

The above hartree units are converted to J/mol for calculation of K where 1 hartress = 4.3597E-18

Studying all the free energies of the (R,R) series and compare them with the (S,S) series, it comes as no surprise that (R,R) product is favoured over (S,S) product as (R,R) is more stable. Indeed, this corresponds with the literature value reporting 92% ee of (R,R) products over that of (S,S).

==== '''Analysis of the Transition State of Epoxidation''' ====
==== '''Shi Fructose Catalyst''' ====
For this section, I will be analyzing the the transition state of 1) styrene and 2) trans-stilbene with the Shi fructose catalyst.

===== '''(R) and (S)-styrene transition state''' =====
The transition state for the formation of (R)-styrene oxide and (S)-styrene oxide are given as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R)-styrene oxide'''
| width="150" | '''(S)-styrene oxide'''
|- align="center"
| width="150" | ''' Structure of Catalyst '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide R.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide S ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| [[File:Steric shi fructose R.png|450px|center]]
| [[File:Steric shi fructose S.png|450px|center]]
|-
|}

 

In the transition state for (R)-styrene, it was discovered that the Re face is reacting with the oxygen of the dioxirane. The phenyl ring is oriented endo with respect to the fructose catalyst. However, the (S)-styrene is reacting at the Si face and the phenyl ring is oriented exo relative to the catalyst.

The approach taken by (R)-styrene and (S)-styrene are restricted to only one due to steric interactions. Therefore, the epoxidation of both styrenes by the Shi catalyst will be stereospecific and retains all the stereochemical information of the reactant. However, whether or not (R)-styrene oxide or (S)-styrene oxide is form is dependent on the relative energies of the transition state. The more stable the transition state, the more likely the product of the transition state will be formed.

So in order to examine this, an example of transition state of both styrenes with Shi catalyst are obtained and analyzed.
 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1303.736813'''
| width="100" | '''-1303.727673'''
| width="150" | '''-0.00914'''
| width="150" | '''6.28E-05'''
| width="150" | '''99.99'''

|-
|}

 

From the above, we can see the predicted high enantiopurity of the reaction favoring the (R) product because of the lower energy of the transition states. To understand the reason, we have to turn to non-covalent interaction (NCI) analysis.

[[File:NCI shi fructose styrene.png|700px|center]]

To complement the NCI analysis, a QTAIM (Quantum Theory of Atoms in Molecules) analysis is conducted as well.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''(R)-styrene transition state'''
| width="200" | '''(S)-styrene transition state'''
|- align="center"
| width="100" | '''[[File:QTAIM R.png|400px|center]]'''
| width="100" | '''[[File:QTAIM S.png|400px|center]]'''
|- align="center"
| colspan="2" width="100" | '''Comments'''
|-
| colspan="2" width="100" | '''Unsurprisingly, QTAIM analysis has also shown that (R)-styrene/Shi catalyst has more interactions with one another. While (R)-styrene has 2 strong interactions, (S)-styrene has only one with the catalyst. Besides, the phenyl ring of (R)-styrene also confers additional positive interaction with the catalyst. QTAIM analysis has also show several interactions between the C=C geminal hydrogen of (R)-styrene intreacting with the oxygen atoms on the dioxacyclopentane ring'''
|-
|}

 

===== '''(R,R) and (S,S)-Stilbene transition state''' =====

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R,R)-Stilbene oxide'''
| width="150" | '''(S,S)-Stilbene oxide'''
|- align="center"
| width="150" | ''' Structure of Transition State '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Stilbene RR ts.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>SS stilbene oxide ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| colspan="2" | [[File:Shi fructose stilbene.png|700px|center]]

|-
|}

 

However, unlike styrene, trans-stilbene seems to approach perpendicularly to the dioxirane. This is proposed to be due to the steric interactions (marked in purple). Based on first inspection, it seems that (S,S)-Stilbene oxide has more steric interactions than (R,R)-Stilbene oxide. Although unsubstantial, it seems like my guess was correct. The (R,R)-stilbene/Shi catalyst transition state is lower in energy.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1534.687808'''
| width="100" | '''-1534.683440'''
| width="150" | '''0.004368'''
| width="150" | '''9.08E-3'''
| width="150" | '''98.20'''

|-
|}

 

NCI Analysis is also done for trans-stilbene

[[File:NCI stilbene.png|700px|center]]

==== '''Jacobsen Catalyst''' ====

For this section, cis-beta methyl styrene transition state will be analyzed.

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-3383.259559'''
| width="100" | '''-3383.251060'''
| width="150" | '''-0.008499'''
| width="150" | '''1.24E-04'''
| width="150" | '''99.98'''
|- align="center"
| width="100" | '''-3383.253442'''
| width="100" | '''-3383.250270'''
| width="150" | '''-0.003172'''
| width="150" | '''3.48E-02'''
| width="150" | '''93.27'''
|-
|}

 

As is obvious from here, the (S,R) transition state is more stable than the (R,S) transition state. Both transition states are exo with respect to the catalyst.

It is not immediately apparent just by looking at the molecule to determine which spatial groups have interactions with one another. Therefore, an NCI analysis is conducted again.

[[File:NCI Jacobsen.png|700px|center]]

Rep:Mod:Computationalreport1C

2013-11-21T22:41:41Z

Xc2611: /* The calculated NMR properties of the product */

= '''Synthesis and Computational Lab: 1C''' =
== '''Part 1: Introduction to Molecular Mechanics''' ==
=== '''Introduction to MMFF94 and MMFF94s''' ===

With the improvement of computational data and computer processing power, the usage of molecular mechanics/dynamics forcefield has become very integrated in predicting properties of chemical molecules. A molecular mechanics/dynamics forcefield should be able to predict characteristics such as molecular geometries, conformational/stereoisomeric energies, vibrational frequencies etc. to a reasonable accuracy as compared to experimental-derived values.

Building on work from Kollman et al. s’ AMBER forcefield and Allinger et al. s’ MM1, MM2, MM3 and MM4, Merck Research Laboratories have managed to optimized and improved the previous computational algorithms and produced MMFF94 (Merck Molecular Force Field 94). One of the most prominent advantages of MMFF94 over other preceeding work is its enhanced prediction accuracy. The reason lies in the fact that MMFF94’s core parameterization utilizes an unprecedently large amount of computational data obtained from ab initio calculations1.

Subsequently after the development of MMFF94, a new “static” variant of the MMFF was introduced i.e. the MMFF94s. Unlike MMFF94 that was developed for the use of molecular dynamics simulations (which can be expensive), MMFF94s was developed with the purpose of energy minimization studies in mind. Although both systems provide identical results for most systems, they differ for amides and unsaturated amines which contain resonance-delocalized trigonal nitrogen atoms2.

In this computational exercise, MMFF94s is used predominantly as oppose to the alternative Universal Force Field (UFF). Although versatile across the entire periodic table, UFF is derived from simple rules and atomic parameters such as fixed hybridization that increases the likelihood of erroneous structural and energetic predictions3.

=== '''Forms of MMFF94s''' ===

Steric energy of a molecule is the energy arise due to its geometry or conformation. Energy minimization of steric energy process ensures that the molecule is in its lowest energy conformation.

MMFF94s assumes that the total steric energy of a molecule can be found by the sum of a few specific interactions in a molecule.

ES = EBS + EAB + E SB + ET + EOOP + EVdW + EEE

'''where the bonded interactions are:'''

ES = Total Steric energy

EBS = Total Bond Stretching energy

EAB = Total Angle Bending energy

ESB = Total Stretch Bending energy

ET = Total Torsional Energy

EOOP = Total Out-Of-Plane Bending energy, and

'''where the non-bonded interactions are:'''

EVdW = Total Van der Waals Energy

EEE = Total Electrostatic Energy

{| border="1" cellspacing="1" cellpadding="10"
|-
| width="300" align="center" | '''Types of Energies'''
! width="600" align="center" | '''Explanation'''
|-
| colspan="2" style="text-align: center;" | '''Bonded Interactions'''
|-
| width="300" align="center" | '''Total Bond Stretching Energy'''
! width="600" align="left" | The total bond stretching energy is related to the vibration energy of the molecules in comparison to the equilibrium bond length. Whenever a bond deviates from the equilibrium bond length, the energy value increases.

MMFF94s uses a quartic function that has the force constant term (relate to bond strength). The quartic function term is superior to the cubic function term (used in MM2) in the sense that it avoid the “cubic stretch catastrophe” where progressive elongation of molecule bond length leads to negative infinity.
|-
| width="300" align="center" | '''Total Angle Bending Energy'''
! width="600" align="left" | Similar to Total Bond Stretching Energy, the total angle bending energy is also related to the vibration energy of the molecules about the equilibrium bond length. However, unlike EBS that measures the bond strength, EAB is associated with the stiffness of the molecules based on the Hookiean potential. Whenever bond angles deviate from the norm during vibration, this energy term increases as well.
|-
| width="300" align="center" | '''Total Stretch-Bending Energy'''
! width="600" align="left" | This energy term takes into account of the energy due to increase in bond length when bond angle between two atoms changes.
|-
| width="300" align="center" | '''Total Torsional Energy'''
! width="600" align="left" | Total torsional energy is the energy required for intermolecular rotation about the bonds. In molecule mechanics, however, this term is often used as a correction that must be added or subtracted to the total energy of the molecule to fit a quantum mechanical calculation about the dihedral angles of bonds.
|-
| width="300" align="center" | '''Total Out-Of-Plane Bending Energy'''
! width="600" align="left" | This energy term refers to the energy needed to deform the dihedral angle (zero degrees) of a planar group of atoms such as carbonyl or amide functional groups.
|-
| colspan="2" style="text-align: center;" | '''Non-Bonded Interactions'''
|-
| width="300" align="center" | '''Total Van der Waals Energy'''
! width="600" align="left" | The total Van der Waals energy term examines the intramolecular interactions such as repulsion or attraction between non-bonded atoms in the molecule. This term is crucial in determining the preferred conformation of the molecule.

MMFF94s employs the novel “Buffered-14-7”. The name is derived from a buffering constant and the 14th and 7th power dependencies of the repulsive and attractive energy in the equation.
|-
| width="300" align="center" | '''Total Electrostatic Energy'''
! width="600" align="left" | The total electrostatic energy functions take into account of the Coulombic potential and partial charge/dipole/atomic point charges interactions within the molecule.
|-

|}

 

== '''Part 2 : Conformational Analysis Using Molecular Mechanics''' ==
=== '''The Hydrogenation of Cyclopentadiene Dimer''' ===

==== '''Endo and exo adduct from the Dimerization of Cyclopentadiene''' ====
Cyclopentadiene will undergo dimerization by Diels-alder reaction to form either an endo or exo adduct.

[[File:XcwDimerization of CP.png|500px|center]]

==== '''Stereoselectivity of Dimerization of Cyclopentadiene''' ====
Although the exo adduct is thermodynamically more stable than the endo adduct, the endo adduct is form preferentially. Using the QST2 method, the transition state of the Diels Alder dimerization was found. It was discovered that due to the secondary orbital interactions in the endo transition state, the endo dimer is formed preferentially (the kinetic product). Hence, it is proven that the Diels Alder dimerization between two cyclopentadiene are kinetically controlled.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Transition State of Dimerization of Cyclopentadiene'''
| '''Imaginary Stretch Frequency (-881.25) of the Endo Transition State (click to animate)'''
| '''Secondary Orbital Interaction (Red overlapping orbitals)'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<uploadedFileContents>EndotsDCPD2.mol
</uploadedFileContents>
</jmolApplet></jmol>
| [[File:Xcwendotsimaginary.gif|300px|center]]
| [[File:XcwSecondary orbital interaction1.jpg|300px|center]]
|-
|}

 

==== '''Asynchronous Bond Formation of Dimerization of Cyclopentadiene''' ====

The initial study of the molecular orbitals of the transition states seemed a bit peculiar. Instead of getting a LUMO with symmetrical orbitals, the calculations showed a HOMO that is asymetric at the carbons where the new sigma bonds will be formed. Running an IRC further, it soon became clear that the asymmetry of the HOMO leads to an asychronous bond formation before leading to the product.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''IRC plot following the Endo Transition State '''
| '''IRC following the Endo Transition State (click to animate)'''
| '''Asymmetry of orbitals at the carbons where the new sigma bonds will be formed'''
|- align="center"
| [[File:XcwendotscyclopentadieneIRC.png|300px|center]]
| [[File:XcwendotsIRC.gif|300px|center]]
| [[File:XcwAsynchronous mo.jpg|300px|center]]
|-
|}

 

==== '''Comparison of Energies between the Endo and Exo adduct of Dicyclopentadiene''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Adduct of Dicyclopentadiene dimerization'''
| '''Exo Adduct of Dicyclopentadiene dimerization'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=19,atomno=1,atomno=2; color green;measure 19 1;measure 19 2;</script>
<uploadedFileContents>XcwEndodimer3.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>Exodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=7,atomno=17; color green;measure 17 7;</script>
<uploadedFileContents>XcwExodimer1.mol</uploadedFileContents>
</jmolApplet></jmol>
|-
|}

 

Using MMFF94s ab initio calculations, the energies for the exo dimer and the endo dimer are derived.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Exodimer'''
| '''55.374'''
| 3.543
| 30.772
| -2.041
| -2.728
| 0.015
| 12.800
| 13.014
|-
| '''Endodimer'''
| '''58.191'''
| 3.468
| 33.187
| -2.082
| -2.950
| 0.023
| 12.360
| 14.186
|-
|}

 

The MMFF94s steric energy (after minimization) for the exo dimer is lower than that of the endo dimer. This is reflected by the large difference for the EEE between the endo dimer and the exo dimer due to unfavourable steric repulsion between the two “arched down” cyclopentene rings.

==== '''Hydrogenation of Dicyclopentadiene''' ====

Hydrogenation of the endo dicyclopentadiene (DCPD) would lead to two potential products: dihydro product 1 and dihydro product 2.

[[File:XcwFormation of Dihydro products.png|500px|center]]

Using MMFF94s, the energy of the two dihydro products are calculated.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Dihydro Product 1'''
| '''50.123'''
| 3.308
| 30.864
| -1.927
| 0.060
| 0.015(2)
| 13.281
| 5.121
|-
| '''Dihydro Product 2'''
| '''41.257'''
| 2.823
| 24.685
| -1.657
| -0.379
| 0.000(2)
| 10.639
| 5.147
|-
| '''Tetrahydro Product'''
| '''39.042'''
| 2.730
| 25.151
| -1.676
| 1.287
| 0.000
| 11.551
| 0.000
|}

 

From the MMFF94s calculation, it can be seen that dihydro product 2 has a lower steric energy than dihydro product 1. Therefore, dihydro product 2 is the thermodynamic product for the hydrogenation of dicylopentadiene. And indeed, this was what was observed by Skala et al.. He observed that the first hydrogenation occur at the norborene part of the molecule (rate of hydrogenation several times faster than that in the cyclopentene ring)6. The first heat of hydrogenation at the norborene is 138.8 kJ/mol while the second hydrogenation at the cyclopentene right is 109.5 kJ/mol6.

From the above results, it is also obvious that tetrahydro product is much more stable than either dihydro product. And yet, studies have shown that the tetrahydro product will only form after prolonged hydrogenation under high temperature. However, subjecting DCPD to high temperature leads to low yield due to cracking of DCPD.

Since thermodynamically it is predicted to form favourably, the fact that it does not could only mean that the hydrogenation of DCPD to tetrahydrodicyclopentadiene (TH-DCPD) is kinetically controlled. Most possibly, the transition state of the hydrogenation of DCPD is highly unstable hence it is unlikely to form.

=== '''Atropisomerism in an Intermediate related to the Synthesis of Taxol''' ===

Atropisomerism is a type of stereoisomerism that is form as a result of hindered rotation about a single bond.

[[File:XcwAtropisomerism example.png|500px|center]]

In the case of the 6,6’-dinitro-2,2’-diphenic acid, rotation about the bonds joining the two substituted phenyl rings would have to overcome large steric interaction between the bulky substituents. The barrier of rotation is high enough for the two conformers to be isolated individually.

In the synthesis of taxol, one of the key intermediates exhibit atropisomerism.

==== '''Atropisomerism in Taxol Synthesis''' ====

For the key intermediate, rotation about the carbon-carbon bonds would lead to two types of atropisomers, each with either the carbonyl group poining upwards or downwards in relative to the bridge.

[[File:XcwIntermediate 9 and Intermediate 10.png|500px|center]]

Once again by using MMFF94s ab initio calculations, the steric energies for the two intermediates are illustrated as below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 9'''
| '''70.571'''
| 7.743
| 28.356
| -0.062
| 0.004
| 0.949
| 33.293
| 0.288
|-
| '''Intermediate 10'''
| '''60.553'''
| 7.599
| 18.838
| -0.139
| 0.199
| 0.844
| 33.269
| -0.056
|-

|}

 

Analyzing the data above, the largest energy difference between Intermediate 9 and Intermediate 10 stems from the EAB which is related to the strain of the ring. Intermediate 9 has an excess of 9.518 kcal/mol EAB as compared to Intermediate 10. This comes as a surprise as intermediate 9 is predicted to be more stable alkene.

The rationale behind the prediction of the stability of intermediate 9 stems from the fact that the through-space distance of the upward-pointing carbonyl oxygen with the carbon-carbon is further than the through space distance between the downward-pointing carbonyl oxygen with the -CH2-CH2- fragment at the norbornene part in intermediate 10.

==== '''Hyperstable Olefins''' ====

Intermediate 9 and Intermediate 10 does not react readily with other reagents during functionalization. This is due to the hyperstability effect found in hyperstable olefins.

Hyperstable olefins are alkenes that contain less strain in the ring (i.e. negative olefin strain values) compared to the parent hydrocarbon. To study this further, further MMFF94s calculation was done to compare Intermediate 10 with the parent hydrocarbon.

[[File:XcwIntermediate10andPH.png|500px|center]]

The energies that we calculated are tabulated as shown below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 10'''
| '''44.878 '''
| 5.211
| 15.488
| -0.267
| -1.655
| 0.998
| 25.014
| 0.088
|-
| '''Parent Hydrocarbon'''
| '''50.564'''
| 4.692
| 21.979
| 0.109
| -0.958
| 0.247
| 24.495
| 0.000
|-

|}

 

Scrutinizing the results, the largest energy difference between intermediate 10 and the parent hydrocarbon stems from the Total Angle Bending Energy, EAB. Since the Total Angle bending energy is related to the angle strain in the molecules, it is apparent that the parent hydrocarbon has more ring strain as compared to the bridgehead olefin.

== '''Part 3 : Spectroscopic Simulation Using Quantum Mechanics''' ==
=== '''Spectroscopy of an Intermediate Related to the Synthesis of Taxol''' ===

Molecule 17 and 18 are derivatives of intermediate 9 and 10. In this exercise, MMFF94s is used to predict the 1H and 13C NMR of molecule 17 and molecule 18.

[[File:XcwIntermediate17&18.png|500px|center]]

==== '''NMR Spectra of Molecule 17''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 17.mol
</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwHNMRMolecule 17 Chair Overall NMR.png|500px|center]]
| [[File:XcwHNMRMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.1825
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| The first three results were fairly straight forward to be deduced and correlate wit experimental data.

The hydrogen atom that is geminally attached to the carbon of the double bonds is the most deshielded due to the ring current anisotropic effect of the ring current

The second most deshielded hydrogen atom is the hydrogen atom on the methyl group on the bridge. The hydrogen atom is pointing directly to the oxygen atom of the carbonyl functional group.

The peaks with an integration height of 4 is assigned to the hydrogen atoms in the 1,3-dithiolane ring fragment.

Subsequent analysis of the 1H NMR became very complicated very quickly for two reasons:

1. Gaussian calculations showed some atoms with an integration height of 3. Comparing their file atom number and checking their chemical environment, it is not possible to find any correlation between them.

2. Some of the peaks in the literature remains unresolved and are given as multiplets or grouped together.

|- align="center"
| 52
| 3.1775
| 1
| '''2.99'''
|- align="center"
| 53,52,50,51
| 3.0867
| 4
| '''3.40-3.10'''
|- align="center"
| 42,43,39
| 2.7445
| 3
| ''' '''
|- align="center"
| 49
| 2.6187
| 1
| ''' '''
|- align="center"
| 34
| 2.4371
| 1
| ''' '''
|- align="center"
| 35
| 2.3782
| 1
| ''' '''
|- align="center"
| 40,37,26
| 2.2730
| 3
| ''' '''
|- align="center"
| 30
| 2.1566
| 1
| ''' '''
|- align="center"
| 36
| 2.1033
| 1
| ''' '''
|- align="center"
| 32,28
| 2.0259
| 2
| ''' '''
|- align="center"
| 25
| 1.8535
| 2
| ''' '''
|- align="center"
| 38,46,27
| 1.5898
| 3
| '''1.25'''
|- align="center"
| 29
| 1.4557
| 1
| ''' '''
|- align="center"
| 31
| 1.0123
| 1
| ''' '''
|- align="center"
| 44,48,45
| 0.9087
| 3
| '''1.10'''
|- align="center"
| 47
| 0.8354
| 1
| ''' '''
|- align="center"
| 33
| 0.5790
| 1
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 17 Chair Overall NMR2.png|500px|center]]
| [[File:XcwMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 216.2725
| 1
| '''218.79'''
| rowspan="10" style="text-align:center;"| [[File:XcwMolecule 17 image for CNMR.jpg|600px|center]]
|- align="center"
| 13
| 144.8626
| 1
| '''144.63'''
|- align="center"
| 14
| 124.7193
| 1
| '''125.33'''
|- align="center"
| 3
| 91.3340
| 1
| '''72.88'''
|- align="center"
| 2
| 60.9568
| 1
| '''56.19'''
|- align="center"
| 1
| 57.0811
| 1
| '''52.52'''
|- align="center"
| 10
| 52.4663
| 1
| '''48.50'''
|- align="center"
| 16
| 51.4857
| 1
| '''46.80'''
|- align="center"
| 9
| 46.9196
| 1
| '''45.76'''
|- align="center"
| 23
| 43.8647
| 1
| '''39.80'''
|- align="center"
| 22
| 41.9450
| 1
| '''38.81'''
| Comments
|- align="center"
| 4
| 41.8724
| 1
| '''35.85'''
| rowspan="9" style="text-align:left;"| The carbon bonded to the oxygen atom is the most deshielded, as is shown in the predicted values and the experimental values. There is a deviation between the values. Quite possibly, this is due to the fact that in reality, the carbonyl functional group is pointing slightly towards the equatorial position rather than a lateral position relative to the ring (as is in the input for Gaussian calculation)

Most of the 1CNMR values that was predicted by Gaussian are all within an acceptable range of deviation. However, there is carbon 3 that has significant deviation between the predicted value and experimental value.

Carbon 3 is the carbon bonded to the two sulphurs in the 1,3-dithiolane ring fragment. Such a huge deviation would possibly mean that the conformer that was given as input to Gaussian differs from the literature.

The above NMR spectra was corrected with a level of theory B3LYP/6-31G(d,p) using TMS as reference and in chloroform.

|- align="center"
| 15
| 35.4348
| 1
| '''32.66'''
|- align="center"
| 11
| 31.1964
| 1
| '''28.79'''
|- align="center"
| 6
| 28.9432
| 1
| '''28.29'''
|- align="center"
| 7
| 28.3640
| 1
| '''26.88'''
|- align="center"
| 12
| 27.3767
| 1
| '''25.66'''
|- align="center"
| 17
| 26.3311
| 1
| '''23.86'''
|- align="center"
| 15
| 24.5483
| 1
| '''20.96'''
|- align="center"
| 18
| 19.7788
| 1
| '''18.71'''
|-
|}
 

==== '''NMR Spectra of Molecule 18''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 18 Boat for Image2.mol</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"-
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 18 Chair Overall NMR.png|500px|center]]
| [[File:Molecule 18 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.2832
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| ''' '''
|- align="center"
| 50
| 3.3175
| 1
| rowspan="4" style="text-align:centre;"| '''3.00-2.70'''
|- align="center"
| 52
| 3.2153
| 1
|- align="center"
| 51,53
| 3.1161
| 2
|- align="center"
| 34,43
| 2.8606
| 2
|- align="center"
| 38
| 2.4549
| 1
| ''' '''
|- align="center"
| 42
| 2.3968
| 1
| ''' '''
|- align="center"
| 25,29,26
| 2.2796
| 3
| ''' '''
|- align="center"
| 39
| 2.0844
| 1
| ''' '''
|- align="center"
| 40,36
| 1.9699
| 2
| ''' '''
|- align="center"
| 37,24
| 1.8519
| 2
| ''' '''
|- align="center"
| 31,27
| 1.6780
| 2
| ''' '''
|- align="center"
| 28
| 1.6175
| 1
| ''' '''
|- align="center"
| 46,49
| 1.4979
| 2
| ''' '''
|- align="center"
| 35
| 1.4150
| 1
| ''' '''
|- align="center"
| 32
| 1.3531
| 1
| ''' '''
|- align="center"
| 48
| 1.1606
| 1
| ''' '''
|- align="center"
| 33,30,47
| 1.0653
| 3
| '''1.03'''
|- align="center"
| 44,45
| 0.9643
| 2
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwMolecule 18 Boat Overall NMR.png|500px|center]]
| [[File:XcwMolecule 18 Boat zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 211.8325
| 1
| '''211.49'''
| rowspan="10" style="text-align:center;"| [[File:Molecule 18 Boat for 13 CNMR.jpg|600px|center]]
|- align="center"
| 13
| 148.6673
| 1
| '''148.72'''
|- align="center"
| 14
| 118.8373
| 1
| '''120.90'''
|- align="center"
| 3
| 89.0869
| 1
| '''74.61'''
|- align="center"
| 2
| 67.8886
| 1
| '''60.53'''
|- align="center"
| 1
| 56.1133
| 1
| '''51.30'''
|- align="center"
| 10
| 55.5998
| 1
| '''50.94'''
|- align="center"
| 16
| 50.1124
| 1
| '''45.53'''
|- align="center"
| 22
| 48.2030
| 1
| '''43.28'''
|- align="center"
| 23
| 44.2222
| 1
| '''40.82'''
|- align="center"
| 4
| 42.0354
| 1
| '''38.73'''
| Comments
|- align="center"
| 9
| 37.5865
| 1
| '''36.78'''
| rowspan="9" style="text-align:left;"| ''' '''
|- align="center"
| 6
| 35.3106
| 1
| '''35.47'''
|- align="center"
| 15
| 31.0459
| 1
| '''30.84'''
|- align="center"
| 7
| 28.8476
| 1
| '''30.00'''
|- align="center"
| 12
| 28.6623
| 1
| '''25.56'''
|- align="center"
| 17
| 25.7393
| 1
| '''25.35'''
|- align="center"
| 11
| 25.2603
| 1
| '''22.21'''
|- align="center"
| 18
| 23.3944
| 1
| '''21.39'''
|- align="center"
| 5
| 21.0478
| 1
| '''19.83'''
|-
|}
 

== '''Part 4 : Analysis of the Properties of the Synthesized Alkene Epoxides''' ==
=== '''The two catalytics systems''' ===

Assymmetric epoxidation of prochiral alkenes may lead to product with different stereochemical outcome as illustrated as below. To solve this problem, different types of asymmetric epoxidation catalyst have been synthesized. In this study, we shall be focusing on Shi asymmetric fructose catalyst as well as Jacobsen asymmetric catalyst.

[[File:Asymmetric catalyst.png|400px|center]]

==== ''' The Shi Asymmetric Fructose Catalyst''' ====

Molecule 21 is the stable precursor of molecule 22, the active catalyst. Molecule 21 can be converted to molecule 22 by using either persulfuric acid or potassium peroxymonosulphate.

[[File:Molecule 21 to 23.png|400px|center]]

The transition state of the Shi epoxidation was a subject of debate for a few moments. However, recent studies have led to the conclusion that the spiro transition state is more favored than the planar transition state. The spiro transition state is the transition that has its dioxirane perpendicularly bisecting the alkene double bond. This is thought to be more favourable due to interactions between the lone pairs of the oxygen with the LUMO of the alkene.

[[File:Spiro and planar ts.png|500px|center]]

==== ''' The Jacobsen Asymmetric Catalyst''' ====

Molecule 23 is the stable precursor of molecule 24, the active catalyst. Molecule 23 can be converted to molecule 24 by using sodium perchlorate.

[[File:Salen, 23 and 24.png|400px|center]]

Jacobsen catalyst is biphasic. The first phase involves the transfer of oxygen to molecule 23. Sodium perchlorate oxidizes Mn(III) to Mn(V).

In the second step, Jacobsen catalyst acts via a radical mechanism. It is thought to be so because epoxidation of trans-alkene by Jacobsen catalyst yield cis-alkene as well. A radical mechanism will lead to the lost of stereochemical information of the molecule.

=== ''' Crystal structure of the two catalyst''' ===
==== '''Molecule 21''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 21'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 21 strucutre.png|600px|center]]'''
|-
| style="text-align:center;" width="150" | ''' Bond '''
| style="text-align:center;" width="150"| ''' Bond Lenghts (Angstrom)'''
| style="text-align:center;" | ''' Evaluation'''
|-
| style="text-align:center;"| ''' O1-C1 '''
| style="text-align:center;"| ''' 1.400'''
| rowspan="10" style="text-align:left;"| [[File:Molecule 21 2.png|300px|center]]

The normal bond length of an C-O bond is 1.430 angstrom.

The most interesting aspect here is O4 and O2. The lone pair of O4 is antiperplanar to the sigma* orbital of the carbonyl group while the lone pair of O2 is anti periplanar to the carbonyl pi* orbital. Donation of electron can occur because of the correct symmetry. Due to the mixing of the orbitals, the C2-O2 and C4-O4 has been conferred with a certain degree of double bond character.

However, due to the lone pair on oxygen being now donated to the carbonyl antibonding orbitals, the O2 and O4 is slightly “electron deficient” and electron density will be pulled away from O2 and O4. That would explain why the bond length increase for O2-C7 and O4-C10. Increase in bond length is an indicator of the weakening of the bond.
|-
| style="text-align:center;"|'''O1-C7'''
| style="text-align:center;"|'''1.413'''
|-
| style="text-align:center;"|'''O2-C7'''
| style="text-align:center;"|'''1.441'''
|-
| style="text-align:center;"|'''O2-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O4-C4'''
| style="text-align:center;"|'''1.396'''
|-
| style="text-align:center;"|'''O4-C10'''
| style="text-align:center;"|'''1.439'''
|-
| style="text-align:center;"|'''O5-C10'''
| style="text-align:center;"|'''1.409'''
|-
| style="text-align:center;"|'''O5-C5'''
| style="text-align:center;"|'''1.416'''
|-
| style="text-align:center;"|'''O6-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O6-C6'''
| style="text-align:center;"|'''1.420'''
|-
|}
 

==== '''Molecule 23''' ====

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 23'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 23 struc.png|600px|center]]'''
|-
| The most outstanding feature from this molecule is the fact that is adopt a puckered form of the square base pyramidal form. This is no surprise that the molecule is almost planar due to the electron delocalization around each side of the salen ligand.

The tery-butyl hydrogen are oriented closely to one another. Non-covalent interaction studies indicated that repulsion would occur for H---H bond length that are less than 2.1 angstrom while favourable interaction may be dominant with bond length above 2.4 angstrom. It was discovered that all 4 hydrogens have bond length more than 2.4 angstrom hence there should not be any significant repulsion between them. Instead, certain amount of attractive force will ensue and that contributes to the overall stability of the molecule

|-
|}
 

=== ''' The calculated NMR properties of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | ''' '''
| width="100" | ''' '''
| width="100" | ''' '''
| width="100" | ''' '''
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Styrene R HNMR.png|200px|center|]]'''
| width="100" | ''' [[File:Styrene S HNMR.png|200px|center|]]'''
| width="100" | ''' [[File:Stilbene RR HNMR.png|200px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|200px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | ''' '''
| width="100" | ''' '''
| width="100" | ''' '''
| width="100" | ''' '''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | ''' [[File:Styrene R CNMR.png|200px|center|]]'''
| width="100" | ''' [[File:Styrene S CNMR.png|200px|center|]]'''
| width="100" | ''' [[File:Stilbene RR CNMR.png|200px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|200px|center|]]'''
|-
|}

 

=== ''' Assigning the absolute configuration of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''Predicted ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg'''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg '''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental conditions'''
| width="100" | '''1.00g/100ml, chloroform, 21 degree Celcisus, 589 nm wavelength '''
| width="100" | '''1.02g/100ml (99% ee), chloroform, 25 degree Celsius, 589 nm wavelength '''
| width="100" | '''1.01g/100ml, ethanol, 22 degree Celsius, 589 nm wavelength '''
| width="100" | '''0.6g/100ml, ethanol, 20 degree Celsius, 589 nm wavelength '''
|- align="left"
| width="100" | ''' Predicted VCD Spectrum'''
| width="100" | '''[[File:Styrene R VCD.png|200px|center|]] '''
| width="100" | '''[[File:Styrene S VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene RR VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene SS VCD.png|200px|center|]]'''
|-
|}

 

All the assignments given in the literature reports are correct although the predicted value differs slightly with the experimental values

=== ''' Analysis of the Transition State for Reactions''' ===
==== '''Predicting Enantiomeric Excess based on Transition State energies''' ====

One of the energy output from Gaussian calculation is the “sum of electronic and thermal free energies”. This is Gibbs Free Energy at 298.15K and 1 atm.

Using this term and invoking a variant of the Curtin-Hammett Principle, it is possible to calculate a predicted enantiomeric excess of one enantiomer over the other.

[[File:Ee and transition state energy.png|800px|center]]

Using the derivations from above and equation (4), we analyze the enantiomeric excess of beta-methyl styrene and the results are tabulated as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1343.022970'''
| width="100" | '''-1343.017942'''
| width="150" | '''-0.005028'''
| width="150" | '''4.88E-03'''
| width="150" | '''99.03'''
|- align="center"
| width="100" | '''-1343.019233'''
| width="100" | '''-1343.015603'''
| width="150" | '''-0.003630'''
| width="150" | '''2.14E-02'''
| width="150" | '''95.80'''
|- align="center"
| width="100" | '''-1343.029272'''
| width="100" | '''-1343.023766'''
| width="150" | '''-0.005506'''
| width="150" | '''2.94E-03'''
| width="150" | '''99.41'''
|- align="center"
| width="100" | '''-1343.032443'''
| width="100" | '''-1343.024742'''
| width="150" | '''-0.007701'''
| width="150" | '''2.88E-04'''
| width="150" | '''99.94'''
|-
|}

 

The above hartree units are converted to J/mol for calculation of K where 1 hartress = 4.3597E-18

Studying all the free energies of the (R,R) series and compare them with the (S,S) series, it comes as no surprise that (R,R) product is favoured over (S,S) product as (R,R) is more stable. Indeed, this corresponds with the literature value reporting 92% ee of (R,R) products over that of (S,S).

==== '''Analysis of the Transition State of Epoxidation''' ====
==== '''Shi Fructose Catalyst''' ====
For this section, I will be analyzing the the transition state of 1) styrene and 2) trans-stilbene with the Shi fructose catalyst.

===== '''(R) and (S)-styrene transition state''' =====
The transition state for the formation of (R)-styrene oxide and (S)-styrene oxide are given as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R)-styrene oxide'''
| width="150" | '''(S)-styrene oxide'''
|- align="center"
| width="150" | ''' Structure of Catalyst '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide R.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide S ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| [[File:Steric shi fructose R.png|450px|center]]
| [[File:Steric shi fructose S.png|450px|center]]
|-
|}

 

In the transition state for (R)-styrene, it was discovered that the Re face is reacting with the oxygen of the dioxirane. The phenyl ring is oriented endo with respect to the fructose catalyst. However, the (S)-styrene is reacting at the Si face and the phenyl ring is oriented exo relative to the catalyst.

The approach taken by (R)-styrene and (S)-styrene are restricted to only one due to steric interactions. Therefore, the epoxidation of both styrenes by the Shi catalyst will be stereospecific and retains all the stereochemical information of the reactant. However, whether or not (R)-styrene oxide or (S)-styrene oxide is form is dependent on the relative energies of the transition state. The more stable the transition state, the more likely the product of the transition state will be formed.

So in order to examine this, an example of transition state of both styrenes with Shi catalyst are obtained and analyzed.
 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1303.736813'''
| width="100" | '''-1303.727673'''
| width="150" | '''-0.00914'''
| width="150" | '''6.28E-05'''
| width="150" | '''99.99'''

|-
|}

 

From the above, we can see the predicted high enantiopurity of the reaction favoring the (R) product because of the lower energy of the transition states. To understand the reason, we have to turn to non-covalent interaction (NCI) analysis.

[[File:NCI shi fructose styrene.png|700px|center]]

To complement the NCI analysis, a QTAIM (Quantum Theory of Atoms in Molecules) analysis is conducted as well.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''(R)-styrene transition state'''
| width="200" | '''(S)-styrene transition state'''
|- align="center"
| width="100" | '''[[File:QTAIM R.png|400px|center]]'''
| width="100" | '''[[File:QTAIM S.png|400px|center]]'''
|- align="center"
| colspan="2" width="100" | '''Comments'''
|-
| colspan="2" width="100" | '''Unsurprisingly, QTAIM analysis has also shown that (R)-styrene/Shi catalyst has more interactions with one another. While (R)-styrene has 2 strong interactions, (S)-styrene has only one with the catalyst. Besides, the phenyl ring of (R)-styrene also confers additional positive interaction with the catalyst. QTAIM analysis has also show several interactions between the C=C geminal hydrogen of (R)-styrene intreacting with the oxygen atoms on the dioxacyclopentane ring'''
|-
|}

 

===== '''(R,R) and (S,S)-Stilbene transition state''' =====

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R,R)-Stilbene oxide'''
| width="150" | '''(S,S)-Stilbene oxide'''
|- align="center"
| width="150" | ''' Structure of Transition State '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Stilbene RR ts.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>SS stilbene oxide ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| colspan="2" | [[File:Shi fructose stilbene.png|700px|center]]

|-
|}

 

However, unlike styrene, trans-stilbene seems to approach perpendicularly to the dioxirane. This is proposed to be due to the steric interactions (marked in purple). Based on first inspection, it seems that (S,S)-Stilbene oxide has more steric interactions than (R,R)-Stilbene oxide. Although unsubstantial, it seems like my guess was correct. The (R,R)-stilbene/Shi catalyst transition state is lower in energy.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1534.687808'''
| width="100" | '''-1534.683440'''
| width="150" | '''0.004368'''
| width="150" | '''9.08E-3'''
| width="150" | '''98.20'''

|-
|}

 

NCI Analysis is also done for trans-stilbene

[[File:NCI stilbene.png|700px|center]]

==== '''Jacobsen Catalyst''' ====

For this section, cis-beta methyl styrene transition state will be analyzed.

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-3383.259559'''
| width="100" | '''-3383.251060'''
| width="150" | '''-0.008499'''
| width="150" | '''1.24E-04'''
| width="150" | '''99.98'''
|- align="center"
| width="100" | '''-3383.253442'''
| width="100" | '''-3383.250270'''
| width="150" | '''-0.003172'''
| width="150" | '''3.48E-02'''
| width="150" | '''93.27'''
|-
|}

 

As is obvious from here, the (S,R) transition state is more stable than the (R,S) transition state. Both transition states are exo with respect to the catalyst.

It is not immediately apparent just by looking at the molecule to determine which spatial groups have interactions with one another. Therefore, an NCI analysis is conducted again.

[[File:NCI Jacobsen.png|700px|center]]

Rep:Mod:Computationalreport1C

2013-11-21T22:27:04Z

Xc2611: /* The calculated NMR properties of the product */

= '''Synthesis and Computational Lab: 1C''' =
== '''Part 1: Introduction to Molecular Mechanics''' ==
=== '''Introduction to MMFF94 and MMFF94s''' ===

With the improvement of computational data and computer processing power, the usage of molecular mechanics/dynamics forcefield has become very integrated in predicting properties of chemical molecules. A molecular mechanics/dynamics forcefield should be able to predict characteristics such as molecular geometries, conformational/stereoisomeric energies, vibrational frequencies etc. to a reasonable accuracy as compared to experimental-derived values.

Building on work from Kollman et al. s’ AMBER forcefield and Allinger et al. s’ MM1, MM2, MM3 and MM4, Merck Research Laboratories have managed to optimized and improved the previous computational algorithms and produced MMFF94 (Merck Molecular Force Field 94). One of the most prominent advantages of MMFF94 over other preceeding work is its enhanced prediction accuracy. The reason lies in the fact that MMFF94’s core parameterization utilizes an unprecedently large amount of computational data obtained from ab initio calculations1.

Subsequently after the development of MMFF94, a new “static” variant of the MMFF was introduced i.e. the MMFF94s. Unlike MMFF94 that was developed for the use of molecular dynamics simulations (which can be expensive), MMFF94s was developed with the purpose of energy minimization studies in mind. Although both systems provide identical results for most systems, they differ for amides and unsaturated amines which contain resonance-delocalized trigonal nitrogen atoms2.

In this computational exercise, MMFF94s is used predominantly as oppose to the alternative Universal Force Field (UFF). Although versatile across the entire periodic table, UFF is derived from simple rules and atomic parameters such as fixed hybridization that increases the likelihood of erroneous structural and energetic predictions3.

=== '''Forms of MMFF94s''' ===

Steric energy of a molecule is the energy arise due to its geometry or conformation. Energy minimization of steric energy process ensures that the molecule is in its lowest energy conformation.

MMFF94s assumes that the total steric energy of a molecule can be found by the sum of a few specific interactions in a molecule.

ES = EBS + EAB + E SB + ET + EOOP + EVdW + EEE

'''where the bonded interactions are:'''

ES = Total Steric energy

EBS = Total Bond Stretching energy

EAB = Total Angle Bending energy

ESB = Total Stretch Bending energy

ET = Total Torsional Energy

EOOP = Total Out-Of-Plane Bending energy, and

'''where the non-bonded interactions are:'''

EVdW = Total Van der Waals Energy

EEE = Total Electrostatic Energy

{| border="1" cellspacing="1" cellpadding="10"
|-
| width="300" align="center" | '''Types of Energies'''
! width="600" align="center" | '''Explanation'''
|-
| colspan="2" style="text-align: center;" | '''Bonded Interactions'''
|-
| width="300" align="center" | '''Total Bond Stretching Energy'''
! width="600" align="left" | The total bond stretching energy is related to the vibration energy of the molecules in comparison to the equilibrium bond length. Whenever a bond deviates from the equilibrium bond length, the energy value increases.

MMFF94s uses a quartic function that has the force constant term (relate to bond strength). The quartic function term is superior to the cubic function term (used in MM2) in the sense that it avoid the “cubic stretch catastrophe” where progressive elongation of molecule bond length leads to negative infinity.
|-
| width="300" align="center" | '''Total Angle Bending Energy'''
! width="600" align="left" | Similar to Total Bond Stretching Energy, the total angle bending energy is also related to the vibration energy of the molecules about the equilibrium bond length. However, unlike EBS that measures the bond strength, EAB is associated with the stiffness of the molecules based on the Hookiean potential. Whenever bond angles deviate from the norm during vibration, this energy term increases as well.
|-
| width="300" align="center" | '''Total Stretch-Bending Energy'''
! width="600" align="left" | This energy term takes into account of the energy due to increase in bond length when bond angle between two atoms changes.
|-
| width="300" align="center" | '''Total Torsional Energy'''
! width="600" align="left" | Total torsional energy is the energy required for intermolecular rotation about the bonds. In molecule mechanics, however, this term is often used as a correction that must be added or subtracted to the total energy of the molecule to fit a quantum mechanical calculation about the dihedral angles of bonds.
|-
| width="300" align="center" | '''Total Out-Of-Plane Bending Energy'''
! width="600" align="left" | This energy term refers to the energy needed to deform the dihedral angle (zero degrees) of a planar group of atoms such as carbonyl or amide functional groups.
|-
| colspan="2" style="text-align: center;" | '''Non-Bonded Interactions'''
|-
| width="300" align="center" | '''Total Van der Waals Energy'''
! width="600" align="left" | The total Van der Waals energy term examines the intramolecular interactions such as repulsion or attraction between non-bonded atoms in the molecule. This term is crucial in determining the preferred conformation of the molecule.

MMFF94s employs the novel “Buffered-14-7”. The name is derived from a buffering constant and the 14th and 7th power dependencies of the repulsive and attractive energy in the equation.
|-
| width="300" align="center" | '''Total Electrostatic Energy'''
! width="600" align="left" | The total electrostatic energy functions take into account of the Coulombic potential and partial charge/dipole/atomic point charges interactions within the molecule.
|-

|}

 

== '''Part 2 : Conformational Analysis Using Molecular Mechanics''' ==
=== '''The Hydrogenation of Cyclopentadiene Dimer''' ===

==== '''Endo and exo adduct from the Dimerization of Cyclopentadiene''' ====
Cyclopentadiene will undergo dimerization by Diels-alder reaction to form either an endo or exo adduct.

[[File:XcwDimerization of CP.png|500px|center]]

==== '''Stereoselectivity of Dimerization of Cyclopentadiene''' ====
Although the exo adduct is thermodynamically more stable than the endo adduct, the endo adduct is form preferentially. Using the QST2 method, the transition state of the Diels Alder dimerization was found. It was discovered that due to the secondary orbital interactions in the endo transition state, the endo dimer is formed preferentially (the kinetic product). Hence, it is proven that the Diels Alder dimerization between two cyclopentadiene are kinetically controlled.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Transition State of Dimerization of Cyclopentadiene'''
| '''Imaginary Stretch Frequency (-881.25) of the Endo Transition State (click to animate)'''
| '''Secondary Orbital Interaction (Red overlapping orbitals)'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<uploadedFileContents>EndotsDCPD2.mol
</uploadedFileContents>
</jmolApplet></jmol>
| [[File:Xcwendotsimaginary.gif|300px|center]]
| [[File:XcwSecondary orbital interaction1.jpg|300px|center]]
|-
|}

 

==== '''Asynchronous Bond Formation of Dimerization of Cyclopentadiene''' ====

The initial study of the molecular orbitals of the transition states seemed a bit peculiar. Instead of getting a LUMO with symmetrical orbitals, the calculations showed a HOMO that is asymetric at the carbons where the new sigma bonds will be formed. Running an IRC further, it soon became clear that the asymmetry of the HOMO leads to an asychronous bond formation before leading to the product.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''IRC plot following the Endo Transition State '''
| '''IRC following the Endo Transition State (click to animate)'''
| '''Asymmetry of orbitals at the carbons where the new sigma bonds will be formed'''
|- align="center"
| [[File:XcwendotscyclopentadieneIRC.png|300px|center]]
| [[File:XcwendotsIRC.gif|300px|center]]
| [[File:XcwAsynchronous mo.jpg|300px|center]]
|-
|}

 

==== '''Comparison of Energies between the Endo and Exo adduct of Dicyclopentadiene''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Adduct of Dicyclopentadiene dimerization'''
| '''Exo Adduct of Dicyclopentadiene dimerization'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=19,atomno=1,atomno=2; color green;measure 19 1;measure 19 2;</script>
<uploadedFileContents>XcwEndodimer3.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>Exodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=7,atomno=17; color green;measure 17 7;</script>
<uploadedFileContents>XcwExodimer1.mol</uploadedFileContents>
</jmolApplet></jmol>
|-
|}

 

Using MMFF94s ab initio calculations, the energies for the exo dimer and the endo dimer are derived.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Exodimer'''
| '''55.374'''
| 3.543
| 30.772
| -2.041
| -2.728
| 0.015
| 12.800
| 13.014
|-
| '''Endodimer'''
| '''58.191'''
| 3.468
| 33.187
| -2.082
| -2.950
| 0.023
| 12.360
| 14.186
|-
|}

 

The MMFF94s steric energy (after minimization) for the exo dimer is lower than that of the endo dimer. This is reflected by the large difference for the EEE between the endo dimer and the exo dimer due to unfavourable steric repulsion between the two “arched down” cyclopentene rings.

==== '''Hydrogenation of Dicyclopentadiene''' ====

Hydrogenation of the endo dicyclopentadiene (DCPD) would lead to two potential products: dihydro product 1 and dihydro product 2.

[[File:XcwFormation of Dihydro products.png|500px|center]]

Using MMFF94s, the energy of the two dihydro products are calculated.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Dihydro Product 1'''
| '''50.123'''
| 3.308
| 30.864
| -1.927
| 0.060
| 0.015(2)
| 13.281
| 5.121
|-
| '''Dihydro Product 2'''
| '''41.257'''
| 2.823
| 24.685
| -1.657
| -0.379
| 0.000(2)
| 10.639
| 5.147
|-
| '''Tetrahydro Product'''
| '''39.042'''
| 2.730
| 25.151
| -1.676
| 1.287
| 0.000
| 11.551
| 0.000
|}

 

From the MMFF94s calculation, it can be seen that dihydro product 2 has a lower steric energy than dihydro product 1. Therefore, dihydro product 2 is the thermodynamic product for the hydrogenation of dicylopentadiene. And indeed, this was what was observed by Skala et al.. He observed that the first hydrogenation occur at the norborene part of the molecule (rate of hydrogenation several times faster than that in the cyclopentene ring)6. The first heat of hydrogenation at the norborene is 138.8 kJ/mol while the second hydrogenation at the cyclopentene right is 109.5 kJ/mol6.

From the above results, it is also obvious that tetrahydro product is much more stable than either dihydro product. And yet, studies have shown that the tetrahydro product will only form after prolonged hydrogenation under high temperature. However, subjecting DCPD to high temperature leads to low yield due to cracking of DCPD.

Since thermodynamically it is predicted to form favourably, the fact that it does not could only mean that the hydrogenation of DCPD to tetrahydrodicyclopentadiene (TH-DCPD) is kinetically controlled. Most possibly, the transition state of the hydrogenation of DCPD is highly unstable hence it is unlikely to form.

=== '''Atropisomerism in an Intermediate related to the Synthesis of Taxol''' ===

Atropisomerism is a type of stereoisomerism that is form as a result of hindered rotation about a single bond.

[[File:XcwAtropisomerism example.png|500px|center]]

In the case of the 6,6’-dinitro-2,2’-diphenic acid, rotation about the bonds joining the two substituted phenyl rings would have to overcome large steric interaction between the bulky substituents. The barrier of rotation is high enough for the two conformers to be isolated individually.

In the synthesis of taxol, one of the key intermediates exhibit atropisomerism.

==== '''Atropisomerism in Taxol Synthesis''' ====

For the key intermediate, rotation about the carbon-carbon bonds would lead to two types of atropisomers, each with either the carbonyl group poining upwards or downwards in relative to the bridge.

[[File:XcwIntermediate 9 and Intermediate 10.png|500px|center]]

Once again by using MMFF94s ab initio calculations, the steric energies for the two intermediates are illustrated as below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 9'''
| '''70.571'''
| 7.743
| 28.356
| -0.062
| 0.004
| 0.949
| 33.293
| 0.288
|-
| '''Intermediate 10'''
| '''60.553'''
| 7.599
| 18.838
| -0.139
| 0.199
| 0.844
| 33.269
| -0.056
|-

|}

 

Analyzing the data above, the largest energy difference between Intermediate 9 and Intermediate 10 stems from the EAB which is related to the strain of the ring. Intermediate 9 has an excess of 9.518 kcal/mol EAB as compared to Intermediate 10. This comes as a surprise as intermediate 9 is predicted to be more stable alkene.

The rationale behind the prediction of the stability of intermediate 9 stems from the fact that the through-space distance of the upward-pointing carbonyl oxygen with the carbon-carbon is further than the through space distance between the downward-pointing carbonyl oxygen with the -CH2-CH2- fragment at the norbornene part in intermediate 10.

==== '''Hyperstable Olefins''' ====

Intermediate 9 and Intermediate 10 does not react readily with other reagents during functionalization. This is due to the hyperstability effect found in hyperstable olefins.

Hyperstable olefins are alkenes that contain less strain in the ring (i.e. negative olefin strain values) compared to the parent hydrocarbon. To study this further, further MMFF94s calculation was done to compare Intermediate 10 with the parent hydrocarbon.

[[File:XcwIntermediate10andPH.png|500px|center]]

The energies that we calculated are tabulated as shown below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 10'''
| '''44.878 '''
| 5.211
| 15.488
| -0.267
| -1.655
| 0.998
| 25.014
| 0.088
|-
| '''Parent Hydrocarbon'''
| '''50.564'''
| 4.692
| 21.979
| 0.109
| -0.958
| 0.247
| 24.495
| 0.000
|-

|}

 

Scrutinizing the results, the largest energy difference between intermediate 10 and the parent hydrocarbon stems from the Total Angle Bending Energy, EAB. Since the Total Angle bending energy is related to the angle strain in the molecules, it is apparent that the parent hydrocarbon has more ring strain as compared to the bridgehead olefin.

== '''Part 3 : Spectroscopic Simulation Using Quantum Mechanics''' ==
=== '''Spectroscopy of an Intermediate Related to the Synthesis of Taxol''' ===

Molecule 17 and 18 are derivatives of intermediate 9 and 10. In this exercise, MMFF94s is used to predict the 1H and 13C NMR of molecule 17 and molecule 18.

[[File:XcwIntermediate17&18.png|500px|center]]

==== '''NMR Spectra of Molecule 17''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 17.mol
</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwHNMRMolecule 17 Chair Overall NMR.png|500px|center]]
| [[File:XcwHNMRMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.1825
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| The first three results were fairly straight forward to be deduced and correlate wit experimental data.

The hydrogen atom that is geminally attached to the carbon of the double bonds is the most deshielded due to the ring current anisotropic effect of the ring current

The second most deshielded hydrogen atom is the hydrogen atom on the methyl group on the bridge. The hydrogen atom is pointing directly to the oxygen atom of the carbonyl functional group.

The peaks with an integration height of 4 is assigned to the hydrogen atoms in the 1,3-dithiolane ring fragment.

Subsequent analysis of the 1H NMR became very complicated very quickly for two reasons:

1. Gaussian calculations showed some atoms with an integration height of 3. Comparing their file atom number and checking their chemical environment, it is not possible to find any correlation between them.

2. Some of the peaks in the literature remains unresolved and are given as multiplets or grouped together.

|- align="center"
| 52
| 3.1775
| 1
| '''2.99'''
|- align="center"
| 53,52,50,51
| 3.0867
| 4
| '''3.40-3.10'''
|- align="center"
| 42,43,39
| 2.7445
| 3
| ''' '''
|- align="center"
| 49
| 2.6187
| 1
| ''' '''
|- align="center"
| 34
| 2.4371
| 1
| ''' '''
|- align="center"
| 35
| 2.3782
| 1
| ''' '''
|- align="center"
| 40,37,26
| 2.2730
| 3
| ''' '''
|- align="center"
| 30
| 2.1566
| 1
| ''' '''
|- align="center"
| 36
| 2.1033
| 1
| ''' '''
|- align="center"
| 32,28
| 2.0259
| 2
| ''' '''
|- align="center"
| 25
| 1.8535
| 2
| ''' '''
|- align="center"
| 38,46,27
| 1.5898
| 3
| '''1.25'''
|- align="center"
| 29
| 1.4557
| 1
| ''' '''
|- align="center"
| 31
| 1.0123
| 1
| ''' '''
|- align="center"
| 44,48,45
| 0.9087
| 3
| '''1.10'''
|- align="center"
| 47
| 0.8354
| 1
| ''' '''
|- align="center"
| 33
| 0.5790
| 1
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 17 Chair Overall NMR2.png|500px|center]]
| [[File:XcwMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 216.2725
| 1
| '''218.79'''
| rowspan="10" style="text-align:center;"| [[File:XcwMolecule 17 image for CNMR.jpg|600px|center]]
|- align="center"
| 13
| 144.8626
| 1
| '''144.63'''
|- align="center"
| 14
| 124.7193
| 1
| '''125.33'''
|- align="center"
| 3
| 91.3340
| 1
| '''72.88'''
|- align="center"
| 2
| 60.9568
| 1
| '''56.19'''
|- align="center"
| 1
| 57.0811
| 1
| '''52.52'''
|- align="center"
| 10
| 52.4663
| 1
| '''48.50'''
|- align="center"
| 16
| 51.4857
| 1
| '''46.80'''
|- align="center"
| 9
| 46.9196
| 1
| '''45.76'''
|- align="center"
| 23
| 43.8647
| 1
| '''39.80'''
|- align="center"
| 22
| 41.9450
| 1
| '''38.81'''
| Comments
|- align="center"
| 4
| 41.8724
| 1
| '''35.85'''
| rowspan="9" style="text-align:left;"| The carbon bonded to the oxygen atom is the most deshielded, as is shown in the predicted values and the experimental values. There is a deviation between the values. Quite possibly, this is due to the fact that in reality, the carbonyl functional group is pointing slightly towards the equatorial position rather than a lateral position relative to the ring (as is in the input for Gaussian calculation)

Most of the 1CNMR values that was predicted by Gaussian are all within an acceptable range of deviation. However, there is carbon 3 that has significant deviation between the predicted value and experimental value.

Carbon 3 is the carbon bonded to the two sulphurs in the 1,3-dithiolane ring fragment. Such a huge deviation would possibly mean that the conformer that was given as input to Gaussian differs from the literature.

The above NMR spectra was corrected with a level of theory B3LYP/6-31G(d,p) using TMS as reference and in chloroform.

|- align="center"
| 15
| 35.4348
| 1
| '''32.66'''
|- align="center"
| 11
| 31.1964
| 1
| '''28.79'''
|- align="center"
| 6
| 28.9432
| 1
| '''28.29'''
|- align="center"
| 7
| 28.3640
| 1
| '''26.88'''
|- align="center"
| 12
| 27.3767
| 1
| '''25.66'''
|- align="center"
| 17
| 26.3311
| 1
| '''23.86'''
|- align="center"
| 15
| 24.5483
| 1
| '''20.96'''
|- align="center"
| 18
| 19.7788
| 1
| '''18.71'''
|-
|}
 

==== '''NMR Spectra of Molecule 18''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 18 Boat for Image2.mol</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"-
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 18 Chair Overall NMR.png|500px|center]]
| [[File:Molecule 18 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.2832
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| ''' '''
|- align="center"
| 50
| 3.3175
| 1
| rowspan="4" style="text-align:centre;"| '''3.00-2.70'''
|- align="center"
| 52
| 3.2153
| 1
|- align="center"
| 51,53
| 3.1161
| 2
|- align="center"
| 34,43
| 2.8606
| 2
|- align="center"
| 38
| 2.4549
| 1
| ''' '''
|- align="center"
| 42
| 2.3968
| 1
| ''' '''
|- align="center"
| 25,29,26
| 2.2796
| 3
| ''' '''
|- align="center"
| 39
| 2.0844
| 1
| ''' '''
|- align="center"
| 40,36
| 1.9699
| 2
| ''' '''
|- align="center"
| 37,24
| 1.8519
| 2
| ''' '''
|- align="center"
| 31,27
| 1.6780
| 2
| ''' '''
|- align="center"
| 28
| 1.6175
| 1
| ''' '''
|- align="center"
| 46,49
| 1.4979
| 2
| ''' '''
|- align="center"
| 35
| 1.4150
| 1
| ''' '''
|- align="center"
| 32
| 1.3531
| 1
| ''' '''
|- align="center"
| 48
| 1.1606
| 1
| ''' '''
|- align="center"
| 33,30,47
| 1.0653
| 3
| '''1.03'''
|- align="center"
| 44,45
| 0.9643
| 2
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwMolecule 18 Boat Overall NMR.png|500px|center]]
| [[File:XcwMolecule 18 Boat zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 211.8325
| 1
| '''211.49'''
| rowspan="10" style="text-align:center;"| [[File:Molecule 18 Boat for 13 CNMR.jpg|600px|center]]
|- align="center"
| 13
| 148.6673
| 1
| '''148.72'''
|- align="center"
| 14
| 118.8373
| 1
| '''120.90'''
|- align="center"
| 3
| 89.0869
| 1
| '''74.61'''
|- align="center"
| 2
| 67.8886
| 1
| '''60.53'''
|- align="center"
| 1
| 56.1133
| 1
| '''51.30'''
|- align="center"
| 10
| 55.5998
| 1
| '''50.94'''
|- align="center"
| 16
| 50.1124
| 1
| '''45.53'''
|- align="center"
| 22
| 48.2030
| 1
| '''43.28'''
|- align="center"
| 23
| 44.2222
| 1
| '''40.82'''
|- align="center"
| 4
| 42.0354
| 1
| '''38.73'''
| Comments
|- align="center"
| 9
| 37.5865
| 1
| '''36.78'''
| rowspan="9" style="text-align:left;"| ''' '''
|- align="center"
| 6
| 35.3106
| 1
| '''35.47'''
|- align="center"
| 15
| 31.0459
| 1
| '''30.84'''
|- align="center"
| 7
| 28.8476
| 1
| '''30.00'''
|- align="center"
| 12
| 28.6623
| 1
| '''25.56'''
|- align="center"
| 17
| 25.7393
| 1
| '''25.35'''
|- align="center"
| 11
| 25.2603
| 1
| '''22.21'''
|- align="center"
| 18
| 23.3944
| 1
| '''21.39'''
|- align="center"
| 5
| 21.0478
| 1
| '''19.83'''
|-
|}
 

== '''Part 4 : Analysis of the Properties of the Synthesized Alkene Epoxides''' ==
=== '''The two catalytics systems''' ===

Assymmetric epoxidation of prochiral alkenes may lead to product with different stereochemical outcome as illustrated as below. To solve this problem, different types of asymmetric epoxidation catalyst have been synthesized. In this study, we shall be focusing on Shi asymmetric fructose catalyst as well as Jacobsen asymmetric catalyst.

[[File:Asymmetric catalyst.png|400px|center]]

==== ''' The Shi Asymmetric Fructose Catalyst''' ====

Molecule 21 is the stable precursor of molecule 22, the active catalyst. Molecule 21 can be converted to molecule 22 by using either persulfuric acid or potassium peroxymonosulphate.

[[File:Molecule 21 to 23.png|400px|center]]

The transition state of the Shi epoxidation was a subject of debate for a few moments. However, recent studies have led to the conclusion that the spiro transition state is more favored than the planar transition state. The spiro transition state is the transition that has its dioxirane perpendicularly bisecting the alkene double bond. This is thought to be more favourable due to interactions between the lone pairs of the oxygen with the LUMO of the alkene.

[[File:Spiro and planar ts.png|500px|center]]

==== ''' The Jacobsen Asymmetric Catalyst''' ====

Molecule 23 is the stable precursor of molecule 24, the active catalyst. Molecule 23 can be converted to molecule 24 by using sodium perchlorate.

[[File:Salen, 23 and 24.png|400px|center]]

Jacobsen catalyst is biphasic. The first phase involves the transfer of oxygen to molecule 23. Sodium perchlorate oxidizes Mn(III) to Mn(V).

In the second step, Jacobsen catalyst acts via a radical mechanism. It is thought to be so because epoxidation of trans-alkene by Jacobsen catalyst yield cis-alkene as well. A radical mechanism will lead to the lost of stereochemical information of the molecule.

=== ''' Crystal structure of the two catalyst''' ===
==== '''Molecule 21''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 21'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 21 strucutre.png|600px|center]]'''
|-
| style="text-align:center;" width="150" | ''' Bond '''
| style="text-align:center;" width="150"| ''' Bond Lenghts (Angstrom)'''
| style="text-align:center;" | ''' Evaluation'''
|-
| style="text-align:center;"| ''' O1-C1 '''
| style="text-align:center;"| ''' 1.400'''
| rowspan="10" style="text-align:left;"| [[File:Molecule 21 2.png|300px|center]]

The normal bond length of an C-O bond is 1.430 angstrom.

The most interesting aspect here is O4 and O2. The lone pair of O4 is antiperplanar to the sigma* orbital of the carbonyl group while the lone pair of O2 is anti periplanar to the carbonyl pi* orbital. Donation of electron can occur because of the correct symmetry. Due to the mixing of the orbitals, the C2-O2 and C4-O4 has been conferred with a certain degree of double bond character.

However, due to the lone pair on oxygen being now donated to the carbonyl antibonding orbitals, the O2 and O4 is slightly “electron deficient” and electron density will be pulled away from O2 and O4. That would explain why the bond length increase for O2-C7 and O4-C10. Increase in bond length is an indicator of the weakening of the bond.
|-
| style="text-align:center;"|'''O1-C7'''
| style="text-align:center;"|'''1.413'''
|-
| style="text-align:center;"|'''O2-C7'''
| style="text-align:center;"|'''1.441'''
|-
| style="text-align:center;"|'''O2-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O4-C4'''
| style="text-align:center;"|'''1.396'''
|-
| style="text-align:center;"|'''O4-C10'''
| style="text-align:center;"|'''1.439'''
|-
| style="text-align:center;"|'''O5-C10'''
| style="text-align:center;"|'''1.409'''
|-
| style="text-align:center;"|'''O5-C5'''
| style="text-align:center;"|'''1.416'''
|-
| style="text-align:center;"|'''O6-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O6-C6'''
| style="text-align:center;"|'''1.420'''
|-
|}
 

==== '''Molecule 23''' ====

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 23'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 23 struc.png|600px|center]]'''
|-
| The most outstanding feature from this molecule is the fact that is adopt a puckered form of the square base pyramidal form. This is no surprise that the molecule is almost planar due to the electron delocalization around each side of the salen ligand.

The tery-butyl hydrogen are oriented closely to one another. Non-covalent interaction studies indicated that repulsion would occur for H---H bond length that are less than 2.1 angstrom while favourable interaction may be dominant with bond length above 2.4 angstrom. It was discovered that all 4 hydrogens have bond length more than 2.4 angstrom hence there should not be any significant repulsion between them. Instead, certain amount of attractive force will ensue and that contributes to the overall stability of the molecule

|-
|}
 

=== ''' The calculated NMR properties of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | ''' '''
| width="100" | ''' '''
| width="100" | ''' '''
| width="100" | ''' '''
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Styrene R HNMR.png|200px|center|]]'''
| width="100" | ''' [[File:Styrene S HNMR.png|200px|center|]]'''
| width="100" | ''' [[File:Stilbene RR HNMR.png|200px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|200px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | '''1.00g/100ml, chloroform, 21 degree Celcisus, 589 nm wavelength '''
| width="100" | '''1.02g/100ml (99% ee), chloroform, 25 degree Celsius, 589 nm wavelength '''
| width="100" | '''1.01g/100ml, ethanol, 22 degree Celsius, 589 nm wavelength '''
| width="100" | '''0.6g/100ml, ethanol, 20 degree Celsius, 589 nm wavelength '''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | ''' [[File:Styrene R CNMR.png|200px|center|]]'''
| width="100" | ''' [[File:Styrene S CNMR.png|200px|center|]]'''
| width="100" | ''' [[File:Stilbene RR CNMR.png|200px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|200px|center|]]'''
|-
|}

 

=== ''' Assigning the absolute configuration of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''Predicted ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg'''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg '''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental conditions'''
| width="100" | '''1.00g/100ml, chloroform, 21 degree Celcisus, 589 nm wavelength '''
| width="100" | '''1.02g/100ml (99% ee), chloroform, 25 degree Celsius, 589 nm wavelength '''
| width="100" | '''1.01g/100ml, ethanol, 22 degree Celsius, 589 nm wavelength '''
| width="100" | '''0.6g/100ml, ethanol, 20 degree Celsius, 589 nm wavelength '''
|- align="left"
| width="100" | ''' Predicted VCD Spectrum'''
| width="100" | '''[[File:Styrene R VCD.png|200px|center|]] '''
| width="100" | '''[[File:Styrene S VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene RR VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene SS VCD.png|200px|center|]]'''
|-
|}

 

All the assignments given in the literature reports are correct although the predicted value differs slightly with the experimental values

=== ''' Analysis of the Transition State for Reactions''' ===
==== '''Predicting Enantiomeric Excess based on Transition State energies''' ====

One of the energy output from Gaussian calculation is the “sum of electronic and thermal free energies”. This is Gibbs Free Energy at 298.15K and 1 atm.

Using this term and invoking a variant of the Curtin-Hammett Principle, it is possible to calculate a predicted enantiomeric excess of one enantiomer over the other.

[[File:Ee and transition state energy.png|800px|center]]

Using the derivations from above and equation (4), we analyze the enantiomeric excess of beta-methyl styrene and the results are tabulated as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1343.022970'''
| width="100" | '''-1343.017942'''
| width="150" | '''-0.005028'''
| width="150" | '''4.88E-03'''
| width="150" | '''99.03'''
|- align="center"
| width="100" | '''-1343.019233'''
| width="100" | '''-1343.015603'''
| width="150" | '''-0.003630'''
| width="150" | '''2.14E-02'''
| width="150" | '''95.80'''
|- align="center"
| width="100" | '''-1343.029272'''
| width="100" | '''-1343.023766'''
| width="150" | '''-0.005506'''
| width="150" | '''2.94E-03'''
| width="150" | '''99.41'''
|- align="center"
| width="100" | '''-1343.032443'''
| width="100" | '''-1343.024742'''
| width="150" | '''-0.007701'''
| width="150" | '''2.88E-04'''
| width="150" | '''99.94'''
|-
|}

 

The above hartree units are converted to J/mol for calculation of K where 1 hartress = 4.3597E-18

Studying all the free energies of the (R,R) series and compare them with the (S,S) series, it comes as no surprise that (R,R) product is favoured over (S,S) product as (R,R) is more stable. Indeed, this corresponds with the literature value reporting 92% ee of (R,R) products over that of (S,S).

==== '''Analysis of the Transition State of Epoxidation''' ====
==== '''Shi Fructose Catalyst''' ====
For this section, I will be analyzing the the transition state of 1) styrene and 2) trans-stilbene with the Shi fructose catalyst.

===== '''(R) and (S)-styrene transition state''' =====
The transition state for the formation of (R)-styrene oxide and (S)-styrene oxide are given as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R)-styrene oxide'''
| width="150" | '''(S)-styrene oxide'''
|- align="center"
| width="150" | ''' Structure of Catalyst '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide R.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide S ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| [[File:Steric shi fructose R.png|450px|center]]
| [[File:Steric shi fructose S.png|450px|center]]
|-
|}

 

In the transition state for (R)-styrene, it was discovered that the Re face is reacting with the oxygen of the dioxirane. The phenyl ring is oriented endo with respect to the fructose catalyst. However, the (S)-styrene is reacting at the Si face and the phenyl ring is oriented exo relative to the catalyst.

The approach taken by (R)-styrene and (S)-styrene are restricted to only one due to steric interactions. Therefore, the epoxidation of both styrenes by the Shi catalyst will be stereospecific and retains all the stereochemical information of the reactant. However, whether or not (R)-styrene oxide or (S)-styrene oxide is form is dependent on the relative energies of the transition state. The more stable the transition state, the more likely the product of the transition state will be formed.

So in order to examine this, an example of transition state of both styrenes with Shi catalyst are obtained and analyzed.
 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1303.736813'''
| width="100" | '''-1303.727673'''
| width="150" | '''-0.00914'''
| width="150" | '''6.28E-05'''
| width="150" | '''99.99'''

|-
|}

 

From the above, we can see the predicted high enantiopurity of the reaction favoring the (R) product because of the lower energy of the transition states. To understand the reason, we have to turn to non-covalent interaction (NCI) analysis.

[[File:NCI shi fructose styrene.png|700px|center]]

To complement the NCI analysis, a QTAIM (Quantum Theory of Atoms in Molecules) analysis is conducted as well.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''(R)-styrene transition state'''
| width="200" | '''(S)-styrene transition state'''
|- align="center"
| width="100" | '''[[File:QTAIM R.png|400px|center]]'''
| width="100" | '''[[File:QTAIM S.png|400px|center]]'''
|- align="center"
| colspan="2" width="100" | '''Comments'''
|-
| colspan="2" width="100" | '''Unsurprisingly, QTAIM analysis has also shown that (R)-styrene/Shi catalyst has more interactions with one another. While (R)-styrene has 2 strong interactions, (S)-styrene has only one with the catalyst. Besides, the phenyl ring of (R)-styrene also confers additional positive interaction with the catalyst. QTAIM analysis has also show several interactions between the C=C geminal hydrogen of (R)-styrene intreacting with the oxygen atoms on the dioxacyclopentane ring'''
|-
|}

 

===== '''(R,R) and (S,S)-Stilbene transition state''' =====

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R,R)-Stilbene oxide'''
| width="150" | '''(S,S)-Stilbene oxide'''
|- align="center"
| width="150" | ''' Structure of Transition State '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Stilbene RR ts.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>SS stilbene oxide ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| colspan="2" | [[File:Shi fructose stilbene.png|700px|center]]

|-
|}

 

However, unlike styrene, trans-stilbene seems to approach perpendicularly to the dioxirane. This is proposed to be due to the steric interactions (marked in purple). Based on first inspection, it seems that (S,S)-Stilbene oxide has more steric interactions than (R,R)-Stilbene oxide. Although unsubstantial, it seems like my guess was correct. The (R,R)-stilbene/Shi catalyst transition state is lower in energy.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1534.687808'''
| width="100" | '''-1534.683440'''
| width="150" | '''0.004368'''
| width="150" | '''9.08E-3'''
| width="150" | '''98.20'''

|-
|}

 

NCI Analysis is also done for trans-stilbene

[[File:NCI stilbene.png|700px|center]]

==== '''Jacobsen Catalyst''' ====

For this section, cis-beta methyl styrene transition state will be analyzed.

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-3383.259559'''
| width="100" | '''-3383.251060'''
| width="150" | '''-0.008499'''
| width="150" | '''1.24E-04'''
| width="150" | '''99.98'''
|- align="center"
| width="100" | '''-3383.253442'''
| width="100" | '''-3383.250270'''
| width="150" | '''-0.003172'''
| width="150" | '''3.48E-02'''
| width="150" | '''93.27'''
|-
|}

 

As is obvious from here, the (S,R) transition state is more stable than the (R,S) transition state. Both transition states are exo with respect to the catalyst.

It is not immediately apparent just by looking at the molecule to determine which spatial groups have interactions with one another. Therefore, an NCI analysis is conducted again.

[[File:NCI Jacobsen.png|700px|center]]

File:Stilbene SS HNMR.png

2013-11-21T22:26:00Z

Xc2611: uploaded a new version of "File:Stilbene SS HNMR.png"

File:Stilbene RR CNMR.png

2013-11-21T22:26:00Z

Xc2611:

File:Styrene S CNMR.png

2013-11-21T22:25:57Z

Xc2611:

File:Styrene R CNMR.png

2013-11-21T22:25:47Z

Xc2611:

Rep:Mod:Computationalreport1C

2013-11-21T22:23:22Z

Xc2611: /* The calculated NMR properties of the product */

= '''Synthesis and Computational Lab: 1C''' =
== '''Part 1: Introduction to Molecular Mechanics''' ==
=== '''Introduction to MMFF94 and MMFF94s''' ===

With the improvement of computational data and computer processing power, the usage of molecular mechanics/dynamics forcefield has become very integrated in predicting properties of chemical molecules. A molecular mechanics/dynamics forcefield should be able to predict characteristics such as molecular geometries, conformational/stereoisomeric energies, vibrational frequencies etc. to a reasonable accuracy as compared to experimental-derived values.

Building on work from Kollman et al. s’ AMBER forcefield and Allinger et al. s’ MM1, MM2, MM3 and MM4, Merck Research Laboratories have managed to optimized and improved the previous computational algorithms and produced MMFF94 (Merck Molecular Force Field 94). One of the most prominent advantages of MMFF94 over other preceeding work is its enhanced prediction accuracy. The reason lies in the fact that MMFF94’s core parameterization utilizes an unprecedently large amount of computational data obtained from ab initio calculations1.

Subsequently after the development of MMFF94, a new “static” variant of the MMFF was introduced i.e. the MMFF94s. Unlike MMFF94 that was developed for the use of molecular dynamics simulations (which can be expensive), MMFF94s was developed with the purpose of energy minimization studies in mind. Although both systems provide identical results for most systems, they differ for amides and unsaturated amines which contain resonance-delocalized trigonal nitrogen atoms2.

In this computational exercise, MMFF94s is used predominantly as oppose to the alternative Universal Force Field (UFF). Although versatile across the entire periodic table, UFF is derived from simple rules and atomic parameters such as fixed hybridization that increases the likelihood of erroneous structural and energetic predictions3.

=== '''Forms of MMFF94s''' ===

Steric energy of a molecule is the energy arise due to its geometry or conformation. Energy minimization of steric energy process ensures that the molecule is in its lowest energy conformation.

MMFF94s assumes that the total steric energy of a molecule can be found by the sum of a few specific interactions in a molecule.

ES = EBS + EAB + E SB + ET + EOOP + EVdW + EEE

'''where the bonded interactions are:'''

ES = Total Steric energy

EBS = Total Bond Stretching energy

EAB = Total Angle Bending energy

ESB = Total Stretch Bending energy

ET = Total Torsional Energy

EOOP = Total Out-Of-Plane Bending energy, and

'''where the non-bonded interactions are:'''

EVdW = Total Van der Waals Energy

EEE = Total Electrostatic Energy

{| border="1" cellspacing="1" cellpadding="10"
|-
| width="300" align="center" | '''Types of Energies'''
! width="600" align="center" | '''Explanation'''
|-
| colspan="2" style="text-align: center;" | '''Bonded Interactions'''
|-
| width="300" align="center" | '''Total Bond Stretching Energy'''
! width="600" align="left" | The total bond stretching energy is related to the vibration energy of the molecules in comparison to the equilibrium bond length. Whenever a bond deviates from the equilibrium bond length, the energy value increases.

MMFF94s uses a quartic function that has the force constant term (relate to bond strength). The quartic function term is superior to the cubic function term (used in MM2) in the sense that it avoid the “cubic stretch catastrophe” where progressive elongation of molecule bond length leads to negative infinity.
|-
| width="300" align="center" | '''Total Angle Bending Energy'''
! width="600" align="left" | Similar to Total Bond Stretching Energy, the total angle bending energy is also related to the vibration energy of the molecules about the equilibrium bond length. However, unlike EBS that measures the bond strength, EAB is associated with the stiffness of the molecules based on the Hookiean potential. Whenever bond angles deviate from the norm during vibration, this energy term increases as well.
|-
| width="300" align="center" | '''Total Stretch-Bending Energy'''
! width="600" align="left" | This energy term takes into account of the energy due to increase in bond length when bond angle between two atoms changes.
|-
| width="300" align="center" | '''Total Torsional Energy'''
! width="600" align="left" | Total torsional energy is the energy required for intermolecular rotation about the bonds. In molecule mechanics, however, this term is often used as a correction that must be added or subtracted to the total energy of the molecule to fit a quantum mechanical calculation about the dihedral angles of bonds.
|-
| width="300" align="center" | '''Total Out-Of-Plane Bending Energy'''
! width="600" align="left" | This energy term refers to the energy needed to deform the dihedral angle (zero degrees) of a planar group of atoms such as carbonyl or amide functional groups.
|-
| colspan="2" style="text-align: center;" | '''Non-Bonded Interactions'''
|-
| width="300" align="center" | '''Total Van der Waals Energy'''
! width="600" align="left" | The total Van der Waals energy term examines the intramolecular interactions such as repulsion or attraction between non-bonded atoms in the molecule. This term is crucial in determining the preferred conformation of the molecule.

MMFF94s employs the novel “Buffered-14-7”. The name is derived from a buffering constant and the 14th and 7th power dependencies of the repulsive and attractive energy in the equation.
|-
| width="300" align="center" | '''Total Electrostatic Energy'''
! width="600" align="left" | The total electrostatic energy functions take into account of the Coulombic potential and partial charge/dipole/atomic point charges interactions within the molecule.
|-

|}

 

== '''Part 2 : Conformational Analysis Using Molecular Mechanics''' ==
=== '''The Hydrogenation of Cyclopentadiene Dimer''' ===

==== '''Endo and exo adduct from the Dimerization of Cyclopentadiene''' ====
Cyclopentadiene will undergo dimerization by Diels-alder reaction to form either an endo or exo adduct.

[[File:XcwDimerization of CP.png|500px|center]]

==== '''Stereoselectivity of Dimerization of Cyclopentadiene''' ====
Although the exo adduct is thermodynamically more stable than the endo adduct, the endo adduct is form preferentially. Using the QST2 method, the transition state of the Diels Alder dimerization was found. It was discovered that due to the secondary orbital interactions in the endo transition state, the endo dimer is formed preferentially (the kinetic product). Hence, it is proven that the Diels Alder dimerization between two cyclopentadiene are kinetically controlled.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Transition State of Dimerization of Cyclopentadiene'''
| '''Imaginary Stretch Frequency (-881.25) of the Endo Transition State (click to animate)'''
| '''Secondary Orbital Interaction (Red overlapping orbitals)'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<uploadedFileContents>EndotsDCPD2.mol
</uploadedFileContents>
</jmolApplet></jmol>
| [[File:Xcwendotsimaginary.gif|300px|center]]
| [[File:XcwSecondary orbital interaction1.jpg|300px|center]]
|-
|}

 

==== '''Asynchronous Bond Formation of Dimerization of Cyclopentadiene''' ====

The initial study of the molecular orbitals of the transition states seemed a bit peculiar. Instead of getting a LUMO with symmetrical orbitals, the calculations showed a HOMO that is asymetric at the carbons where the new sigma bonds will be formed. Running an IRC further, it soon became clear that the asymmetry of the HOMO leads to an asychronous bond formation before leading to the product.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''IRC plot following the Endo Transition State '''
| '''IRC following the Endo Transition State (click to animate)'''
| '''Asymmetry of orbitals at the carbons where the new sigma bonds will be formed'''
|- align="center"
| [[File:XcwendotscyclopentadieneIRC.png|300px|center]]
| [[File:XcwendotsIRC.gif|300px|center]]
| [[File:XcwAsynchronous mo.jpg|300px|center]]
|-
|}

 

==== '''Comparison of Energies between the Endo and Exo adduct of Dicyclopentadiene''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Adduct of Dicyclopentadiene dimerization'''
| '''Exo Adduct of Dicyclopentadiene dimerization'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=19,atomno=1,atomno=2; color green;measure 19 1;measure 19 2;</script>
<uploadedFileContents>XcwEndodimer3.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>Exodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=7,atomno=17; color green;measure 17 7;</script>
<uploadedFileContents>XcwExodimer1.mol</uploadedFileContents>
</jmolApplet></jmol>
|-
|}

 

Using MMFF94s ab initio calculations, the energies for the exo dimer and the endo dimer are derived.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Exodimer'''
| '''55.374'''
| 3.543
| 30.772
| -2.041
| -2.728
| 0.015
| 12.800
| 13.014
|-
| '''Endodimer'''
| '''58.191'''
| 3.468
| 33.187
| -2.082
| -2.950
| 0.023
| 12.360
| 14.186
|-
|}

 

The MMFF94s steric energy (after minimization) for the exo dimer is lower than that of the endo dimer. This is reflected by the large difference for the EEE between the endo dimer and the exo dimer due to unfavourable steric repulsion between the two “arched down” cyclopentene rings.

==== '''Hydrogenation of Dicyclopentadiene''' ====

Hydrogenation of the endo dicyclopentadiene (DCPD) would lead to two potential products: dihydro product 1 and dihydro product 2.

[[File:XcwFormation of Dihydro products.png|500px|center]]

Using MMFF94s, the energy of the two dihydro products are calculated.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Dihydro Product 1'''
| '''50.123'''
| 3.308
| 30.864
| -1.927
| 0.060
| 0.015(2)
| 13.281
| 5.121
|-
| '''Dihydro Product 2'''
| '''41.257'''
| 2.823
| 24.685
| -1.657
| -0.379
| 0.000(2)
| 10.639
| 5.147
|-
| '''Tetrahydro Product'''
| '''39.042'''
| 2.730
| 25.151
| -1.676
| 1.287
| 0.000
| 11.551
| 0.000
|}

 

From the MMFF94s calculation, it can be seen that dihydro product 2 has a lower steric energy than dihydro product 1. Therefore, dihydro product 2 is the thermodynamic product for the hydrogenation of dicylopentadiene. And indeed, this was what was observed by Skala et al.. He observed that the first hydrogenation occur at the norborene part of the molecule (rate of hydrogenation several times faster than that in the cyclopentene ring)6. The first heat of hydrogenation at the norborene is 138.8 kJ/mol while the second hydrogenation at the cyclopentene right is 109.5 kJ/mol6.

From the above results, it is also obvious that tetrahydro product is much more stable than either dihydro product. And yet, studies have shown that the tetrahydro product will only form after prolonged hydrogenation under high temperature. However, subjecting DCPD to high temperature leads to low yield due to cracking of DCPD.

Since thermodynamically it is predicted to form favourably, the fact that it does not could only mean that the hydrogenation of DCPD to tetrahydrodicyclopentadiene (TH-DCPD) is kinetically controlled. Most possibly, the transition state of the hydrogenation of DCPD is highly unstable hence it is unlikely to form.

=== '''Atropisomerism in an Intermediate related to the Synthesis of Taxol''' ===

Atropisomerism is a type of stereoisomerism that is form as a result of hindered rotation about a single bond.

[[File:XcwAtropisomerism example.png|500px|center]]

In the case of the 6,6’-dinitro-2,2’-diphenic acid, rotation about the bonds joining the two substituted phenyl rings would have to overcome large steric interaction between the bulky substituents. The barrier of rotation is high enough for the two conformers to be isolated individually.

In the synthesis of taxol, one of the key intermediates exhibit atropisomerism.

==== '''Atropisomerism in Taxol Synthesis''' ====

For the key intermediate, rotation about the carbon-carbon bonds would lead to two types of atropisomers, each with either the carbonyl group poining upwards or downwards in relative to the bridge.

[[File:XcwIntermediate 9 and Intermediate 10.png|500px|center]]

Once again by using MMFF94s ab initio calculations, the steric energies for the two intermediates are illustrated as below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 9'''
| '''70.571'''
| 7.743
| 28.356
| -0.062
| 0.004
| 0.949
| 33.293
| 0.288
|-
| '''Intermediate 10'''
| '''60.553'''
| 7.599
| 18.838
| -0.139
| 0.199
| 0.844
| 33.269
| -0.056
|-

|}

 

Analyzing the data above, the largest energy difference between Intermediate 9 and Intermediate 10 stems from the EAB which is related to the strain of the ring. Intermediate 9 has an excess of 9.518 kcal/mol EAB as compared to Intermediate 10. This comes as a surprise as intermediate 9 is predicted to be more stable alkene.

The rationale behind the prediction of the stability of intermediate 9 stems from the fact that the through-space distance of the upward-pointing carbonyl oxygen with the carbon-carbon is further than the through space distance between the downward-pointing carbonyl oxygen with the -CH2-CH2- fragment at the norbornene part in intermediate 10.

==== '''Hyperstable Olefins''' ====

Intermediate 9 and Intermediate 10 does not react readily with other reagents during functionalization. This is due to the hyperstability effect found in hyperstable olefins.

Hyperstable olefins are alkenes that contain less strain in the ring (i.e. negative olefin strain values) compared to the parent hydrocarbon. To study this further, further MMFF94s calculation was done to compare Intermediate 10 with the parent hydrocarbon.

[[File:XcwIntermediate10andPH.png|500px|center]]

The energies that we calculated are tabulated as shown below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 10'''
| '''44.878 '''
| 5.211
| 15.488
| -0.267
| -1.655
| 0.998
| 25.014
| 0.088
|-
| '''Parent Hydrocarbon'''
| '''50.564'''
| 4.692
| 21.979
| 0.109
| -0.958
| 0.247
| 24.495
| 0.000
|-

|}

 

Scrutinizing the results, the largest energy difference between intermediate 10 and the parent hydrocarbon stems from the Total Angle Bending Energy, EAB. Since the Total Angle bending energy is related to the angle strain in the molecules, it is apparent that the parent hydrocarbon has more ring strain as compared to the bridgehead olefin.

== '''Part 3 : Spectroscopic Simulation Using Quantum Mechanics''' ==
=== '''Spectroscopy of an Intermediate Related to the Synthesis of Taxol''' ===

Molecule 17 and 18 are derivatives of intermediate 9 and 10. In this exercise, MMFF94s is used to predict the 1H and 13C NMR of molecule 17 and molecule 18.

[[File:XcwIntermediate17&18.png|500px|center]]

==== '''NMR Spectra of Molecule 17''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 17.mol
</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwHNMRMolecule 17 Chair Overall NMR.png|500px|center]]
| [[File:XcwHNMRMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.1825
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| The first three results were fairly straight forward to be deduced and correlate wit experimental data.

The hydrogen atom that is geminally attached to the carbon of the double bonds is the most deshielded due to the ring current anisotropic effect of the ring current

The second most deshielded hydrogen atom is the hydrogen atom on the methyl group on the bridge. The hydrogen atom is pointing directly to the oxygen atom of the carbonyl functional group.

The peaks with an integration height of 4 is assigned to the hydrogen atoms in the 1,3-dithiolane ring fragment.

Subsequent analysis of the 1H NMR became very complicated very quickly for two reasons:

1. Gaussian calculations showed some atoms with an integration height of 3. Comparing their file atom number and checking their chemical environment, it is not possible to find any correlation between them.

2. Some of the peaks in the literature remains unresolved and are given as multiplets or grouped together.

|- align="center"
| 52
| 3.1775
| 1
| '''2.99'''
|- align="center"
| 53,52,50,51
| 3.0867
| 4
| '''3.40-3.10'''
|- align="center"
| 42,43,39
| 2.7445
| 3
| ''' '''
|- align="center"
| 49
| 2.6187
| 1
| ''' '''
|- align="center"
| 34
| 2.4371
| 1
| ''' '''
|- align="center"
| 35
| 2.3782
| 1
| ''' '''
|- align="center"
| 40,37,26
| 2.2730
| 3
| ''' '''
|- align="center"
| 30
| 2.1566
| 1
| ''' '''
|- align="center"
| 36
| 2.1033
| 1
| ''' '''
|- align="center"
| 32,28
| 2.0259
| 2
| ''' '''
|- align="center"
| 25
| 1.8535
| 2
| ''' '''
|- align="center"
| 38,46,27
| 1.5898
| 3
| '''1.25'''
|- align="center"
| 29
| 1.4557
| 1
| ''' '''
|- align="center"
| 31
| 1.0123
| 1
| ''' '''
|- align="center"
| 44,48,45
| 0.9087
| 3
| '''1.10'''
|- align="center"
| 47
| 0.8354
| 1
| ''' '''
|- align="center"
| 33
| 0.5790
| 1
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 17 Chair Overall NMR2.png|500px|center]]
| [[File:XcwMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 216.2725
| 1
| '''218.79'''
| rowspan="10" style="text-align:center;"| [[File:XcwMolecule 17 image for CNMR.jpg|600px|center]]
|- align="center"
| 13
| 144.8626
| 1
| '''144.63'''
|- align="center"
| 14
| 124.7193
| 1
| '''125.33'''
|- align="center"
| 3
| 91.3340
| 1
| '''72.88'''
|- align="center"
| 2
| 60.9568
| 1
| '''56.19'''
|- align="center"
| 1
| 57.0811
| 1
| '''52.52'''
|- align="center"
| 10
| 52.4663
| 1
| '''48.50'''
|- align="center"
| 16
| 51.4857
| 1
| '''46.80'''
|- align="center"
| 9
| 46.9196
| 1
| '''45.76'''
|- align="center"
| 23
| 43.8647
| 1
| '''39.80'''
|- align="center"
| 22
| 41.9450
| 1
| '''38.81'''
| Comments
|- align="center"
| 4
| 41.8724
| 1
| '''35.85'''
| rowspan="9" style="text-align:left;"| The carbon bonded to the oxygen atom is the most deshielded, as is shown in the predicted values and the experimental values. There is a deviation between the values. Quite possibly, this is due to the fact that in reality, the carbonyl functional group is pointing slightly towards the equatorial position rather than a lateral position relative to the ring (as is in the input for Gaussian calculation)

Most of the 1CNMR values that was predicted by Gaussian are all within an acceptable range of deviation. However, there is carbon 3 that has significant deviation between the predicted value and experimental value.

Carbon 3 is the carbon bonded to the two sulphurs in the 1,3-dithiolane ring fragment. Such a huge deviation would possibly mean that the conformer that was given as input to Gaussian differs from the literature.

The above NMR spectra was corrected with a level of theory B3LYP/6-31G(d,p) using TMS as reference and in chloroform.

|- align="center"
| 15
| 35.4348
| 1
| '''32.66'''
|- align="center"
| 11
| 31.1964
| 1
| '''28.79'''
|- align="center"
| 6
| 28.9432
| 1
| '''28.29'''
|- align="center"
| 7
| 28.3640
| 1
| '''26.88'''
|- align="center"
| 12
| 27.3767
| 1
| '''25.66'''
|- align="center"
| 17
| 26.3311
| 1
| '''23.86'''
|- align="center"
| 15
| 24.5483
| 1
| '''20.96'''
|- align="center"
| 18
| 19.7788
| 1
| '''18.71'''
|-
|}
 

==== '''NMR Spectra of Molecule 18''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 18 Boat for Image2.mol</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"-
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 18 Chair Overall NMR.png|500px|center]]
| [[File:Molecule 18 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.2832
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| ''' '''
|- align="center"
| 50
| 3.3175
| 1
| rowspan="4" style="text-align:centre;"| '''3.00-2.70'''
|- align="center"
| 52
| 3.2153
| 1
|- align="center"
| 51,53
| 3.1161
| 2
|- align="center"
| 34,43
| 2.8606
| 2
|- align="center"
| 38
| 2.4549
| 1
| ''' '''
|- align="center"
| 42
| 2.3968
| 1
| ''' '''
|- align="center"
| 25,29,26
| 2.2796
| 3
| ''' '''
|- align="center"
| 39
| 2.0844
| 1
| ''' '''
|- align="center"
| 40,36
| 1.9699
| 2
| ''' '''
|- align="center"
| 37,24
| 1.8519
| 2
| ''' '''
|- align="center"
| 31,27
| 1.6780
| 2
| ''' '''
|- align="center"
| 28
| 1.6175
| 1
| ''' '''
|- align="center"
| 46,49
| 1.4979
| 2
| ''' '''
|- align="center"
| 35
| 1.4150
| 1
| ''' '''
|- align="center"
| 32
| 1.3531
| 1
| ''' '''
|- align="center"
| 48
| 1.1606
| 1
| ''' '''
|- align="center"
| 33,30,47
| 1.0653
| 3
| '''1.03'''
|- align="center"
| 44,45
| 0.9643
| 2
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwMolecule 18 Boat Overall NMR.png|500px|center]]
| [[File:XcwMolecule 18 Boat zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 211.8325
| 1
| '''211.49'''
| rowspan="10" style="text-align:center;"| [[File:Molecule 18 Boat for 13 CNMR.jpg|600px|center]]
|- align="center"
| 13
| 148.6673
| 1
| '''148.72'''
|- align="center"
| 14
| 118.8373
| 1
| '''120.90'''
|- align="center"
| 3
| 89.0869
| 1
| '''74.61'''
|- align="center"
| 2
| 67.8886
| 1
| '''60.53'''
|- align="center"
| 1
| 56.1133
| 1
| '''51.30'''
|- align="center"
| 10
| 55.5998
| 1
| '''50.94'''
|- align="center"
| 16
| 50.1124
| 1
| '''45.53'''
|- align="center"
| 22
| 48.2030
| 1
| '''43.28'''
|- align="center"
| 23
| 44.2222
| 1
| '''40.82'''
|- align="center"
| 4
| 42.0354
| 1
| '''38.73'''
| Comments
|- align="center"
| 9
| 37.5865
| 1
| '''36.78'''
| rowspan="9" style="text-align:left;"| ''' '''
|- align="center"
| 6
| 35.3106
| 1
| '''35.47'''
|- align="center"
| 15
| 31.0459
| 1
| '''30.84'''
|- align="center"
| 7
| 28.8476
| 1
| '''30.00'''
|- align="center"
| 12
| 28.6623
| 1
| '''25.56'''
|- align="center"
| 17
| 25.7393
| 1
| '''25.35'''
|- align="center"
| 11
| 25.2603
| 1
| '''22.21'''
|- align="center"
| 18
| 23.3944
| 1
| '''21.39'''
|- align="center"
| 5
| 21.0478
| 1
| '''19.83'''
|-
|}
 

== '''Part 4 : Analysis of the Properties of the Synthesized Alkene Epoxides''' ==
=== '''The two catalytics systems''' ===

Assymmetric epoxidation of prochiral alkenes may lead to product with different stereochemical outcome as illustrated as below. To solve this problem, different types of asymmetric epoxidation catalyst have been synthesized. In this study, we shall be focusing on Shi asymmetric fructose catalyst as well as Jacobsen asymmetric catalyst.

[[File:Asymmetric catalyst.png|400px|center]]

==== ''' The Shi Asymmetric Fructose Catalyst''' ====

Molecule 21 is the stable precursor of molecule 22, the active catalyst. Molecule 21 can be converted to molecule 22 by using either persulfuric acid or potassium peroxymonosulphate.

[[File:Molecule 21 to 23.png|400px|center]]

The transition state of the Shi epoxidation was a subject of debate for a few moments. However, recent studies have led to the conclusion that the spiro transition state is more favored than the planar transition state. The spiro transition state is the transition that has its dioxirane perpendicularly bisecting the alkene double bond. This is thought to be more favourable due to interactions between the lone pairs of the oxygen with the LUMO of the alkene.

[[File:Spiro and planar ts.png|500px|center]]

==== ''' The Jacobsen Asymmetric Catalyst''' ====

Molecule 23 is the stable precursor of molecule 24, the active catalyst. Molecule 23 can be converted to molecule 24 by using sodium perchlorate.

[[File:Salen, 23 and 24.png|400px|center]]

Jacobsen catalyst is biphasic. The first phase involves the transfer of oxygen to molecule 23. Sodium perchlorate oxidizes Mn(III) to Mn(V).

In the second step, Jacobsen catalyst acts via a radical mechanism. It is thought to be so because epoxidation of trans-alkene by Jacobsen catalyst yield cis-alkene as well. A radical mechanism will lead to the lost of stereochemical information of the molecule.

=== ''' Crystal structure of the two catalyst''' ===
==== '''Molecule 21''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 21'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 21 strucutre.png|600px|center]]'''
|-
| style="text-align:center;" width="150" | ''' Bond '''
| style="text-align:center;" width="150"| ''' Bond Lenghts (Angstrom)'''
| style="text-align:center;" | ''' Evaluation'''
|-
| style="text-align:center;"| ''' O1-C1 '''
| style="text-align:center;"| ''' 1.400'''
| rowspan="10" style="text-align:left;"| [[File:Molecule 21 2.png|300px|center]]

The normal bond length of an C-O bond is 1.430 angstrom.

The most interesting aspect here is O4 and O2. The lone pair of O4 is antiperplanar to the sigma* orbital of the carbonyl group while the lone pair of O2 is anti periplanar to the carbonyl pi* orbital. Donation of electron can occur because of the correct symmetry. Due to the mixing of the orbitals, the C2-O2 and C4-O4 has been conferred with a certain degree of double bond character.

However, due to the lone pair on oxygen being now donated to the carbonyl antibonding orbitals, the O2 and O4 is slightly “electron deficient” and electron density will be pulled away from O2 and O4. That would explain why the bond length increase for O2-C7 and O4-C10. Increase in bond length is an indicator of the weakening of the bond.
|-
| style="text-align:center;"|'''O1-C7'''
| style="text-align:center;"|'''1.413'''
|-
| style="text-align:center;"|'''O2-C7'''
| style="text-align:center;"|'''1.441'''
|-
| style="text-align:center;"|'''O2-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O4-C4'''
| style="text-align:center;"|'''1.396'''
|-
| style="text-align:center;"|'''O4-C10'''
| style="text-align:center;"|'''1.439'''
|-
| style="text-align:center;"|'''O5-C10'''
| style="text-align:center;"|'''1.409'''
|-
| style="text-align:center;"|'''O5-C5'''
| style="text-align:center;"|'''1.416'''
|-
| style="text-align:center;"|'''O6-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O6-C6'''
| style="text-align:center;"|'''1.420'''
|-
|}
 

==== '''Molecule 23''' ====

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 23'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 23 struc.png|600px|center]]'''
|-
| The most outstanding feature from this molecule is the fact that is adopt a puckered form of the square base pyramidal form. This is no surprise that the molecule is almost planar due to the electron delocalization around each side of the salen ligand.

The tery-butyl hydrogen are oriented closely to one another. Non-covalent interaction studies indicated that repulsion would occur for H---H bond length that are less than 2.1 angstrom while favourable interaction may be dominant with bond length above 2.4 angstrom. It was discovered that all 4 hydrogens have bond length more than 2.4 angstrom hence there should not be any significant repulsion between them. Instead, certain amount of attractive force will ensue and that contributes to the overall stability of the molecule

|-
|}
 

=== ''' The calculated NMR properties of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''1H NMR data'''
| width="100" | ''' '''
| width="100" | ''' '''
| width="100" | ''' '''
| width="100" | ''' '''
|- align="left"
| width="100" | '''1H NMR Spectra'''
| width="100" | ''' [[File:Styrene R HNMR.png|200px|center|]]'''
| width="100" | ''' [[File:Styrene S HNMR.png|200px|center|]]'''
| width="100" | ''' [[File:Stilbene RR HNMR.png|200px|center|]]'''
| width="100" | ''' [[File:Stilbene SS HNMR.png|200px|center|]]'''
|- align="left"
| width="100" | '''13C NMR data'''
| width="100" | '''1.00g/100ml, chloroform, 21 degree Celcisus, 589 nm wavelength '''
| width="100" | '''1.02g/100ml (99% ee), chloroform, 25 degree Celsius, 589 nm wavelength '''
| width="100" | '''1.01g/100ml, ethanol, 22 degree Celsius, 589 nm wavelength '''
| width="100" | '''0.6g/100ml, ethanol, 20 degree Celsius, 589 nm wavelength '''
|- align="left"
| width="100" | '''13C NMR Spectra'''
| width="100" | '''[[File:Styrene R VCD.png|200px|center|]] '''
| width="100" | '''[[File:Styrene S VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene RR VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene SS VCD.png|200px|center|]]'''
|-
|}

 

=== ''' Assigning the absolute configuration of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''Predicted ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg'''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg '''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental conditions'''
| width="100" | '''1.00g/100ml, chloroform, 21 degree Celcisus, 589 nm wavelength '''
| width="100" | '''1.02g/100ml (99% ee), chloroform, 25 degree Celsius, 589 nm wavelength '''
| width="100" | '''1.01g/100ml, ethanol, 22 degree Celsius, 589 nm wavelength '''
| width="100" | '''0.6g/100ml, ethanol, 20 degree Celsius, 589 nm wavelength '''
|- align="left"
| width="100" | ''' Predicted VCD Spectrum'''
| width="100" | '''[[File:Styrene R VCD.png|200px|center|]] '''
| width="100" | '''[[File:Styrene S VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene RR VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene SS VCD.png|200px|center|]]'''
|-
|}

 

All the assignments given in the literature reports are correct although the predicted value differs slightly with the experimental values

=== ''' Analysis of the Transition State for Reactions''' ===
==== '''Predicting Enantiomeric Excess based on Transition State energies''' ====

One of the energy output from Gaussian calculation is the “sum of electronic and thermal free energies”. This is Gibbs Free Energy at 298.15K and 1 atm.

Using this term and invoking a variant of the Curtin-Hammett Principle, it is possible to calculate a predicted enantiomeric excess of one enantiomer over the other.

[[File:Ee and transition state energy.png|800px|center]]

Using the derivations from above and equation (4), we analyze the enantiomeric excess of beta-methyl styrene and the results are tabulated as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1343.022970'''
| width="100" | '''-1343.017942'''
| width="150" | '''-0.005028'''
| width="150" | '''4.88E-03'''
| width="150" | '''99.03'''
|- align="center"
| width="100" | '''-1343.019233'''
| width="100" | '''-1343.015603'''
| width="150" | '''-0.003630'''
| width="150" | '''2.14E-02'''
| width="150" | '''95.80'''
|- align="center"
| width="100" | '''-1343.029272'''
| width="100" | '''-1343.023766'''
| width="150" | '''-0.005506'''
| width="150" | '''2.94E-03'''
| width="150" | '''99.41'''
|- align="center"
| width="100" | '''-1343.032443'''
| width="100" | '''-1343.024742'''
| width="150" | '''-0.007701'''
| width="150" | '''2.88E-04'''
| width="150" | '''99.94'''
|-
|}

 

The above hartree units are converted to J/mol for calculation of K where 1 hartress = 4.3597E-18

Studying all the free energies of the (R,R) series and compare them with the (S,S) series, it comes as no surprise that (R,R) product is favoured over (S,S) product as (R,R) is more stable. Indeed, this corresponds with the literature value reporting 92% ee of (R,R) products over that of (S,S).

==== '''Analysis of the Transition State of Epoxidation''' ====
==== '''Shi Fructose Catalyst''' ====
For this section, I will be analyzing the the transition state of 1) styrene and 2) trans-stilbene with the Shi fructose catalyst.

===== '''(R) and (S)-styrene transition state''' =====
The transition state for the formation of (R)-styrene oxide and (S)-styrene oxide are given as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R)-styrene oxide'''
| width="150" | '''(S)-styrene oxide'''
|- align="center"
| width="150" | ''' Structure of Catalyst '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide R.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide S ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| [[File:Steric shi fructose R.png|450px|center]]
| [[File:Steric shi fructose S.png|450px|center]]
|-
|}

 

In the transition state for (R)-styrene, it was discovered that the Re face is reacting with the oxygen of the dioxirane. The phenyl ring is oriented endo with respect to the fructose catalyst. However, the (S)-styrene is reacting at the Si face and the phenyl ring is oriented exo relative to the catalyst.

The approach taken by (R)-styrene and (S)-styrene are restricted to only one due to steric interactions. Therefore, the epoxidation of both styrenes by the Shi catalyst will be stereospecific and retains all the stereochemical information of the reactant. However, whether or not (R)-styrene oxide or (S)-styrene oxide is form is dependent on the relative energies of the transition state. The more stable the transition state, the more likely the product of the transition state will be formed.

So in order to examine this, an example of transition state of both styrenes with Shi catalyst are obtained and analyzed.
 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1303.736813'''
| width="100" | '''-1303.727673'''
| width="150" | '''-0.00914'''
| width="150" | '''6.28E-05'''
| width="150" | '''99.99'''

|-
|}

 

From the above, we can see the predicted high enantiopurity of the reaction favoring the (R) product because of the lower energy of the transition states. To understand the reason, we have to turn to non-covalent interaction (NCI) analysis.

[[File:NCI shi fructose styrene.png|700px|center]]

To complement the NCI analysis, a QTAIM (Quantum Theory of Atoms in Molecules) analysis is conducted as well.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''(R)-styrene transition state'''
| width="200" | '''(S)-styrene transition state'''
|- align="center"
| width="100" | '''[[File:QTAIM R.png|400px|center]]'''
| width="100" | '''[[File:QTAIM S.png|400px|center]]'''
|- align="center"
| colspan="2" width="100" | '''Comments'''
|-
| colspan="2" width="100" | '''Unsurprisingly, QTAIM analysis has also shown that (R)-styrene/Shi catalyst has more interactions with one another. While (R)-styrene has 2 strong interactions, (S)-styrene has only one with the catalyst. Besides, the phenyl ring of (R)-styrene also confers additional positive interaction with the catalyst. QTAIM analysis has also show several interactions between the C=C geminal hydrogen of (R)-styrene intreacting with the oxygen atoms on the dioxacyclopentane ring'''
|-
|}

 

===== '''(R,R) and (S,S)-Stilbene transition state''' =====

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R,R)-Stilbene oxide'''
| width="150" | '''(S,S)-Stilbene oxide'''
|- align="center"
| width="150" | ''' Structure of Transition State '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Stilbene RR ts.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>SS stilbene oxide ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| colspan="2" | [[File:Shi fructose stilbene.png|700px|center]]

|-
|}

 

However, unlike styrene, trans-stilbene seems to approach perpendicularly to the dioxirane. This is proposed to be due to the steric interactions (marked in purple). Based on first inspection, it seems that (S,S)-Stilbene oxide has more steric interactions than (R,R)-Stilbene oxide. Although unsubstantial, it seems like my guess was correct. The (R,R)-stilbene/Shi catalyst transition state is lower in energy.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1534.687808'''
| width="100" | '''-1534.683440'''
| width="150" | '''0.004368'''
| width="150" | '''9.08E-3'''
| width="150" | '''98.20'''

|-
|}

 

NCI Analysis is also done for trans-stilbene

[[File:NCI stilbene.png|700px|center]]

==== '''Jacobsen Catalyst''' ====

For this section, cis-beta methyl styrene transition state will be analyzed.

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-3383.259559'''
| width="100" | '''-3383.251060'''
| width="150" | '''-0.008499'''
| width="150" | '''1.24E-04'''
| width="150" | '''99.98'''
|- align="center"
| width="100" | '''-3383.253442'''
| width="100" | '''-3383.250270'''
| width="150" | '''-0.003172'''
| width="150" | '''3.48E-02'''
| width="150" | '''93.27'''
|-
|}

 

As is obvious from here, the (S,R) transition state is more stable than the (R,S) transition state. Both transition states are exo with respect to the catalyst.

It is not immediately apparent just by looking at the molecule to determine which spatial groups have interactions with one another. Therefore, an NCI analysis is conducted again.

[[File:NCI Jacobsen.png|700px|center]]

File:Stilbene SS HNMR.png

2013-11-21T22:22:21Z

Xc2611:

File:Stilbene RR HNMR.png

2013-11-21T22:22:17Z

Xc2611:

File:Styrene S HNMR.png

2013-11-21T22:22:16Z

Xc2611:

File:Styrene R HNMR.png

2013-11-21T22:22:04Z

Xc2611:

Rep:Mod:Computationalreport1C

2013-11-21T21:52:32Z

Xc2611: /* Assigning the absolute configuration of the product */

= '''Synthesis and Computational Lab: 1C''' =
== '''Part 1: Introduction to Molecular Mechanics''' ==
=== '''Introduction to MMFF94 and MMFF94s''' ===

With the improvement of computational data and computer processing power, the usage of molecular mechanics/dynamics forcefield has become very integrated in predicting properties of chemical molecules. A molecular mechanics/dynamics forcefield should be able to predict characteristics such as molecular geometries, conformational/stereoisomeric energies, vibrational frequencies etc. to a reasonable accuracy as compared to experimental-derived values.

Building on work from Kollman et al. s’ AMBER forcefield and Allinger et al. s’ MM1, MM2, MM3 and MM4, Merck Research Laboratories have managed to optimized and improved the previous computational algorithms and produced MMFF94 (Merck Molecular Force Field 94). One of the most prominent advantages of MMFF94 over other preceeding work is its enhanced prediction accuracy. The reason lies in the fact that MMFF94’s core parameterization utilizes an unprecedently large amount of computational data obtained from ab initio calculations1.

Subsequently after the development of MMFF94, a new “static” variant of the MMFF was introduced i.e. the MMFF94s. Unlike MMFF94 that was developed for the use of molecular dynamics simulations (which can be expensive), MMFF94s was developed with the purpose of energy minimization studies in mind. Although both systems provide identical results for most systems, they differ for amides and unsaturated amines which contain resonance-delocalized trigonal nitrogen atoms2.

In this computational exercise, MMFF94s is used predominantly as oppose to the alternative Universal Force Field (UFF). Although versatile across the entire periodic table, UFF is derived from simple rules and atomic parameters such as fixed hybridization that increases the likelihood of erroneous structural and energetic predictions3.

=== '''Forms of MMFF94s''' ===

Steric energy of a molecule is the energy arise due to its geometry or conformation. Energy minimization of steric energy process ensures that the molecule is in its lowest energy conformation.

MMFF94s assumes that the total steric energy of a molecule can be found by the sum of a few specific interactions in a molecule.

ES = EBS + EAB + E SB + ET + EOOP + EVdW + EEE

'''where the bonded interactions are:'''

ES = Total Steric energy

EBS = Total Bond Stretching energy

EAB = Total Angle Bending energy

ESB = Total Stretch Bending energy

ET = Total Torsional Energy

EOOP = Total Out-Of-Plane Bending energy, and

'''where the non-bonded interactions are:'''

EVdW = Total Van der Waals Energy

EEE = Total Electrostatic Energy

{| border="1" cellspacing="1" cellpadding="10"
|-
| width="300" align="center" | '''Types of Energies'''
! width="600" align="center" | '''Explanation'''
|-
| colspan="2" style="text-align: center;" | '''Bonded Interactions'''
|-
| width="300" align="center" | '''Total Bond Stretching Energy'''
! width="600" align="left" | The total bond stretching energy is related to the vibration energy of the molecules in comparison to the equilibrium bond length. Whenever a bond deviates from the equilibrium bond length, the energy value increases.

MMFF94s uses a quartic function that has the force constant term (relate to bond strength). The quartic function term is superior to the cubic function term (used in MM2) in the sense that it avoid the “cubic stretch catastrophe” where progressive elongation of molecule bond length leads to negative infinity.
|-
| width="300" align="center" | '''Total Angle Bending Energy'''
! width="600" align="left" | Similar to Total Bond Stretching Energy, the total angle bending energy is also related to the vibration energy of the molecules about the equilibrium bond length. However, unlike EBS that measures the bond strength, EAB is associated with the stiffness of the molecules based on the Hookiean potential. Whenever bond angles deviate from the norm during vibration, this energy term increases as well.
|-
| width="300" align="center" | '''Total Stretch-Bending Energy'''
! width="600" align="left" | This energy term takes into account of the energy due to increase in bond length when bond angle between two atoms changes.
|-
| width="300" align="center" | '''Total Torsional Energy'''
! width="600" align="left" | Total torsional energy is the energy required for intermolecular rotation about the bonds. In molecule mechanics, however, this term is often used as a correction that must be added or subtracted to the total energy of the molecule to fit a quantum mechanical calculation about the dihedral angles of bonds.
|-
| width="300" align="center" | '''Total Out-Of-Plane Bending Energy'''
! width="600" align="left" | This energy term refers to the energy needed to deform the dihedral angle (zero degrees) of a planar group of atoms such as carbonyl or amide functional groups.
|-
| colspan="2" style="text-align: center;" | '''Non-Bonded Interactions'''
|-
| width="300" align="center" | '''Total Van der Waals Energy'''
! width="600" align="left" | The total Van der Waals energy term examines the intramolecular interactions such as repulsion or attraction between non-bonded atoms in the molecule. This term is crucial in determining the preferred conformation of the molecule.

MMFF94s employs the novel “Buffered-14-7”. The name is derived from a buffering constant and the 14th and 7th power dependencies of the repulsive and attractive energy in the equation.
|-
| width="300" align="center" | '''Total Electrostatic Energy'''
! width="600" align="left" | The total electrostatic energy functions take into account of the Coulombic potential and partial charge/dipole/atomic point charges interactions within the molecule.
|-

|}

 

== '''Part 2 : Conformational Analysis Using Molecular Mechanics''' ==
=== '''The Hydrogenation of Cyclopentadiene Dimer''' ===

==== '''Endo and exo adduct from the Dimerization of Cyclopentadiene''' ====
Cyclopentadiene will undergo dimerization by Diels-alder reaction to form either an endo or exo adduct.

[[File:XcwDimerization of CP.png|500px|center]]

==== '''Stereoselectivity of Dimerization of Cyclopentadiene''' ====
Although the exo adduct is thermodynamically more stable than the endo adduct, the endo adduct is form preferentially. Using the QST2 method, the transition state of the Diels Alder dimerization was found. It was discovered that due to the secondary orbital interactions in the endo transition state, the endo dimer is formed preferentially (the kinetic product). Hence, it is proven that the Diels Alder dimerization between two cyclopentadiene are kinetically controlled.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Transition State of Dimerization of Cyclopentadiene'''
| '''Imaginary Stretch Frequency (-881.25) of the Endo Transition State (click to animate)'''
| '''Secondary Orbital Interaction (Red overlapping orbitals)'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<uploadedFileContents>EndotsDCPD2.mol
</uploadedFileContents>
</jmolApplet></jmol>
| [[File:Xcwendotsimaginary.gif|300px|center]]
| [[File:XcwSecondary orbital interaction1.jpg|300px|center]]
|-
|}

 

==== '''Asynchronous Bond Formation of Dimerization of Cyclopentadiene''' ====

The initial study of the molecular orbitals of the transition states seemed a bit peculiar. Instead of getting a LUMO with symmetrical orbitals, the calculations showed a HOMO that is asymetric at the carbons where the new sigma bonds will be formed. Running an IRC further, it soon became clear that the asymmetry of the HOMO leads to an asychronous bond formation before leading to the product.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''IRC plot following the Endo Transition State '''
| '''IRC following the Endo Transition State (click to animate)'''
| '''Asymmetry of orbitals at the carbons where the new sigma bonds will be formed'''
|- align="center"
| [[File:XcwendotscyclopentadieneIRC.png|300px|center]]
| [[File:XcwendotsIRC.gif|300px|center]]
| [[File:XcwAsynchronous mo.jpg|300px|center]]
|-
|}

 

==== '''Comparison of Energies between the Endo and Exo adduct of Dicyclopentadiene''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Adduct of Dicyclopentadiene dimerization'''
| '''Exo Adduct of Dicyclopentadiene dimerization'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=19,atomno=1,atomno=2; color green;measure 19 1;measure 19 2;</script>
<uploadedFileContents>XcwEndodimer3.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>Exodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=7,atomno=17; color green;measure 17 7;</script>
<uploadedFileContents>XcwExodimer1.mol</uploadedFileContents>
</jmolApplet></jmol>
|-
|}

 

Using MMFF94s ab initio calculations, the energies for the exo dimer and the endo dimer are derived.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Exodimer'''
| '''55.374'''
| 3.543
| 30.772
| -2.041
| -2.728
| 0.015
| 12.800
| 13.014
|-
| '''Endodimer'''
| '''58.191'''
| 3.468
| 33.187
| -2.082
| -2.950
| 0.023
| 12.360
| 14.186
|-
|}

 

The MMFF94s steric energy (after minimization) for the exo dimer is lower than that of the endo dimer. This is reflected by the large difference for the EEE between the endo dimer and the exo dimer due to unfavourable steric repulsion between the two “arched down” cyclopentene rings.

==== '''Hydrogenation of Dicyclopentadiene''' ====

Hydrogenation of the endo dicyclopentadiene (DCPD) would lead to two potential products: dihydro product 1 and dihydro product 2.

[[File:XcwFormation of Dihydro products.png|500px|center]]

Using MMFF94s, the energy of the two dihydro products are calculated.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Dihydro Product 1'''
| '''50.123'''
| 3.308
| 30.864
| -1.927
| 0.060
| 0.015(2)
| 13.281
| 5.121
|-
| '''Dihydro Product 2'''
| '''41.257'''
| 2.823
| 24.685
| -1.657
| -0.379
| 0.000(2)
| 10.639
| 5.147
|-
| '''Tetrahydro Product'''
| '''39.042'''
| 2.730
| 25.151
| -1.676
| 1.287
| 0.000
| 11.551
| 0.000
|}

 

From the MMFF94s calculation, it can be seen that dihydro product 2 has a lower steric energy than dihydro product 1. Therefore, dihydro product 2 is the thermodynamic product for the hydrogenation of dicylopentadiene. And indeed, this was what was observed by Skala et al.. He observed that the first hydrogenation occur at the norborene part of the molecule (rate of hydrogenation several times faster than that in the cyclopentene ring)6. The first heat of hydrogenation at the norborene is 138.8 kJ/mol while the second hydrogenation at the cyclopentene right is 109.5 kJ/mol6.

From the above results, it is also obvious that tetrahydro product is much more stable than either dihydro product. And yet, studies have shown that the tetrahydro product will only form after prolonged hydrogenation under high temperature. However, subjecting DCPD to high temperature leads to low yield due to cracking of DCPD.

Since thermodynamically it is predicted to form favourably, the fact that it does not could only mean that the hydrogenation of DCPD to tetrahydrodicyclopentadiene (TH-DCPD) is kinetically controlled. Most possibly, the transition state of the hydrogenation of DCPD is highly unstable hence it is unlikely to form.

=== '''Atropisomerism in an Intermediate related to the Synthesis of Taxol''' ===

Atropisomerism is a type of stereoisomerism that is form as a result of hindered rotation about a single bond.

[[File:XcwAtropisomerism example.png|500px|center]]

In the case of the 6,6’-dinitro-2,2’-diphenic acid, rotation about the bonds joining the two substituted phenyl rings would have to overcome large steric interaction between the bulky substituents. The barrier of rotation is high enough for the two conformers to be isolated individually.

In the synthesis of taxol, one of the key intermediates exhibit atropisomerism.

==== '''Atropisomerism in Taxol Synthesis''' ====

For the key intermediate, rotation about the carbon-carbon bonds would lead to two types of atropisomers, each with either the carbonyl group poining upwards or downwards in relative to the bridge.

[[File:XcwIntermediate 9 and Intermediate 10.png|500px|center]]

Once again by using MMFF94s ab initio calculations, the steric energies for the two intermediates are illustrated as below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 9'''
| '''70.571'''
| 7.743
| 28.356
| -0.062
| 0.004
| 0.949
| 33.293
| 0.288
|-
| '''Intermediate 10'''
| '''60.553'''
| 7.599
| 18.838
| -0.139
| 0.199
| 0.844
| 33.269
| -0.056
|-

|}

 

Analyzing the data above, the largest energy difference between Intermediate 9 and Intermediate 10 stems from the EAB which is related to the strain of the ring. Intermediate 9 has an excess of 9.518 kcal/mol EAB as compared to Intermediate 10. This comes as a surprise as intermediate 9 is predicted to be more stable alkene.

The rationale behind the prediction of the stability of intermediate 9 stems from the fact that the through-space distance of the upward-pointing carbonyl oxygen with the carbon-carbon is further than the through space distance between the downward-pointing carbonyl oxygen with the -CH2-CH2- fragment at the norbornene part in intermediate 10.

==== '''Hyperstable Olefins''' ====

Intermediate 9 and Intermediate 10 does not react readily with other reagents during functionalization. This is due to the hyperstability effect found in hyperstable olefins.

Hyperstable olefins are alkenes that contain less strain in the ring (i.e. negative olefin strain values) compared to the parent hydrocarbon. To study this further, further MMFF94s calculation was done to compare Intermediate 10 with the parent hydrocarbon.

[[File:XcwIntermediate10andPH.png|500px|center]]

The energies that we calculated are tabulated as shown below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 10'''
| '''44.878 '''
| 5.211
| 15.488
| -0.267
| -1.655
| 0.998
| 25.014
| 0.088
|-
| '''Parent Hydrocarbon'''
| '''50.564'''
| 4.692
| 21.979
| 0.109
| -0.958
| 0.247
| 24.495
| 0.000
|-

|}

 

Scrutinizing the results, the largest energy difference between intermediate 10 and the parent hydrocarbon stems from the Total Angle Bending Energy, EAB. Since the Total Angle bending energy is related to the angle strain in the molecules, it is apparent that the parent hydrocarbon has more ring strain as compared to the bridgehead olefin.

== '''Part 3 : Spectroscopic Simulation Using Quantum Mechanics''' ==
=== '''Spectroscopy of an Intermediate Related to the Synthesis of Taxol''' ===

Molecule 17 and 18 are derivatives of intermediate 9 and 10. In this exercise, MMFF94s is used to predict the 1H and 13C NMR of molecule 17 and molecule 18.

[[File:XcwIntermediate17&18.png|500px|center]]

==== '''NMR Spectra of Molecule 17''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 17.mol
</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwHNMRMolecule 17 Chair Overall NMR.png|500px|center]]
| [[File:XcwHNMRMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.1825
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| The first three results were fairly straight forward to be deduced and correlate wit experimental data.

The hydrogen atom that is geminally attached to the carbon of the double bonds is the most deshielded due to the ring current anisotropic effect of the ring current

The second most deshielded hydrogen atom is the hydrogen atom on the methyl group on the bridge. The hydrogen atom is pointing directly to the oxygen atom of the carbonyl functional group.

The peaks with an integration height of 4 is assigned to the hydrogen atoms in the 1,3-dithiolane ring fragment.

Subsequent analysis of the 1H NMR became very complicated very quickly for two reasons:

1. Gaussian calculations showed some atoms with an integration height of 3. Comparing their file atom number and checking their chemical environment, it is not possible to find any correlation between them.

2. Some of the peaks in the literature remains unresolved and are given as multiplets or grouped together.

|- align="center"
| 52
| 3.1775
| 1
| '''2.99'''
|- align="center"
| 53,52,50,51
| 3.0867
| 4
| '''3.40-3.10'''
|- align="center"
| 42,43,39
| 2.7445
| 3
| ''' '''
|- align="center"
| 49
| 2.6187
| 1
| ''' '''
|- align="center"
| 34
| 2.4371
| 1
| ''' '''
|- align="center"
| 35
| 2.3782
| 1
| ''' '''
|- align="center"
| 40,37,26
| 2.2730
| 3
| ''' '''
|- align="center"
| 30
| 2.1566
| 1
| ''' '''
|- align="center"
| 36
| 2.1033
| 1
| ''' '''
|- align="center"
| 32,28
| 2.0259
| 2
| ''' '''
|- align="center"
| 25
| 1.8535
| 2
| ''' '''
|- align="center"
| 38,46,27
| 1.5898
| 3
| '''1.25'''
|- align="center"
| 29
| 1.4557
| 1
| ''' '''
|- align="center"
| 31
| 1.0123
| 1
| ''' '''
|- align="center"
| 44,48,45
| 0.9087
| 3
| '''1.10'''
|- align="center"
| 47
| 0.8354
| 1
| ''' '''
|- align="center"
| 33
| 0.5790
| 1
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 17 Chair Overall NMR2.png|500px|center]]
| [[File:XcwMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 216.2725
| 1
| '''218.79'''
| rowspan="10" style="text-align:center;"| [[File:XcwMolecule 17 image for CNMR.jpg|600px|center]]
|- align="center"
| 13
| 144.8626
| 1
| '''144.63'''
|- align="center"
| 14
| 124.7193
| 1
| '''125.33'''
|- align="center"
| 3
| 91.3340
| 1
| '''72.88'''
|- align="center"
| 2
| 60.9568
| 1
| '''56.19'''
|- align="center"
| 1
| 57.0811
| 1
| '''52.52'''
|- align="center"
| 10
| 52.4663
| 1
| '''48.50'''
|- align="center"
| 16
| 51.4857
| 1
| '''46.80'''
|- align="center"
| 9
| 46.9196
| 1
| '''45.76'''
|- align="center"
| 23
| 43.8647
| 1
| '''39.80'''
|- align="center"
| 22
| 41.9450
| 1
| '''38.81'''
| Comments
|- align="center"
| 4
| 41.8724
| 1
| '''35.85'''
| rowspan="9" style="text-align:left;"| The carbon bonded to the oxygen atom is the most deshielded, as is shown in the predicted values and the experimental values. There is a deviation between the values. Quite possibly, this is due to the fact that in reality, the carbonyl functional group is pointing slightly towards the equatorial position rather than a lateral position relative to the ring (as is in the input for Gaussian calculation)

Most of the 1CNMR values that was predicted by Gaussian are all within an acceptable range of deviation. However, there is carbon 3 that has significant deviation between the predicted value and experimental value.

Carbon 3 is the carbon bonded to the two sulphurs in the 1,3-dithiolane ring fragment. Such a huge deviation would possibly mean that the conformer that was given as input to Gaussian differs from the literature.

The above NMR spectra was corrected with a level of theory B3LYP/6-31G(d,p) using TMS as reference and in chloroform.

|- align="center"
| 15
| 35.4348
| 1
| '''32.66'''
|- align="center"
| 11
| 31.1964
| 1
| '''28.79'''
|- align="center"
| 6
| 28.9432
| 1
| '''28.29'''
|- align="center"
| 7
| 28.3640
| 1
| '''26.88'''
|- align="center"
| 12
| 27.3767
| 1
| '''25.66'''
|- align="center"
| 17
| 26.3311
| 1
| '''23.86'''
|- align="center"
| 15
| 24.5483
| 1
| '''20.96'''
|- align="center"
| 18
| 19.7788
| 1
| '''18.71'''
|-
|}
 

==== '''NMR Spectra of Molecule 18''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 18 Boat for Image2.mol</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"-
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 18 Chair Overall NMR.png|500px|center]]
| [[File:Molecule 18 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.2832
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| ''' '''
|- align="center"
| 50
| 3.3175
| 1
| rowspan="4" style="text-align:centre;"| '''3.00-2.70'''
|- align="center"
| 52
| 3.2153
| 1
|- align="center"
| 51,53
| 3.1161
| 2
|- align="center"
| 34,43
| 2.8606
| 2
|- align="center"
| 38
| 2.4549
| 1
| ''' '''
|- align="center"
| 42
| 2.3968
| 1
| ''' '''
|- align="center"
| 25,29,26
| 2.2796
| 3
| ''' '''
|- align="center"
| 39
| 2.0844
| 1
| ''' '''
|- align="center"
| 40,36
| 1.9699
| 2
| ''' '''
|- align="center"
| 37,24
| 1.8519
| 2
| ''' '''
|- align="center"
| 31,27
| 1.6780
| 2
| ''' '''
|- align="center"
| 28
| 1.6175
| 1
| ''' '''
|- align="center"
| 46,49
| 1.4979
| 2
| ''' '''
|- align="center"
| 35
| 1.4150
| 1
| ''' '''
|- align="center"
| 32
| 1.3531
| 1
| ''' '''
|- align="center"
| 48
| 1.1606
| 1
| ''' '''
|- align="center"
| 33,30,47
| 1.0653
| 3
| '''1.03'''
|- align="center"
| 44,45
| 0.9643
| 2
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwMolecule 18 Boat Overall NMR.png|500px|center]]
| [[File:XcwMolecule 18 Boat zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 211.8325
| 1
| '''211.49'''
| rowspan="10" style="text-align:center;"| [[File:Molecule 18 Boat for 13 CNMR.jpg|600px|center]]
|- align="center"
| 13
| 148.6673
| 1
| '''148.72'''
|- align="center"
| 14
| 118.8373
| 1
| '''120.90'''
|- align="center"
| 3
| 89.0869
| 1
| '''74.61'''
|- align="center"
| 2
| 67.8886
| 1
| '''60.53'''
|- align="center"
| 1
| 56.1133
| 1
| '''51.30'''
|- align="center"
| 10
| 55.5998
| 1
| '''50.94'''
|- align="center"
| 16
| 50.1124
| 1
| '''45.53'''
|- align="center"
| 22
| 48.2030
| 1
| '''43.28'''
|- align="center"
| 23
| 44.2222
| 1
| '''40.82'''
|- align="center"
| 4
| 42.0354
| 1
| '''38.73'''
| Comments
|- align="center"
| 9
| 37.5865
| 1
| '''36.78'''
| rowspan="9" style="text-align:left;"| ''' '''
|- align="center"
| 6
| 35.3106
| 1
| '''35.47'''
|- align="center"
| 15
| 31.0459
| 1
| '''30.84'''
|- align="center"
| 7
| 28.8476
| 1
| '''30.00'''
|- align="center"
| 12
| 28.6623
| 1
| '''25.56'''
|- align="center"
| 17
| 25.7393
| 1
| '''25.35'''
|- align="center"
| 11
| 25.2603
| 1
| '''22.21'''
|- align="center"
| 18
| 23.3944
| 1
| '''21.39'''
|- align="center"
| 5
| 21.0478
| 1
| '''19.83'''
|-
|}
 

== '''Part 4 : Analysis of the Properties of the Synthesized Alkene Epoxides''' ==
=== '''The two catalytics systems''' ===

Assymmetric epoxidation of prochiral alkenes may lead to product with different stereochemical outcome as illustrated as below. To solve this problem, different types of asymmetric epoxidation catalyst have been synthesized. In this study, we shall be focusing on Shi asymmetric fructose catalyst as well as Jacobsen asymmetric catalyst.

[[File:Asymmetric catalyst.png|400px|center]]

==== ''' The Shi Asymmetric Fructose Catalyst''' ====

Molecule 21 is the stable precursor of molecule 22, the active catalyst. Molecule 21 can be converted to molecule 22 by using either persulfuric acid or potassium peroxymonosulphate.

[[File:Molecule 21 to 23.png|400px|center]]

The transition state of the Shi epoxidation was a subject of debate for a few moments. However, recent studies have led to the conclusion that the spiro transition state is more favored than the planar transition state. The spiro transition state is the transition that has its dioxirane perpendicularly bisecting the alkene double bond. This is thought to be more favourable due to interactions between the lone pairs of the oxygen with the LUMO of the alkene.

[[File:Spiro and planar ts.png|500px|center]]

==== ''' The Jacobsen Asymmetric Catalyst''' ====

Molecule 23 is the stable precursor of molecule 24, the active catalyst. Molecule 23 can be converted to molecule 24 by using sodium perchlorate.

[[File:Salen, 23 and 24.png|400px|center]]

Jacobsen catalyst is biphasic. The first phase involves the transfer of oxygen to molecule 23. Sodium perchlorate oxidizes Mn(III) to Mn(V).

In the second step, Jacobsen catalyst acts via a radical mechanism. It is thought to be so because epoxidation of trans-alkene by Jacobsen catalyst yield cis-alkene as well. A radical mechanism will lead to the lost of stereochemical information of the molecule.

=== ''' Crystal structure of the two catalyst''' ===
==== '''Molecule 21''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 21'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 21 strucutre.png|600px|center]]'''
|-
| style="text-align:center;" width="150" | ''' Bond '''
| style="text-align:center;" width="150"| ''' Bond Lenghts (Angstrom)'''
| style="text-align:center;" | ''' Evaluation'''
|-
| style="text-align:center;"| ''' O1-C1 '''
| style="text-align:center;"| ''' 1.400'''
| rowspan="10" style="text-align:left;"| [[File:Molecule 21 2.png|300px|center]]

The normal bond length of an C-O bond is 1.430 angstrom.

The most interesting aspect here is O4 and O2. The lone pair of O4 is antiperplanar to the sigma* orbital of the carbonyl group while the lone pair of O2 is anti periplanar to the carbonyl pi* orbital. Donation of electron can occur because of the correct symmetry. Due to the mixing of the orbitals, the C2-O2 and C4-O4 has been conferred with a certain degree of double bond character.

However, due to the lone pair on oxygen being now donated to the carbonyl antibonding orbitals, the O2 and O4 is slightly “electron deficient” and electron density will be pulled away from O2 and O4. That would explain why the bond length increase for O2-C7 and O4-C10. Increase in bond length is an indicator of the weakening of the bond.
|-
| style="text-align:center;"|'''O1-C7'''
| style="text-align:center;"|'''1.413'''
|-
| style="text-align:center;"|'''O2-C7'''
| style="text-align:center;"|'''1.441'''
|-
| style="text-align:center;"|'''O2-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O4-C4'''
| style="text-align:center;"|'''1.396'''
|-
| style="text-align:center;"|'''O4-C10'''
| style="text-align:center;"|'''1.439'''
|-
| style="text-align:center;"|'''O5-C10'''
| style="text-align:center;"|'''1.409'''
|-
| style="text-align:center;"|'''O5-C5'''
| style="text-align:center;"|'''1.416'''
|-
| style="text-align:center;"|'''O6-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O6-C6'''
| style="text-align:center;"|'''1.420'''
|-
|}
 

==== '''Molecule 23''' ====

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 23'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 23 struc.png|600px|center]]'''
|-
| The most outstanding feature from this molecule is the fact that is adopt a puckered form of the square base pyramidal form. This is no surprise that the molecule is almost planar due to the electron delocalization around each side of the salen ligand.

The tery-butyl hydrogen are oriented closely to one another. Non-covalent interaction studies indicated that repulsion would occur for H---H bond length that are less than 2.1 angstrom while favourable interaction may be dominant with bond length above 2.4 angstrom. It was discovered that all 4 hydrogens have bond length more than 2.4 angstrom hence there should not be any significant repulsion between them. Instead, certain amount of attractive force will ensue and that contributes to the overall stability of the molecule

|-
|}
 

=== ''' The calculated NMR properties of the product''' ===

=== ''' Assigning the absolute configuration of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''Predicted ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg'''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg '''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental conditions'''
| width="100" | '''1.00g/100ml, chloroform, 21 degree Celcisus, 589 nm wavelength '''
| width="100" | '''1.02g/100ml (99% ee), chloroform, 25 degree Celsius, 589 nm wavelength '''
| width="100" | '''1.01g/100ml, ethanol, 22 degree Celsius, 589 nm wavelength '''
| width="100" | '''0.6g/100ml, ethanol, 20 degree Celsius, 589 nm wavelength '''
|- align="left"
| width="100" | ''' Predicted VCD Spectrum'''
| width="100" | '''[[File:Styrene R VCD.png|200px|center|]] '''
| width="100" | '''[[File:Styrene S VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene RR VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene SS VCD.png|200px|center|]]'''
|-
|}

 

All the assignments given in the literature reports are correct although the predicted value differs slightly with the experimental values

=== ''' Analysis of the Transition State for Reactions''' ===
==== '''Predicting Enantiomeric Excess based on Transition State energies''' ====

One of the energy output from Gaussian calculation is the “sum of electronic and thermal free energies”. This is Gibbs Free Energy at 298.15K and 1 atm.

Using this term and invoking a variant of the Curtin-Hammett Principle, it is possible to calculate a predicted enantiomeric excess of one enantiomer over the other.

[[File:Ee and transition state energy.png|800px|center]]

Using the derivations from above and equation (4), we analyze the enantiomeric excess of beta-methyl styrene and the results are tabulated as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1343.022970'''
| width="100" | '''-1343.017942'''
| width="150" | '''-0.005028'''
| width="150" | '''4.88E-03'''
| width="150" | '''99.03'''
|- align="center"
| width="100" | '''-1343.019233'''
| width="100" | '''-1343.015603'''
| width="150" | '''-0.003630'''
| width="150" | '''2.14E-02'''
| width="150" | '''95.80'''
|- align="center"
| width="100" | '''-1343.029272'''
| width="100" | '''-1343.023766'''
| width="150" | '''-0.005506'''
| width="150" | '''2.94E-03'''
| width="150" | '''99.41'''
|- align="center"
| width="100" | '''-1343.032443'''
| width="100" | '''-1343.024742'''
| width="150" | '''-0.007701'''
| width="150" | '''2.88E-04'''
| width="150" | '''99.94'''
|-
|}

 

The above hartree units are converted to J/mol for calculation of K where 1 hartress = 4.3597E-18

Studying all the free energies of the (R,R) series and compare them with the (S,S) series, it comes as no surprise that (R,R) product is favoured over (S,S) product as (R,R) is more stable. Indeed, this corresponds with the literature value reporting 92% ee of (R,R) products over that of (S,S).

==== '''Analysis of the Transition State of Epoxidation''' ====
==== '''Shi Fructose Catalyst''' ====
For this section, I will be analyzing the the transition state of 1) styrene and 2) trans-stilbene with the Shi fructose catalyst.

===== '''(R) and (S)-styrene transition state''' =====
The transition state for the formation of (R)-styrene oxide and (S)-styrene oxide are given as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R)-styrene oxide'''
| width="150" | '''(S)-styrene oxide'''
|- align="center"
| width="150" | ''' Structure of Catalyst '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide R.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide S ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| [[File:Steric shi fructose R.png|450px|center]]
| [[File:Steric shi fructose S.png|450px|center]]
|-
|}

 

In the transition state for (R)-styrene, it was discovered that the Re face is reacting with the oxygen of the dioxirane. The phenyl ring is oriented endo with respect to the fructose catalyst. However, the (S)-styrene is reacting at the Si face and the phenyl ring is oriented exo relative to the catalyst.

The approach taken by (R)-styrene and (S)-styrene are restricted to only one due to steric interactions. Therefore, the epoxidation of both styrenes by the Shi catalyst will be stereospecific and retains all the stereochemical information of the reactant. However, whether or not (R)-styrene oxide or (S)-styrene oxide is form is dependent on the relative energies of the transition state. The more stable the transition state, the more likely the product of the transition state will be formed.

So in order to examine this, an example of transition state of both styrenes with Shi catalyst are obtained and analyzed.
 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1303.736813'''
| width="100" | '''-1303.727673'''
| width="150" | '''-0.00914'''
| width="150" | '''6.28E-05'''
| width="150" | '''99.99'''

|-
|}

 

From the above, we can see the predicted high enantiopurity of the reaction favoring the (R) product because of the lower energy of the transition states. To understand the reason, we have to turn to non-covalent interaction (NCI) analysis.

[[File:NCI shi fructose styrene.png|700px|center]]

To complement the NCI analysis, a QTAIM (Quantum Theory of Atoms in Molecules) analysis is conducted as well.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''(R)-styrene transition state'''
| width="200" | '''(S)-styrene transition state'''
|- align="center"
| width="100" | '''[[File:QTAIM R.png|400px|center]]'''
| width="100" | '''[[File:QTAIM S.png|400px|center]]'''
|- align="center"
| colspan="2" width="100" | '''Comments'''
|-
| colspan="2" width="100" | '''Unsurprisingly, QTAIM analysis has also shown that (R)-styrene/Shi catalyst has more interactions with one another. While (R)-styrene has 2 strong interactions, (S)-styrene has only one with the catalyst. Besides, the phenyl ring of (R)-styrene also confers additional positive interaction with the catalyst. QTAIM analysis has also show several interactions between the C=C geminal hydrogen of (R)-styrene intreacting with the oxygen atoms on the dioxacyclopentane ring'''
|-
|}

 

===== '''(R,R) and (S,S)-Stilbene transition state''' =====

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R,R)-Stilbene oxide'''
| width="150" | '''(S,S)-Stilbene oxide'''
|- align="center"
| width="150" | ''' Structure of Transition State '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Stilbene RR ts.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>SS stilbene oxide ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| colspan="2" | [[File:Shi fructose stilbene.png|700px|center]]

|-
|}

 

However, unlike styrene, trans-stilbene seems to approach perpendicularly to the dioxirane. This is proposed to be due to the steric interactions (marked in purple). Based on first inspection, it seems that (S,S)-Stilbene oxide has more steric interactions than (R,R)-Stilbene oxide. Although unsubstantial, it seems like my guess was correct. The (R,R)-stilbene/Shi catalyst transition state is lower in energy.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1534.687808'''
| width="100" | '''-1534.683440'''
| width="150" | '''0.004368'''
| width="150" | '''9.08E-3'''
| width="150" | '''98.20'''

|-
|}

 

NCI Analysis is also done for trans-stilbene

[[File:NCI stilbene.png|700px|center]]

==== '''Jacobsen Catalyst''' ====

For this section, cis-beta methyl styrene transition state will be analyzed.

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-3383.259559'''
| width="100" | '''-3383.251060'''
| width="150" | '''-0.008499'''
| width="150" | '''1.24E-04'''
| width="150" | '''99.98'''
|- align="center"
| width="100" | '''-3383.253442'''
| width="100" | '''-3383.250270'''
| width="150" | '''-0.003172'''
| width="150" | '''3.48E-02'''
| width="150" | '''93.27'''
|-
|}

 

As is obvious from here, the (S,R) transition state is more stable than the (R,S) transition state. Both transition states are exo with respect to the catalyst.

It is not immediately apparent just by looking at the molecule to determine which spatial groups have interactions with one another. Therefore, an NCI analysis is conducted again.

[[File:NCI Jacobsen.png|700px|center]]

Rep:Mod:Computationalreport1C

2013-11-21T21:51:32Z

Xc2611: /* Assigning the absolute configuration of the product */

= '''Synthesis and Computational Lab: 1C''' =
== '''Part 1: Introduction to Molecular Mechanics''' ==
=== '''Introduction to MMFF94 and MMFF94s''' ===

With the improvement of computational data and computer processing power, the usage of molecular mechanics/dynamics forcefield has become very integrated in predicting properties of chemical molecules. A molecular mechanics/dynamics forcefield should be able to predict characteristics such as molecular geometries, conformational/stereoisomeric energies, vibrational frequencies etc. to a reasonable accuracy as compared to experimental-derived values.

Building on work from Kollman et al. s’ AMBER forcefield and Allinger et al. s’ MM1, MM2, MM3 and MM4, Merck Research Laboratories have managed to optimized and improved the previous computational algorithms and produced MMFF94 (Merck Molecular Force Field 94). One of the most prominent advantages of MMFF94 over other preceeding work is its enhanced prediction accuracy. The reason lies in the fact that MMFF94’s core parameterization utilizes an unprecedently large amount of computational data obtained from ab initio calculations1.

Subsequently after the development of MMFF94, a new “static” variant of the MMFF was introduced i.e. the MMFF94s. Unlike MMFF94 that was developed for the use of molecular dynamics simulations (which can be expensive), MMFF94s was developed with the purpose of energy minimization studies in mind. Although both systems provide identical results for most systems, they differ for amides and unsaturated amines which contain resonance-delocalized trigonal nitrogen atoms2.

In this computational exercise, MMFF94s is used predominantly as oppose to the alternative Universal Force Field (UFF). Although versatile across the entire periodic table, UFF is derived from simple rules and atomic parameters such as fixed hybridization that increases the likelihood of erroneous structural and energetic predictions3.

=== '''Forms of MMFF94s''' ===

Steric energy of a molecule is the energy arise due to its geometry or conformation. Energy minimization of steric energy process ensures that the molecule is in its lowest energy conformation.

MMFF94s assumes that the total steric energy of a molecule can be found by the sum of a few specific interactions in a molecule.

ES = EBS + EAB + E SB + ET + EOOP + EVdW + EEE

'''where the bonded interactions are:'''

ES = Total Steric energy

EBS = Total Bond Stretching energy

EAB = Total Angle Bending energy

ESB = Total Stretch Bending energy

ET = Total Torsional Energy

EOOP = Total Out-Of-Plane Bending energy, and

'''where the non-bonded interactions are:'''

EVdW = Total Van der Waals Energy

EEE = Total Electrostatic Energy

{| border="1" cellspacing="1" cellpadding="10"
|-
| width="300" align="center" | '''Types of Energies'''
! width="600" align="center" | '''Explanation'''
|-
| colspan="2" style="text-align: center;" | '''Bonded Interactions'''
|-
| width="300" align="center" | '''Total Bond Stretching Energy'''
! width="600" align="left" | The total bond stretching energy is related to the vibration energy of the molecules in comparison to the equilibrium bond length. Whenever a bond deviates from the equilibrium bond length, the energy value increases.

MMFF94s uses a quartic function that has the force constant term (relate to bond strength). The quartic function term is superior to the cubic function term (used in MM2) in the sense that it avoid the “cubic stretch catastrophe” where progressive elongation of molecule bond length leads to negative infinity.
|-
| width="300" align="center" | '''Total Angle Bending Energy'''
! width="600" align="left" | Similar to Total Bond Stretching Energy, the total angle bending energy is also related to the vibration energy of the molecules about the equilibrium bond length. However, unlike EBS that measures the bond strength, EAB is associated with the stiffness of the molecules based on the Hookiean potential. Whenever bond angles deviate from the norm during vibration, this energy term increases as well.
|-
| width="300" align="center" | '''Total Stretch-Bending Energy'''
! width="600" align="left" | This energy term takes into account of the energy due to increase in bond length when bond angle between two atoms changes.
|-
| width="300" align="center" | '''Total Torsional Energy'''
! width="600" align="left" | Total torsional energy is the energy required for intermolecular rotation about the bonds. In molecule mechanics, however, this term is often used as a correction that must be added or subtracted to the total energy of the molecule to fit a quantum mechanical calculation about the dihedral angles of bonds.
|-
| width="300" align="center" | '''Total Out-Of-Plane Bending Energy'''
! width="600" align="left" | This energy term refers to the energy needed to deform the dihedral angle (zero degrees) of a planar group of atoms such as carbonyl or amide functional groups.
|-
| colspan="2" style="text-align: center;" | '''Non-Bonded Interactions'''
|-
| width="300" align="center" | '''Total Van der Waals Energy'''
! width="600" align="left" | The total Van der Waals energy term examines the intramolecular interactions such as repulsion or attraction between non-bonded atoms in the molecule. This term is crucial in determining the preferred conformation of the molecule.

MMFF94s employs the novel “Buffered-14-7”. The name is derived from a buffering constant and the 14th and 7th power dependencies of the repulsive and attractive energy in the equation.
|-
| width="300" align="center" | '''Total Electrostatic Energy'''
! width="600" align="left" | The total electrostatic energy functions take into account of the Coulombic potential and partial charge/dipole/atomic point charges interactions within the molecule.
|-

|}

 

== '''Part 2 : Conformational Analysis Using Molecular Mechanics''' ==
=== '''The Hydrogenation of Cyclopentadiene Dimer''' ===

==== '''Endo and exo adduct from the Dimerization of Cyclopentadiene''' ====
Cyclopentadiene will undergo dimerization by Diels-alder reaction to form either an endo or exo adduct.

[[File:XcwDimerization of CP.png|500px|center]]

==== '''Stereoselectivity of Dimerization of Cyclopentadiene''' ====
Although the exo adduct is thermodynamically more stable than the endo adduct, the endo adduct is form preferentially. Using the QST2 method, the transition state of the Diels Alder dimerization was found. It was discovered that due to the secondary orbital interactions in the endo transition state, the endo dimer is formed preferentially (the kinetic product). Hence, it is proven that the Diels Alder dimerization between two cyclopentadiene are kinetically controlled.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Transition State of Dimerization of Cyclopentadiene'''
| '''Imaginary Stretch Frequency (-881.25) of the Endo Transition State (click to animate)'''
| '''Secondary Orbital Interaction (Red overlapping orbitals)'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<uploadedFileContents>EndotsDCPD2.mol
</uploadedFileContents>
</jmolApplet></jmol>
| [[File:Xcwendotsimaginary.gif|300px|center]]
| [[File:XcwSecondary orbital interaction1.jpg|300px|center]]
|-
|}

 

==== '''Asynchronous Bond Formation of Dimerization of Cyclopentadiene''' ====

The initial study of the molecular orbitals of the transition states seemed a bit peculiar. Instead of getting a LUMO with symmetrical orbitals, the calculations showed a HOMO that is asymetric at the carbons where the new sigma bonds will be formed. Running an IRC further, it soon became clear that the asymmetry of the HOMO leads to an asychronous bond formation before leading to the product.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''IRC plot following the Endo Transition State '''
| '''IRC following the Endo Transition State (click to animate)'''
| '''Asymmetry of orbitals at the carbons where the new sigma bonds will be formed'''
|- align="center"
| [[File:XcwendotscyclopentadieneIRC.png|300px|center]]
| [[File:XcwendotsIRC.gif|300px|center]]
| [[File:XcwAsynchronous mo.jpg|300px|center]]
|-
|}

 

==== '''Comparison of Energies between the Endo and Exo adduct of Dicyclopentadiene''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Adduct of Dicyclopentadiene dimerization'''
| '''Exo Adduct of Dicyclopentadiene dimerization'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=19,atomno=1,atomno=2; color green;measure 19 1;measure 19 2;</script>
<uploadedFileContents>XcwEndodimer3.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>Exodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=7,atomno=17; color green;measure 17 7;</script>
<uploadedFileContents>XcwExodimer1.mol</uploadedFileContents>
</jmolApplet></jmol>
|-
|}

 

Using MMFF94s ab initio calculations, the energies for the exo dimer and the endo dimer are derived.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Exodimer'''
| '''55.374'''
| 3.543
| 30.772
| -2.041
| -2.728
| 0.015
| 12.800
| 13.014
|-
| '''Endodimer'''
| '''58.191'''
| 3.468
| 33.187
| -2.082
| -2.950
| 0.023
| 12.360
| 14.186
|-
|}

 

The MMFF94s steric energy (after minimization) for the exo dimer is lower than that of the endo dimer. This is reflected by the large difference for the EEE between the endo dimer and the exo dimer due to unfavourable steric repulsion between the two “arched down” cyclopentene rings.

==== '''Hydrogenation of Dicyclopentadiene''' ====

Hydrogenation of the endo dicyclopentadiene (DCPD) would lead to two potential products: dihydro product 1 and dihydro product 2.

[[File:XcwFormation of Dihydro products.png|500px|center]]

Using MMFF94s, the energy of the two dihydro products are calculated.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Dihydro Product 1'''
| '''50.123'''
| 3.308
| 30.864
| -1.927
| 0.060
| 0.015(2)
| 13.281
| 5.121
|-
| '''Dihydro Product 2'''
| '''41.257'''
| 2.823
| 24.685
| -1.657
| -0.379
| 0.000(2)
| 10.639
| 5.147
|-
| '''Tetrahydro Product'''
| '''39.042'''
| 2.730
| 25.151
| -1.676
| 1.287
| 0.000
| 11.551
| 0.000
|}

 

From the MMFF94s calculation, it can be seen that dihydro product 2 has a lower steric energy than dihydro product 1. Therefore, dihydro product 2 is the thermodynamic product for the hydrogenation of dicylopentadiene. And indeed, this was what was observed by Skala et al.. He observed that the first hydrogenation occur at the norborene part of the molecule (rate of hydrogenation several times faster than that in the cyclopentene ring)6. The first heat of hydrogenation at the norborene is 138.8 kJ/mol while the second hydrogenation at the cyclopentene right is 109.5 kJ/mol6.

From the above results, it is also obvious that tetrahydro product is much more stable than either dihydro product. And yet, studies have shown that the tetrahydro product will only form after prolonged hydrogenation under high temperature. However, subjecting DCPD to high temperature leads to low yield due to cracking of DCPD.

Since thermodynamically it is predicted to form favourably, the fact that it does not could only mean that the hydrogenation of DCPD to tetrahydrodicyclopentadiene (TH-DCPD) is kinetically controlled. Most possibly, the transition state of the hydrogenation of DCPD is highly unstable hence it is unlikely to form.

=== '''Atropisomerism in an Intermediate related to the Synthesis of Taxol''' ===

Atropisomerism is a type of stereoisomerism that is form as a result of hindered rotation about a single bond.

[[File:XcwAtropisomerism example.png|500px|center]]

In the case of the 6,6’-dinitro-2,2’-diphenic acid, rotation about the bonds joining the two substituted phenyl rings would have to overcome large steric interaction between the bulky substituents. The barrier of rotation is high enough for the two conformers to be isolated individually.

In the synthesis of taxol, one of the key intermediates exhibit atropisomerism.

==== '''Atropisomerism in Taxol Synthesis''' ====

For the key intermediate, rotation about the carbon-carbon bonds would lead to two types of atropisomers, each with either the carbonyl group poining upwards or downwards in relative to the bridge.

[[File:XcwIntermediate 9 and Intermediate 10.png|500px|center]]

Once again by using MMFF94s ab initio calculations, the steric energies for the two intermediates are illustrated as below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 9'''
| '''70.571'''
| 7.743
| 28.356
| -0.062
| 0.004
| 0.949
| 33.293
| 0.288
|-
| '''Intermediate 10'''
| '''60.553'''
| 7.599
| 18.838
| -0.139
| 0.199
| 0.844
| 33.269
| -0.056
|-

|}

 

Analyzing the data above, the largest energy difference between Intermediate 9 and Intermediate 10 stems from the EAB which is related to the strain of the ring. Intermediate 9 has an excess of 9.518 kcal/mol EAB as compared to Intermediate 10. This comes as a surprise as intermediate 9 is predicted to be more stable alkene.

The rationale behind the prediction of the stability of intermediate 9 stems from the fact that the through-space distance of the upward-pointing carbonyl oxygen with the carbon-carbon is further than the through space distance between the downward-pointing carbonyl oxygen with the -CH2-CH2- fragment at the norbornene part in intermediate 10.

==== '''Hyperstable Olefins''' ====

Intermediate 9 and Intermediate 10 does not react readily with other reagents during functionalization. This is due to the hyperstability effect found in hyperstable olefins.

Hyperstable olefins are alkenes that contain less strain in the ring (i.e. negative olefin strain values) compared to the parent hydrocarbon. To study this further, further MMFF94s calculation was done to compare Intermediate 10 with the parent hydrocarbon.

[[File:XcwIntermediate10andPH.png|500px|center]]

The energies that we calculated are tabulated as shown below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 10'''
| '''44.878 '''
| 5.211
| 15.488
| -0.267
| -1.655
| 0.998
| 25.014
| 0.088
|-
| '''Parent Hydrocarbon'''
| '''50.564'''
| 4.692
| 21.979
| 0.109
| -0.958
| 0.247
| 24.495
| 0.000
|-

|}

 

Scrutinizing the results, the largest energy difference between intermediate 10 and the parent hydrocarbon stems from the Total Angle Bending Energy, EAB. Since the Total Angle bending energy is related to the angle strain in the molecules, it is apparent that the parent hydrocarbon has more ring strain as compared to the bridgehead olefin.

== '''Part 3 : Spectroscopic Simulation Using Quantum Mechanics''' ==
=== '''Spectroscopy of an Intermediate Related to the Synthesis of Taxol''' ===

Molecule 17 and 18 are derivatives of intermediate 9 and 10. In this exercise, MMFF94s is used to predict the 1H and 13C NMR of molecule 17 and molecule 18.

[[File:XcwIntermediate17&18.png|500px|center]]

==== '''NMR Spectra of Molecule 17''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 17.mol
</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwHNMRMolecule 17 Chair Overall NMR.png|500px|center]]
| [[File:XcwHNMRMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.1825
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| The first three results were fairly straight forward to be deduced and correlate wit experimental data.

The hydrogen atom that is geminally attached to the carbon of the double bonds is the most deshielded due to the ring current anisotropic effect of the ring current

The second most deshielded hydrogen atom is the hydrogen atom on the methyl group on the bridge. The hydrogen atom is pointing directly to the oxygen atom of the carbonyl functional group.

The peaks with an integration height of 4 is assigned to the hydrogen atoms in the 1,3-dithiolane ring fragment.

Subsequent analysis of the 1H NMR became very complicated very quickly for two reasons:

1. Gaussian calculations showed some atoms with an integration height of 3. Comparing their file atom number and checking their chemical environment, it is not possible to find any correlation between them.

2. Some of the peaks in the literature remains unresolved and are given as multiplets or grouped together.

|- align="center"
| 52
| 3.1775
| 1
| '''2.99'''
|- align="center"
| 53,52,50,51
| 3.0867
| 4
| '''3.40-3.10'''
|- align="center"
| 42,43,39
| 2.7445
| 3
| ''' '''
|- align="center"
| 49
| 2.6187
| 1
| ''' '''
|- align="center"
| 34
| 2.4371
| 1
| ''' '''
|- align="center"
| 35
| 2.3782
| 1
| ''' '''
|- align="center"
| 40,37,26
| 2.2730
| 3
| ''' '''
|- align="center"
| 30
| 2.1566
| 1
| ''' '''
|- align="center"
| 36
| 2.1033
| 1
| ''' '''
|- align="center"
| 32,28
| 2.0259
| 2
| ''' '''
|- align="center"
| 25
| 1.8535
| 2
| ''' '''
|- align="center"
| 38,46,27
| 1.5898
| 3
| '''1.25'''
|- align="center"
| 29
| 1.4557
| 1
| ''' '''
|- align="center"
| 31
| 1.0123
| 1
| ''' '''
|- align="center"
| 44,48,45
| 0.9087
| 3
| '''1.10'''
|- align="center"
| 47
| 0.8354
| 1
| ''' '''
|- align="center"
| 33
| 0.5790
| 1
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 17 Chair Overall NMR2.png|500px|center]]
| [[File:XcwMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 216.2725
| 1
| '''218.79'''
| rowspan="10" style="text-align:center;"| [[File:XcwMolecule 17 image for CNMR.jpg|600px|center]]
|- align="center"
| 13
| 144.8626
| 1
| '''144.63'''
|- align="center"
| 14
| 124.7193
| 1
| '''125.33'''
|- align="center"
| 3
| 91.3340
| 1
| '''72.88'''
|- align="center"
| 2
| 60.9568
| 1
| '''56.19'''
|- align="center"
| 1
| 57.0811
| 1
| '''52.52'''
|- align="center"
| 10
| 52.4663
| 1
| '''48.50'''
|- align="center"
| 16
| 51.4857
| 1
| '''46.80'''
|- align="center"
| 9
| 46.9196
| 1
| '''45.76'''
|- align="center"
| 23
| 43.8647
| 1
| '''39.80'''
|- align="center"
| 22
| 41.9450
| 1
| '''38.81'''
| Comments
|- align="center"
| 4
| 41.8724
| 1
| '''35.85'''
| rowspan="9" style="text-align:left;"| The carbon bonded to the oxygen atom is the most deshielded, as is shown in the predicted values and the experimental values. There is a deviation between the values. Quite possibly, this is due to the fact that in reality, the carbonyl functional group is pointing slightly towards the equatorial position rather than a lateral position relative to the ring (as is in the input for Gaussian calculation)

Most of the 1CNMR values that was predicted by Gaussian are all within an acceptable range of deviation. However, there is carbon 3 that has significant deviation between the predicted value and experimental value.

Carbon 3 is the carbon bonded to the two sulphurs in the 1,3-dithiolane ring fragment. Such a huge deviation would possibly mean that the conformer that was given as input to Gaussian differs from the literature.

The above NMR spectra was corrected with a level of theory B3LYP/6-31G(d,p) using TMS as reference and in chloroform.

|- align="center"
| 15
| 35.4348
| 1
| '''32.66'''
|- align="center"
| 11
| 31.1964
| 1
| '''28.79'''
|- align="center"
| 6
| 28.9432
| 1
| '''28.29'''
|- align="center"
| 7
| 28.3640
| 1
| '''26.88'''
|- align="center"
| 12
| 27.3767
| 1
| '''25.66'''
|- align="center"
| 17
| 26.3311
| 1
| '''23.86'''
|- align="center"
| 15
| 24.5483
| 1
| '''20.96'''
|- align="center"
| 18
| 19.7788
| 1
| '''18.71'''
|-
|}
 

==== '''NMR Spectra of Molecule 18''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 18 Boat for Image2.mol</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"-
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 18 Chair Overall NMR.png|500px|center]]
| [[File:Molecule 18 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.2832
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| ''' '''
|- align="center"
| 50
| 3.3175
| 1
| rowspan="4" style="text-align:centre;"| '''3.00-2.70'''
|- align="center"
| 52
| 3.2153
| 1
|- align="center"
| 51,53
| 3.1161
| 2
|- align="center"
| 34,43
| 2.8606
| 2
|- align="center"
| 38
| 2.4549
| 1
| ''' '''
|- align="center"
| 42
| 2.3968
| 1
| ''' '''
|- align="center"
| 25,29,26
| 2.2796
| 3
| ''' '''
|- align="center"
| 39
| 2.0844
| 1
| ''' '''
|- align="center"
| 40,36
| 1.9699
| 2
| ''' '''
|- align="center"
| 37,24
| 1.8519
| 2
| ''' '''
|- align="center"
| 31,27
| 1.6780
| 2
| ''' '''
|- align="center"
| 28
| 1.6175
| 1
| ''' '''
|- align="center"
| 46,49
| 1.4979
| 2
| ''' '''
|- align="center"
| 35
| 1.4150
| 1
| ''' '''
|- align="center"
| 32
| 1.3531
| 1
| ''' '''
|- align="center"
| 48
| 1.1606
| 1
| ''' '''
|- align="center"
| 33,30,47
| 1.0653
| 3
| '''1.03'''
|- align="center"
| 44,45
| 0.9643
| 2
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwMolecule 18 Boat Overall NMR.png|500px|center]]
| [[File:XcwMolecule 18 Boat zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 211.8325
| 1
| '''211.49'''
| rowspan="10" style="text-align:center;"| [[File:Molecule 18 Boat for 13 CNMR.jpg|600px|center]]
|- align="center"
| 13
| 148.6673
| 1
| '''148.72'''
|- align="center"
| 14
| 118.8373
| 1
| '''120.90'''
|- align="center"
| 3
| 89.0869
| 1
| '''74.61'''
|- align="center"
| 2
| 67.8886
| 1
| '''60.53'''
|- align="center"
| 1
| 56.1133
| 1
| '''51.30'''
|- align="center"
| 10
| 55.5998
| 1
| '''50.94'''
|- align="center"
| 16
| 50.1124
| 1
| '''45.53'''
|- align="center"
| 22
| 48.2030
| 1
| '''43.28'''
|- align="center"
| 23
| 44.2222
| 1
| '''40.82'''
|- align="center"
| 4
| 42.0354
| 1
| '''38.73'''
| Comments
|- align="center"
| 9
| 37.5865
| 1
| '''36.78'''
| rowspan="9" style="text-align:left;"| ''' '''
|- align="center"
| 6
| 35.3106
| 1
| '''35.47'''
|- align="center"
| 15
| 31.0459
| 1
| '''30.84'''
|- align="center"
| 7
| 28.8476
| 1
| '''30.00'''
|- align="center"
| 12
| 28.6623
| 1
| '''25.56'''
|- align="center"
| 17
| 25.7393
| 1
| '''25.35'''
|- align="center"
| 11
| 25.2603
| 1
| '''22.21'''
|- align="center"
| 18
| 23.3944
| 1
| '''21.39'''
|- align="center"
| 5
| 21.0478
| 1
| '''19.83'''
|-
|}
 

== '''Part 4 : Analysis of the Properties of the Synthesized Alkene Epoxides''' ==
=== '''The two catalytics systems''' ===

Assymmetric epoxidation of prochiral alkenes may lead to product with different stereochemical outcome as illustrated as below. To solve this problem, different types of asymmetric epoxidation catalyst have been synthesized. In this study, we shall be focusing on Shi asymmetric fructose catalyst as well as Jacobsen asymmetric catalyst.

[[File:Asymmetric catalyst.png|400px|center]]

==== ''' The Shi Asymmetric Fructose Catalyst''' ====

Molecule 21 is the stable precursor of molecule 22, the active catalyst. Molecule 21 can be converted to molecule 22 by using either persulfuric acid or potassium peroxymonosulphate.

[[File:Molecule 21 to 23.png|400px|center]]

The transition state of the Shi epoxidation was a subject of debate for a few moments. However, recent studies have led to the conclusion that the spiro transition state is more favored than the planar transition state. The spiro transition state is the transition that has its dioxirane perpendicularly bisecting the alkene double bond. This is thought to be more favourable due to interactions between the lone pairs of the oxygen with the LUMO of the alkene.

[[File:Spiro and planar ts.png|500px|center]]

==== ''' The Jacobsen Asymmetric Catalyst''' ====

Molecule 23 is the stable precursor of molecule 24, the active catalyst. Molecule 23 can be converted to molecule 24 by using sodium perchlorate.

[[File:Salen, 23 and 24.png|400px|center]]

Jacobsen catalyst is biphasic. The first phase involves the transfer of oxygen to molecule 23. Sodium perchlorate oxidizes Mn(III) to Mn(V).

In the second step, Jacobsen catalyst acts via a radical mechanism. It is thought to be so because epoxidation of trans-alkene by Jacobsen catalyst yield cis-alkene as well. A radical mechanism will lead to the lost of stereochemical information of the molecule.

=== ''' Crystal structure of the two catalyst''' ===
==== '''Molecule 21''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 21'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 21 strucutre.png|600px|center]]'''
|-
| style="text-align:center;" width="150" | ''' Bond '''
| style="text-align:center;" width="150"| ''' Bond Lenghts (Angstrom)'''
| style="text-align:center;" | ''' Evaluation'''
|-
| style="text-align:center;"| ''' O1-C1 '''
| style="text-align:center;"| ''' 1.400'''
| rowspan="10" style="text-align:left;"| [[File:Molecule 21 2.png|300px|center]]

The normal bond length of an C-O bond is 1.430 angstrom.

The most interesting aspect here is O4 and O2. The lone pair of O4 is antiperplanar to the sigma* orbital of the carbonyl group while the lone pair of O2 is anti periplanar to the carbonyl pi* orbital. Donation of electron can occur because of the correct symmetry. Due to the mixing of the orbitals, the C2-O2 and C4-O4 has been conferred with a certain degree of double bond character.

However, due to the lone pair on oxygen being now donated to the carbonyl antibonding orbitals, the O2 and O4 is slightly “electron deficient” and electron density will be pulled away from O2 and O4. That would explain why the bond length increase for O2-C7 and O4-C10. Increase in bond length is an indicator of the weakening of the bond.
|-
| style="text-align:center;"|'''O1-C7'''
| style="text-align:center;"|'''1.413'''
|-
| style="text-align:center;"|'''O2-C7'''
| style="text-align:center;"|'''1.441'''
|-
| style="text-align:center;"|'''O2-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O4-C4'''
| style="text-align:center;"|'''1.396'''
|-
| style="text-align:center;"|'''O4-C10'''
| style="text-align:center;"|'''1.439'''
|-
| style="text-align:center;"|'''O5-C10'''
| style="text-align:center;"|'''1.409'''
|-
| style="text-align:center;"|'''O5-C5'''
| style="text-align:center;"|'''1.416'''
|-
| style="text-align:center;"|'''O6-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O6-C6'''
| style="text-align:center;"|'''1.420'''
|-
|}
 

==== '''Molecule 23''' ====

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 23'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 23 struc.png|600px|center]]'''
|-
| The most outstanding feature from this molecule is the fact that is adopt a puckered form of the square base pyramidal form. This is no surprise that the molecule is almost planar due to the electron delocalization around each side of the salen ligand.

The tery-butyl hydrogen are oriented closely to one another. Non-covalent interaction studies indicated that repulsion would occur for H---H bond length that are less than 2.1 angstrom while favourable interaction may be dominant with bond length above 2.4 angstrom. It was discovered that all 4 hydrogens have bond length more than 2.4 angstrom hence there should not be any significant repulsion between them. Instead, certain amount of attractive force will ensue and that contributes to the overall stability of the molecule

|-
|}
 

=== ''' The calculated NMR properties of the product''' ===

=== ''' Assigning the absolute configuration of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''Predicted ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg'''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg '''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental conditions'''
| width="100" | '''1.00g/100ml, chloroform, 21 degree Celcisus, 589 nm wavelength '''
| width="100" | '''1.02g/100ml (99% ee), chloroform, 25 degree Celsius, 589 nm wavelength '''
| width="100" | '''1.01g/100ml, ethanol, 22 degree Celsius, 589 nm wavelength '''
| width="100" | '''0.6g/100ml, ethanol, 20 degree Celsius, 589 nm wavelength '''
|- align="left"
| width="100" | ''' Predicted VCD Spectrum'''
| width="100" | '''[[File:Styrene R VCD.png|200px|center|]] '''
| width="100" | '''[[File:Styrene S VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene RR VCD.png|200px|center|]]'''
| width="100" | '''[[File:Stilbene SS VCD.png|200px|center|]]'''
|-
|}

 

=== ''' Analysis of the Transition State for Reactions''' ===
==== '''Predicting Enantiomeric Excess based on Transition State energies''' ====

One of the energy output from Gaussian calculation is the “sum of electronic and thermal free energies”. This is Gibbs Free Energy at 298.15K and 1 atm.

Using this term and invoking a variant of the Curtin-Hammett Principle, it is possible to calculate a predicted enantiomeric excess of one enantiomer over the other.

[[File:Ee and transition state energy.png|800px|center]]

Using the derivations from above and equation (4), we analyze the enantiomeric excess of beta-methyl styrene and the results are tabulated as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1343.022970'''
| width="100" | '''-1343.017942'''
| width="150" | '''-0.005028'''
| width="150" | '''4.88E-03'''
| width="150" | '''99.03'''
|- align="center"
| width="100" | '''-1343.019233'''
| width="100" | '''-1343.015603'''
| width="150" | '''-0.003630'''
| width="150" | '''2.14E-02'''
| width="150" | '''95.80'''
|- align="center"
| width="100" | '''-1343.029272'''
| width="100" | '''-1343.023766'''
| width="150" | '''-0.005506'''
| width="150" | '''2.94E-03'''
| width="150" | '''99.41'''
|- align="center"
| width="100" | '''-1343.032443'''
| width="100" | '''-1343.024742'''
| width="150" | '''-0.007701'''
| width="150" | '''2.88E-04'''
| width="150" | '''99.94'''
|-
|}

 

The above hartree units are converted to J/mol for calculation of K where 1 hartress = 4.3597E-18

Studying all the free energies of the (R,R) series and compare them with the (S,S) series, it comes as no surprise that (R,R) product is favoured over (S,S) product as (R,R) is more stable. Indeed, this corresponds with the literature value reporting 92% ee of (R,R) products over that of (S,S).

==== '''Analysis of the Transition State of Epoxidation''' ====
==== '''Shi Fructose Catalyst''' ====
For this section, I will be analyzing the the transition state of 1) styrene and 2) trans-stilbene with the Shi fructose catalyst.

===== '''(R) and (S)-styrene transition state''' =====
The transition state for the formation of (R)-styrene oxide and (S)-styrene oxide are given as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R)-styrene oxide'''
| width="150" | '''(S)-styrene oxide'''
|- align="center"
| width="150" | ''' Structure of Catalyst '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide R.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide S ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| [[File:Steric shi fructose R.png|450px|center]]
| [[File:Steric shi fructose S.png|450px|center]]
|-
|}

 

In the transition state for (R)-styrene, it was discovered that the Re face is reacting with the oxygen of the dioxirane. The phenyl ring is oriented endo with respect to the fructose catalyst. However, the (S)-styrene is reacting at the Si face and the phenyl ring is oriented exo relative to the catalyst.

The approach taken by (R)-styrene and (S)-styrene are restricted to only one due to steric interactions. Therefore, the epoxidation of both styrenes by the Shi catalyst will be stereospecific and retains all the stereochemical information of the reactant. However, whether or not (R)-styrene oxide or (S)-styrene oxide is form is dependent on the relative energies of the transition state. The more stable the transition state, the more likely the product of the transition state will be formed.

So in order to examine this, an example of transition state of both styrenes with Shi catalyst are obtained and analyzed.
 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1303.736813'''
| width="100" | '''-1303.727673'''
| width="150" | '''-0.00914'''
| width="150" | '''6.28E-05'''
| width="150" | '''99.99'''

|-
|}

 

From the above, we can see the predicted high enantiopurity of the reaction favoring the (R) product because of the lower energy of the transition states. To understand the reason, we have to turn to non-covalent interaction (NCI) analysis.

[[File:NCI shi fructose styrene.png|700px|center]]

To complement the NCI analysis, a QTAIM (Quantum Theory of Atoms in Molecules) analysis is conducted as well.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''(R)-styrene transition state'''
| width="200" | '''(S)-styrene transition state'''
|- align="center"
| width="100" | '''[[File:QTAIM R.png|400px|center]]'''
| width="100" | '''[[File:QTAIM S.png|400px|center]]'''
|- align="center"
| colspan="2" width="100" | '''Comments'''
|-
| colspan="2" width="100" | '''Unsurprisingly, QTAIM analysis has also shown that (R)-styrene/Shi catalyst has more interactions with one another. While (R)-styrene has 2 strong interactions, (S)-styrene has only one with the catalyst. Besides, the phenyl ring of (R)-styrene also confers additional positive interaction with the catalyst. QTAIM analysis has also show several interactions between the C=C geminal hydrogen of (R)-styrene intreacting with the oxygen atoms on the dioxacyclopentane ring'''
|-
|}

 

===== '''(R,R) and (S,S)-Stilbene transition state''' =====

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R,R)-Stilbene oxide'''
| width="150" | '''(S,S)-Stilbene oxide'''
|- align="center"
| width="150" | ''' Structure of Transition State '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Stilbene RR ts.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>SS stilbene oxide ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| colspan="2" | [[File:Shi fructose stilbene.png|700px|center]]

|-
|}

 

However, unlike styrene, trans-stilbene seems to approach perpendicularly to the dioxirane. This is proposed to be due to the steric interactions (marked in purple). Based on first inspection, it seems that (S,S)-Stilbene oxide has more steric interactions than (R,R)-Stilbene oxide. Although unsubstantial, it seems like my guess was correct. The (R,R)-stilbene/Shi catalyst transition state is lower in energy.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1534.687808'''
| width="100" | '''-1534.683440'''
| width="150" | '''0.004368'''
| width="150" | '''9.08E-3'''
| width="150" | '''98.20'''

|-
|}

 

NCI Analysis is also done for trans-stilbene

[[File:NCI stilbene.png|700px|center]]

==== '''Jacobsen Catalyst''' ====

For this section, cis-beta methyl styrene transition state will be analyzed.

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-3383.259559'''
| width="100" | '''-3383.251060'''
| width="150" | '''-0.008499'''
| width="150" | '''1.24E-04'''
| width="150" | '''99.98'''
|- align="center"
| width="100" | '''-3383.253442'''
| width="100" | '''-3383.250270'''
| width="150" | '''-0.003172'''
| width="150" | '''3.48E-02'''
| width="150" | '''93.27'''
|-
|}

 

As is obvious from here, the (S,R) transition state is more stable than the (R,S) transition state. Both transition states are exo with respect to the catalyst.

It is not immediately apparent just by looking at the molecule to determine which spatial groups have interactions with one another. Therefore, an NCI analysis is conducted again.

[[File:NCI Jacobsen.png|700px|center]]

Rep:Mod:Computationalreport1C

2013-11-21T21:51:11Z

Xc2611: /* Assigning the absolute configuration of the product */

= '''Synthesis and Computational Lab: 1C''' =
== '''Part 1: Introduction to Molecular Mechanics''' ==
=== '''Introduction to MMFF94 and MMFF94s''' ===

With the improvement of computational data and computer processing power, the usage of molecular mechanics/dynamics forcefield has become very integrated in predicting properties of chemical molecules. A molecular mechanics/dynamics forcefield should be able to predict characteristics such as molecular geometries, conformational/stereoisomeric energies, vibrational frequencies etc. to a reasonable accuracy as compared to experimental-derived values.

Building on work from Kollman et al. s’ AMBER forcefield and Allinger et al. s’ MM1, MM2, MM3 and MM4, Merck Research Laboratories have managed to optimized and improved the previous computational algorithms and produced MMFF94 (Merck Molecular Force Field 94). One of the most prominent advantages of MMFF94 over other preceeding work is its enhanced prediction accuracy. The reason lies in the fact that MMFF94’s core parameterization utilizes an unprecedently large amount of computational data obtained from ab initio calculations1.

Subsequently after the development of MMFF94, a new “static” variant of the MMFF was introduced i.e. the MMFF94s. Unlike MMFF94 that was developed for the use of molecular dynamics simulations (which can be expensive), MMFF94s was developed with the purpose of energy minimization studies in mind. Although both systems provide identical results for most systems, they differ for amides and unsaturated amines which contain resonance-delocalized trigonal nitrogen atoms2.

In this computational exercise, MMFF94s is used predominantly as oppose to the alternative Universal Force Field (UFF). Although versatile across the entire periodic table, UFF is derived from simple rules and atomic parameters such as fixed hybridization that increases the likelihood of erroneous structural and energetic predictions3.

=== '''Forms of MMFF94s''' ===

Steric energy of a molecule is the energy arise due to its geometry or conformation. Energy minimization of steric energy process ensures that the molecule is in its lowest energy conformation.

MMFF94s assumes that the total steric energy of a molecule can be found by the sum of a few specific interactions in a molecule.

ES = EBS + EAB + E SB + ET + EOOP + EVdW + EEE

'''where the bonded interactions are:'''

ES = Total Steric energy

EBS = Total Bond Stretching energy

EAB = Total Angle Bending energy

ESB = Total Stretch Bending energy

ET = Total Torsional Energy

EOOP = Total Out-Of-Plane Bending energy, and

'''where the non-bonded interactions are:'''

EVdW = Total Van der Waals Energy

EEE = Total Electrostatic Energy

{| border="1" cellspacing="1" cellpadding="10"
|-
| width="300" align="center" | '''Types of Energies'''
! width="600" align="center" | '''Explanation'''
|-
| colspan="2" style="text-align: center;" | '''Bonded Interactions'''
|-
| width="300" align="center" | '''Total Bond Stretching Energy'''
! width="600" align="left" | The total bond stretching energy is related to the vibration energy of the molecules in comparison to the equilibrium bond length. Whenever a bond deviates from the equilibrium bond length, the energy value increases.

MMFF94s uses a quartic function that has the force constant term (relate to bond strength). The quartic function term is superior to the cubic function term (used in MM2) in the sense that it avoid the “cubic stretch catastrophe” where progressive elongation of molecule bond length leads to negative infinity.
|-
| width="300" align="center" | '''Total Angle Bending Energy'''
! width="600" align="left" | Similar to Total Bond Stretching Energy, the total angle bending energy is also related to the vibration energy of the molecules about the equilibrium bond length. However, unlike EBS that measures the bond strength, EAB is associated with the stiffness of the molecules based on the Hookiean potential. Whenever bond angles deviate from the norm during vibration, this energy term increases as well.
|-
| width="300" align="center" | '''Total Stretch-Bending Energy'''
! width="600" align="left" | This energy term takes into account of the energy due to increase in bond length when bond angle between two atoms changes.
|-
| width="300" align="center" | '''Total Torsional Energy'''
! width="600" align="left" | Total torsional energy is the energy required for intermolecular rotation about the bonds. In molecule mechanics, however, this term is often used as a correction that must be added or subtracted to the total energy of the molecule to fit a quantum mechanical calculation about the dihedral angles of bonds.
|-
| width="300" align="center" | '''Total Out-Of-Plane Bending Energy'''
! width="600" align="left" | This energy term refers to the energy needed to deform the dihedral angle (zero degrees) of a planar group of atoms such as carbonyl or amide functional groups.
|-
| colspan="2" style="text-align: center;" | '''Non-Bonded Interactions'''
|-
| width="300" align="center" | '''Total Van der Waals Energy'''
! width="600" align="left" | The total Van der Waals energy term examines the intramolecular interactions such as repulsion or attraction between non-bonded atoms in the molecule. This term is crucial in determining the preferred conformation of the molecule.

MMFF94s employs the novel “Buffered-14-7”. The name is derived from a buffering constant and the 14th and 7th power dependencies of the repulsive and attractive energy in the equation.
|-
| width="300" align="center" | '''Total Electrostatic Energy'''
! width="600" align="left" | The total electrostatic energy functions take into account of the Coulombic potential and partial charge/dipole/atomic point charges interactions within the molecule.
|-

|}

 

== '''Part 2 : Conformational Analysis Using Molecular Mechanics''' ==
=== '''The Hydrogenation of Cyclopentadiene Dimer''' ===

==== '''Endo and exo adduct from the Dimerization of Cyclopentadiene''' ====
Cyclopentadiene will undergo dimerization by Diels-alder reaction to form either an endo or exo adduct.

[[File:XcwDimerization of CP.png|500px|center]]

==== '''Stereoselectivity of Dimerization of Cyclopentadiene''' ====
Although the exo adduct is thermodynamically more stable than the endo adduct, the endo adduct is form preferentially. Using the QST2 method, the transition state of the Diels Alder dimerization was found. It was discovered that due to the secondary orbital interactions in the endo transition state, the endo dimer is formed preferentially (the kinetic product). Hence, it is proven that the Diels Alder dimerization between two cyclopentadiene are kinetically controlled.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Transition State of Dimerization of Cyclopentadiene'''
| '''Imaginary Stretch Frequency (-881.25) of the Endo Transition State (click to animate)'''
| '''Secondary Orbital Interaction (Red overlapping orbitals)'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<uploadedFileContents>EndotsDCPD2.mol
</uploadedFileContents>
</jmolApplet></jmol>
| [[File:Xcwendotsimaginary.gif|300px|center]]
| [[File:XcwSecondary orbital interaction1.jpg|300px|center]]
|-
|}

 

==== '''Asynchronous Bond Formation of Dimerization of Cyclopentadiene''' ====

The initial study of the molecular orbitals of the transition states seemed a bit peculiar. Instead of getting a LUMO with symmetrical orbitals, the calculations showed a HOMO that is asymetric at the carbons where the new sigma bonds will be formed. Running an IRC further, it soon became clear that the asymmetry of the HOMO leads to an asychronous bond formation before leading to the product.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''IRC plot following the Endo Transition State '''
| '''IRC following the Endo Transition State (click to animate)'''
| '''Asymmetry of orbitals at the carbons where the new sigma bonds will be formed'''
|- align="center"
| [[File:XcwendotscyclopentadieneIRC.png|300px|center]]
| [[File:XcwendotsIRC.gif|300px|center]]
| [[File:XcwAsynchronous mo.jpg|300px|center]]
|-
|}

 

==== '''Comparison of Energies between the Endo and Exo adduct of Dicyclopentadiene''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Adduct of Dicyclopentadiene dimerization'''
| '''Exo Adduct of Dicyclopentadiene dimerization'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=19,atomno=1,atomno=2; color green;measure 19 1;measure 19 2;</script>
<uploadedFileContents>XcwEndodimer3.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>Exodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=7,atomno=17; color green;measure 17 7;</script>
<uploadedFileContents>XcwExodimer1.mol</uploadedFileContents>
</jmolApplet></jmol>
|-
|}

 

Using MMFF94s ab initio calculations, the energies for the exo dimer and the endo dimer are derived.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Exodimer'''
| '''55.374'''
| 3.543
| 30.772
| -2.041
| -2.728
| 0.015
| 12.800
| 13.014
|-
| '''Endodimer'''
| '''58.191'''
| 3.468
| 33.187
| -2.082
| -2.950
| 0.023
| 12.360
| 14.186
|-
|}

 

The MMFF94s steric energy (after minimization) for the exo dimer is lower than that of the endo dimer. This is reflected by the large difference for the EEE between the endo dimer and the exo dimer due to unfavourable steric repulsion between the two “arched down” cyclopentene rings.

==== '''Hydrogenation of Dicyclopentadiene''' ====

Hydrogenation of the endo dicyclopentadiene (DCPD) would lead to two potential products: dihydro product 1 and dihydro product 2.

[[File:XcwFormation of Dihydro products.png|500px|center]]

Using MMFF94s, the energy of the two dihydro products are calculated.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Dihydro Product 1'''
| '''50.123'''
| 3.308
| 30.864
| -1.927
| 0.060
| 0.015(2)
| 13.281
| 5.121
|-
| '''Dihydro Product 2'''
| '''41.257'''
| 2.823
| 24.685
| -1.657
| -0.379
| 0.000(2)
| 10.639
| 5.147
|-
| '''Tetrahydro Product'''
| '''39.042'''
| 2.730
| 25.151
| -1.676
| 1.287
| 0.000
| 11.551
| 0.000
|}

 

From the MMFF94s calculation, it can be seen that dihydro product 2 has a lower steric energy than dihydro product 1. Therefore, dihydro product 2 is the thermodynamic product for the hydrogenation of dicylopentadiene. And indeed, this was what was observed by Skala et al.. He observed that the first hydrogenation occur at the norborene part of the molecule (rate of hydrogenation several times faster than that in the cyclopentene ring)6. The first heat of hydrogenation at the norborene is 138.8 kJ/mol while the second hydrogenation at the cyclopentene right is 109.5 kJ/mol6.

From the above results, it is also obvious that tetrahydro product is much more stable than either dihydro product. And yet, studies have shown that the tetrahydro product will only form after prolonged hydrogenation under high temperature. However, subjecting DCPD to high temperature leads to low yield due to cracking of DCPD.

Since thermodynamically it is predicted to form favourably, the fact that it does not could only mean that the hydrogenation of DCPD to tetrahydrodicyclopentadiene (TH-DCPD) is kinetically controlled. Most possibly, the transition state of the hydrogenation of DCPD is highly unstable hence it is unlikely to form.

=== '''Atropisomerism in an Intermediate related to the Synthesis of Taxol''' ===

Atropisomerism is a type of stereoisomerism that is form as a result of hindered rotation about a single bond.

[[File:XcwAtropisomerism example.png|500px|center]]

In the case of the 6,6’-dinitro-2,2’-diphenic acid, rotation about the bonds joining the two substituted phenyl rings would have to overcome large steric interaction between the bulky substituents. The barrier of rotation is high enough for the two conformers to be isolated individually.

In the synthesis of taxol, one of the key intermediates exhibit atropisomerism.

==== '''Atropisomerism in Taxol Synthesis''' ====

For the key intermediate, rotation about the carbon-carbon bonds would lead to two types of atropisomers, each with either the carbonyl group poining upwards or downwards in relative to the bridge.

[[File:XcwIntermediate 9 and Intermediate 10.png|500px|center]]

Once again by using MMFF94s ab initio calculations, the steric energies for the two intermediates are illustrated as below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 9'''
| '''70.571'''
| 7.743
| 28.356
| -0.062
| 0.004
| 0.949
| 33.293
| 0.288
|-
| '''Intermediate 10'''
| '''60.553'''
| 7.599
| 18.838
| -0.139
| 0.199
| 0.844
| 33.269
| -0.056
|-

|}

 

Analyzing the data above, the largest energy difference between Intermediate 9 and Intermediate 10 stems from the EAB which is related to the strain of the ring. Intermediate 9 has an excess of 9.518 kcal/mol EAB as compared to Intermediate 10. This comes as a surprise as intermediate 9 is predicted to be more stable alkene.

The rationale behind the prediction of the stability of intermediate 9 stems from the fact that the through-space distance of the upward-pointing carbonyl oxygen with the carbon-carbon is further than the through space distance between the downward-pointing carbonyl oxygen with the -CH2-CH2- fragment at the norbornene part in intermediate 10.

==== '''Hyperstable Olefins''' ====

Intermediate 9 and Intermediate 10 does not react readily with other reagents during functionalization. This is due to the hyperstability effect found in hyperstable olefins.

Hyperstable olefins are alkenes that contain less strain in the ring (i.e. negative olefin strain values) compared to the parent hydrocarbon. To study this further, further MMFF94s calculation was done to compare Intermediate 10 with the parent hydrocarbon.

[[File:XcwIntermediate10andPH.png|500px|center]]

The energies that we calculated are tabulated as shown below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 10'''
| '''44.878 '''
| 5.211
| 15.488
| -0.267
| -1.655
| 0.998
| 25.014
| 0.088
|-
| '''Parent Hydrocarbon'''
| '''50.564'''
| 4.692
| 21.979
| 0.109
| -0.958
| 0.247
| 24.495
| 0.000
|-

|}

 

Scrutinizing the results, the largest energy difference between intermediate 10 and the parent hydrocarbon stems from the Total Angle Bending Energy, EAB. Since the Total Angle bending energy is related to the angle strain in the molecules, it is apparent that the parent hydrocarbon has more ring strain as compared to the bridgehead olefin.

== '''Part 3 : Spectroscopic Simulation Using Quantum Mechanics''' ==
=== '''Spectroscopy of an Intermediate Related to the Synthesis of Taxol''' ===

Molecule 17 and 18 are derivatives of intermediate 9 and 10. In this exercise, MMFF94s is used to predict the 1H and 13C NMR of molecule 17 and molecule 18.

[[File:XcwIntermediate17&18.png|500px|center]]

==== '''NMR Spectra of Molecule 17''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 17.mol
</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwHNMRMolecule 17 Chair Overall NMR.png|500px|center]]
| [[File:XcwHNMRMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.1825
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| The first three results were fairly straight forward to be deduced and correlate wit experimental data.

The hydrogen atom that is geminally attached to the carbon of the double bonds is the most deshielded due to the ring current anisotropic effect of the ring current

The second most deshielded hydrogen atom is the hydrogen atom on the methyl group on the bridge. The hydrogen atom is pointing directly to the oxygen atom of the carbonyl functional group.

The peaks with an integration height of 4 is assigned to the hydrogen atoms in the 1,3-dithiolane ring fragment.

Subsequent analysis of the 1H NMR became very complicated very quickly for two reasons:

1. Gaussian calculations showed some atoms with an integration height of 3. Comparing their file atom number and checking their chemical environment, it is not possible to find any correlation between them.

2. Some of the peaks in the literature remains unresolved and are given as multiplets or grouped together.

|- align="center"
| 52
| 3.1775
| 1
| '''2.99'''
|- align="center"
| 53,52,50,51
| 3.0867
| 4
| '''3.40-3.10'''
|- align="center"
| 42,43,39
| 2.7445
| 3
| ''' '''
|- align="center"
| 49
| 2.6187
| 1
| ''' '''
|- align="center"
| 34
| 2.4371
| 1
| ''' '''
|- align="center"
| 35
| 2.3782
| 1
| ''' '''
|- align="center"
| 40,37,26
| 2.2730
| 3
| ''' '''
|- align="center"
| 30
| 2.1566
| 1
| ''' '''
|- align="center"
| 36
| 2.1033
| 1
| ''' '''
|- align="center"
| 32,28
| 2.0259
| 2
| ''' '''
|- align="center"
| 25
| 1.8535
| 2
| ''' '''
|- align="center"
| 38,46,27
| 1.5898
| 3
| '''1.25'''
|- align="center"
| 29
| 1.4557
| 1
| ''' '''
|- align="center"
| 31
| 1.0123
| 1
| ''' '''
|- align="center"
| 44,48,45
| 0.9087
| 3
| '''1.10'''
|- align="center"
| 47
| 0.8354
| 1
| ''' '''
|- align="center"
| 33
| 0.5790
| 1
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 17 Chair Overall NMR2.png|500px|center]]
| [[File:XcwMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 216.2725
| 1
| '''218.79'''
| rowspan="10" style="text-align:center;"| [[File:XcwMolecule 17 image for CNMR.jpg|600px|center]]
|- align="center"
| 13
| 144.8626
| 1
| '''144.63'''
|- align="center"
| 14
| 124.7193
| 1
| '''125.33'''
|- align="center"
| 3
| 91.3340
| 1
| '''72.88'''
|- align="center"
| 2
| 60.9568
| 1
| '''56.19'''
|- align="center"
| 1
| 57.0811
| 1
| '''52.52'''
|- align="center"
| 10
| 52.4663
| 1
| '''48.50'''
|- align="center"
| 16
| 51.4857
| 1
| '''46.80'''
|- align="center"
| 9
| 46.9196
| 1
| '''45.76'''
|- align="center"
| 23
| 43.8647
| 1
| '''39.80'''
|- align="center"
| 22
| 41.9450
| 1
| '''38.81'''
| Comments
|- align="center"
| 4
| 41.8724
| 1
| '''35.85'''
| rowspan="9" style="text-align:left;"| The carbon bonded to the oxygen atom is the most deshielded, as is shown in the predicted values and the experimental values. There is a deviation between the values. Quite possibly, this is due to the fact that in reality, the carbonyl functional group is pointing slightly towards the equatorial position rather than a lateral position relative to the ring (as is in the input for Gaussian calculation)

Most of the 1CNMR values that was predicted by Gaussian are all within an acceptable range of deviation. However, there is carbon 3 that has significant deviation between the predicted value and experimental value.

Carbon 3 is the carbon bonded to the two sulphurs in the 1,3-dithiolane ring fragment. Such a huge deviation would possibly mean that the conformer that was given as input to Gaussian differs from the literature.

The above NMR spectra was corrected with a level of theory B3LYP/6-31G(d,p) using TMS as reference and in chloroform.

|- align="center"
| 15
| 35.4348
| 1
| '''32.66'''
|- align="center"
| 11
| 31.1964
| 1
| '''28.79'''
|- align="center"
| 6
| 28.9432
| 1
| '''28.29'''
|- align="center"
| 7
| 28.3640
| 1
| '''26.88'''
|- align="center"
| 12
| 27.3767
| 1
| '''25.66'''
|- align="center"
| 17
| 26.3311
| 1
| '''23.86'''
|- align="center"
| 15
| 24.5483
| 1
| '''20.96'''
|- align="center"
| 18
| 19.7788
| 1
| '''18.71'''
|-
|}
 

==== '''NMR Spectra of Molecule 18''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 18 Boat for Image2.mol</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"-
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 18 Chair Overall NMR.png|500px|center]]
| [[File:Molecule 18 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.2832
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| ''' '''
|- align="center"
| 50
| 3.3175
| 1
| rowspan="4" style="text-align:centre;"| '''3.00-2.70'''
|- align="center"
| 52
| 3.2153
| 1
|- align="center"
| 51,53
| 3.1161
| 2
|- align="center"
| 34,43
| 2.8606
| 2
|- align="center"
| 38
| 2.4549
| 1
| ''' '''
|- align="center"
| 42
| 2.3968
| 1
| ''' '''
|- align="center"
| 25,29,26
| 2.2796
| 3
| ''' '''
|- align="center"
| 39
| 2.0844
| 1
| ''' '''
|- align="center"
| 40,36
| 1.9699
| 2
| ''' '''
|- align="center"
| 37,24
| 1.8519
| 2
| ''' '''
|- align="center"
| 31,27
| 1.6780
| 2
| ''' '''
|- align="center"
| 28
| 1.6175
| 1
| ''' '''
|- align="center"
| 46,49
| 1.4979
| 2
| ''' '''
|- align="center"
| 35
| 1.4150
| 1
| ''' '''
|- align="center"
| 32
| 1.3531
| 1
| ''' '''
|- align="center"
| 48
| 1.1606
| 1
| ''' '''
|- align="center"
| 33,30,47
| 1.0653
| 3
| '''1.03'''
|- align="center"
| 44,45
| 0.9643
| 2
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwMolecule 18 Boat Overall NMR.png|500px|center]]
| [[File:XcwMolecule 18 Boat zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 211.8325
| 1
| '''211.49'''
| rowspan="10" style="text-align:center;"| [[File:Molecule 18 Boat for 13 CNMR.jpg|600px|center]]
|- align="center"
| 13
| 148.6673
| 1
| '''148.72'''
|- align="center"
| 14
| 118.8373
| 1
| '''120.90'''
|- align="center"
| 3
| 89.0869
| 1
| '''74.61'''
|- align="center"
| 2
| 67.8886
| 1
| '''60.53'''
|- align="center"
| 1
| 56.1133
| 1
| '''51.30'''
|- align="center"
| 10
| 55.5998
| 1
| '''50.94'''
|- align="center"
| 16
| 50.1124
| 1
| '''45.53'''
|- align="center"
| 22
| 48.2030
| 1
| '''43.28'''
|- align="center"
| 23
| 44.2222
| 1
| '''40.82'''
|- align="center"
| 4
| 42.0354
| 1
| '''38.73'''
| Comments
|- align="center"
| 9
| 37.5865
| 1
| '''36.78'''
| rowspan="9" style="text-align:left;"| ''' '''
|- align="center"
| 6
| 35.3106
| 1
| '''35.47'''
|- align="center"
| 15
| 31.0459
| 1
| '''30.84'''
|- align="center"
| 7
| 28.8476
| 1
| '''30.00'''
|- align="center"
| 12
| 28.6623
| 1
| '''25.56'''
|- align="center"
| 17
| 25.7393
| 1
| '''25.35'''
|- align="center"
| 11
| 25.2603
| 1
| '''22.21'''
|- align="center"
| 18
| 23.3944
| 1
| '''21.39'''
|- align="center"
| 5
| 21.0478
| 1
| '''19.83'''
|-
|}
 

== '''Part 4 : Analysis of the Properties of the Synthesized Alkene Epoxides''' ==
=== '''The two catalytics systems''' ===

Assymmetric epoxidation of prochiral alkenes may lead to product with different stereochemical outcome as illustrated as below. To solve this problem, different types of asymmetric epoxidation catalyst have been synthesized. In this study, we shall be focusing on Shi asymmetric fructose catalyst as well as Jacobsen asymmetric catalyst.

[[File:Asymmetric catalyst.png|400px|center]]

==== ''' The Shi Asymmetric Fructose Catalyst''' ====

Molecule 21 is the stable precursor of molecule 22, the active catalyst. Molecule 21 can be converted to molecule 22 by using either persulfuric acid or potassium peroxymonosulphate.

[[File:Molecule 21 to 23.png|400px|center]]

The transition state of the Shi epoxidation was a subject of debate for a few moments. However, recent studies have led to the conclusion that the spiro transition state is more favored than the planar transition state. The spiro transition state is the transition that has its dioxirane perpendicularly bisecting the alkene double bond. This is thought to be more favourable due to interactions between the lone pairs of the oxygen with the LUMO of the alkene.

[[File:Spiro and planar ts.png|500px|center]]

==== ''' The Jacobsen Asymmetric Catalyst''' ====

Molecule 23 is the stable precursor of molecule 24, the active catalyst. Molecule 23 can be converted to molecule 24 by using sodium perchlorate.

[[File:Salen, 23 and 24.png|400px|center]]

Jacobsen catalyst is biphasic. The first phase involves the transfer of oxygen to molecule 23. Sodium perchlorate oxidizes Mn(III) to Mn(V).

In the second step, Jacobsen catalyst acts via a radical mechanism. It is thought to be so because epoxidation of trans-alkene by Jacobsen catalyst yield cis-alkene as well. A radical mechanism will lead to the lost of stereochemical information of the molecule.

=== ''' Crystal structure of the two catalyst''' ===
==== '''Molecule 21''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 21'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 21 strucutre.png|600px|center]]'''
|-
| style="text-align:center;" width="150" | ''' Bond '''
| style="text-align:center;" width="150"| ''' Bond Lenghts (Angstrom)'''
| style="text-align:center;" | ''' Evaluation'''
|-
| style="text-align:center;"| ''' O1-C1 '''
| style="text-align:center;"| ''' 1.400'''
| rowspan="10" style="text-align:left;"| [[File:Molecule 21 2.png|300px|center]]

The normal bond length of an C-O bond is 1.430 angstrom.

The most interesting aspect here is O4 and O2. The lone pair of O4 is antiperplanar to the sigma* orbital of the carbonyl group while the lone pair of O2 is anti periplanar to the carbonyl pi* orbital. Donation of electron can occur because of the correct symmetry. Due to the mixing of the orbitals, the C2-O2 and C4-O4 has been conferred with a certain degree of double bond character.

However, due to the lone pair on oxygen being now donated to the carbonyl antibonding orbitals, the O2 and O4 is slightly “electron deficient” and electron density will be pulled away from O2 and O4. That would explain why the bond length increase for O2-C7 and O4-C10. Increase in bond length is an indicator of the weakening of the bond.
|-
| style="text-align:center;"|'''O1-C7'''
| style="text-align:center;"|'''1.413'''
|-
| style="text-align:center;"|'''O2-C7'''
| style="text-align:center;"|'''1.441'''
|-
| style="text-align:center;"|'''O2-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O4-C4'''
| style="text-align:center;"|'''1.396'''
|-
| style="text-align:center;"|'''O4-C10'''
| style="text-align:center;"|'''1.439'''
|-
| style="text-align:center;"|'''O5-C10'''
| style="text-align:center;"|'''1.409'''
|-
| style="text-align:center;"|'''O5-C5'''
| style="text-align:center;"|'''1.416'''
|-
| style="text-align:center;"|'''O6-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O6-C6'''
| style="text-align:center;"|'''1.420'''
|-
|}
 

==== '''Molecule 23''' ====

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 23'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 23 struc.png|600px|center]]'''
|-
| The most outstanding feature from this molecule is the fact that is adopt a puckered form of the square base pyramidal form. This is no surprise that the molecule is almost planar due to the electron delocalization around each side of the salen ligand.

The tery-butyl hydrogen are oriented closely to one another. Non-covalent interaction studies indicated that repulsion would occur for H---H bond length that are less than 2.1 angstrom while favourable interaction may be dominant with bond length above 2.4 angstrom. It was discovered that all 4 hydrogens have bond length more than 2.4 angstrom hence there should not be any significant repulsion between them. Instead, certain amount of attractive force will ensue and that contributes to the overall stability of the molecule

|-
|}
 

=== ''' The calculated NMR properties of the product''' ===

=== ''' Assigning the absolute configuration of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''Predicted ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg'''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg '''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental conditions'''
| width="100" | '''1.00g/100ml, chloroform, 21 degree Celcisus, 589 nm wavelength '''
| width="100" | '''1.02g/100ml (99% ee), chloroform, 25 degree Celsius, 589 nm wavelength '''
| width="100" | '''1.01g/100ml, ethanol, 22 degree Celsius, 589 nm wavelength '''
| width="100" | '''0.6g/100ml, ethanol, 20 degree Celsius, 589 nm wavelength '''
|- align="left"
| width="100" | ''' Predicted VCD Spectrum'''
| width="100" | '''[[File:Styrene R VCD.png|300px|center|]] '''
| width="100" | '''[[File:Styrene S VCD.png|300px|center|]]'''
| width="100" | '''[[File:Stilbene RR VCD.png|300px|center|]]'''
| width="100" | '''[[File:Stilbene SS VCD.png|300px|center|]]'''
|-
|}

 

=== ''' Analysis of the Transition State for Reactions''' ===
==== '''Predicting Enantiomeric Excess based on Transition State energies''' ====

One of the energy output from Gaussian calculation is the “sum of electronic and thermal free energies”. This is Gibbs Free Energy at 298.15K and 1 atm.

Using this term and invoking a variant of the Curtin-Hammett Principle, it is possible to calculate a predicted enantiomeric excess of one enantiomer over the other.

[[File:Ee and transition state energy.png|800px|center]]

Using the derivations from above and equation (4), we analyze the enantiomeric excess of beta-methyl styrene and the results are tabulated as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1343.022970'''
| width="100" | '''-1343.017942'''
| width="150" | '''-0.005028'''
| width="150" | '''4.88E-03'''
| width="150" | '''99.03'''
|- align="center"
| width="100" | '''-1343.019233'''
| width="100" | '''-1343.015603'''
| width="150" | '''-0.003630'''
| width="150" | '''2.14E-02'''
| width="150" | '''95.80'''
|- align="center"
| width="100" | '''-1343.029272'''
| width="100" | '''-1343.023766'''
| width="150" | '''-0.005506'''
| width="150" | '''2.94E-03'''
| width="150" | '''99.41'''
|- align="center"
| width="100" | '''-1343.032443'''
| width="100" | '''-1343.024742'''
| width="150" | '''-0.007701'''
| width="150" | '''2.88E-04'''
| width="150" | '''99.94'''
|-
|}

 

The above hartree units are converted to J/mol for calculation of K where 1 hartress = 4.3597E-18

Studying all the free energies of the (R,R) series and compare them with the (S,S) series, it comes as no surprise that (R,R) product is favoured over (S,S) product as (R,R) is more stable. Indeed, this corresponds with the literature value reporting 92% ee of (R,R) products over that of (S,S).

==== '''Analysis of the Transition State of Epoxidation''' ====
==== '''Shi Fructose Catalyst''' ====
For this section, I will be analyzing the the transition state of 1) styrene and 2) trans-stilbene with the Shi fructose catalyst.

===== '''(R) and (S)-styrene transition state''' =====
The transition state for the formation of (R)-styrene oxide and (S)-styrene oxide are given as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R)-styrene oxide'''
| width="150" | '''(S)-styrene oxide'''
|- align="center"
| width="150" | ''' Structure of Catalyst '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide R.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide S ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| [[File:Steric shi fructose R.png|450px|center]]
| [[File:Steric shi fructose S.png|450px|center]]
|-
|}

 

In the transition state for (R)-styrene, it was discovered that the Re face is reacting with the oxygen of the dioxirane. The phenyl ring is oriented endo with respect to the fructose catalyst. However, the (S)-styrene is reacting at the Si face and the phenyl ring is oriented exo relative to the catalyst.

The approach taken by (R)-styrene and (S)-styrene are restricted to only one due to steric interactions. Therefore, the epoxidation of both styrenes by the Shi catalyst will be stereospecific and retains all the stereochemical information of the reactant. However, whether or not (R)-styrene oxide or (S)-styrene oxide is form is dependent on the relative energies of the transition state. The more stable the transition state, the more likely the product of the transition state will be formed.

So in order to examine this, an example of transition state of both styrenes with Shi catalyst are obtained and analyzed.
 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1303.736813'''
| width="100" | '''-1303.727673'''
| width="150" | '''-0.00914'''
| width="150" | '''6.28E-05'''
| width="150" | '''99.99'''

|-
|}

 

From the above, we can see the predicted high enantiopurity of the reaction favoring the (R) product because of the lower energy of the transition states. To understand the reason, we have to turn to non-covalent interaction (NCI) analysis.

[[File:NCI shi fructose styrene.png|700px|center]]

To complement the NCI analysis, a QTAIM (Quantum Theory of Atoms in Molecules) analysis is conducted as well.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''(R)-styrene transition state'''
| width="200" | '''(S)-styrene transition state'''
|- align="center"
| width="100" | '''[[File:QTAIM R.png|400px|center]]'''
| width="100" | '''[[File:QTAIM S.png|400px|center]]'''
|- align="center"
| colspan="2" width="100" | '''Comments'''
|-
| colspan="2" width="100" | '''Unsurprisingly, QTAIM analysis has also shown that (R)-styrene/Shi catalyst has more interactions with one another. While (R)-styrene has 2 strong interactions, (S)-styrene has only one with the catalyst. Besides, the phenyl ring of (R)-styrene also confers additional positive interaction with the catalyst. QTAIM analysis has also show several interactions between the C=C geminal hydrogen of (R)-styrene intreacting with the oxygen atoms on the dioxacyclopentane ring'''
|-
|}

 

===== '''(R,R) and (S,S)-Stilbene transition state''' =====

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R,R)-Stilbene oxide'''
| width="150" | '''(S,S)-Stilbene oxide'''
|- align="center"
| width="150" | ''' Structure of Transition State '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Stilbene RR ts.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>SS stilbene oxide ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| colspan="2" | [[File:Shi fructose stilbene.png|700px|center]]

|-
|}

 

However, unlike styrene, trans-stilbene seems to approach perpendicularly to the dioxirane. This is proposed to be due to the steric interactions (marked in purple). Based on first inspection, it seems that (S,S)-Stilbene oxide has more steric interactions than (R,R)-Stilbene oxide. Although unsubstantial, it seems like my guess was correct. The (R,R)-stilbene/Shi catalyst transition state is lower in energy.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1534.687808'''
| width="100" | '''-1534.683440'''
| width="150" | '''0.004368'''
| width="150" | '''9.08E-3'''
| width="150" | '''98.20'''

|-
|}

 

NCI Analysis is also done for trans-stilbene

[[File:NCI stilbene.png|700px|center]]

==== '''Jacobsen Catalyst''' ====

For this section, cis-beta methyl styrene transition state will be analyzed.

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-3383.259559'''
| width="100" | '''-3383.251060'''
| width="150" | '''-0.008499'''
| width="150" | '''1.24E-04'''
| width="150" | '''99.98'''
|- align="center"
| width="100" | '''-3383.253442'''
| width="100" | '''-3383.250270'''
| width="150" | '''-0.003172'''
| width="150" | '''3.48E-02'''
| width="150" | '''93.27'''
|-
|}

 

As is obvious from here, the (S,R) transition state is more stable than the (R,S) transition state. Both transition states are exo with respect to the catalyst.

It is not immediately apparent just by looking at the molecule to determine which spatial groups have interactions with one another. Therefore, an NCI analysis is conducted again.

[[File:NCI Jacobsen.png|700px|center]]

File:Stilbene SS VCD.png

2013-11-21T21:49:34Z

Xc2611:

File:Stilbene RR VCD.png

2013-11-21T21:49:33Z

Xc2611:

File:Styrene S VCD.png

2013-11-21T21:49:28Z

Xc2611:

File:Styrene R VCD.png

2013-11-21T21:49:26Z

Xc2611:

Rep:Mod:Computationalreport1C

2013-11-21T21:47:37Z

Xc2611: /* Assigning the absolute configuration of the product */

= '''Synthesis and Computational Lab: 1C''' =
== '''Part 1: Introduction to Molecular Mechanics''' ==
=== '''Introduction to MMFF94 and MMFF94s''' ===

With the improvement of computational data and computer processing power, the usage of molecular mechanics/dynamics forcefield has become very integrated in predicting properties of chemical molecules. A molecular mechanics/dynamics forcefield should be able to predict characteristics such as molecular geometries, conformational/stereoisomeric energies, vibrational frequencies etc. to a reasonable accuracy as compared to experimental-derived values.

Building on work from Kollman et al. s’ AMBER forcefield and Allinger et al. s’ MM1, MM2, MM3 and MM4, Merck Research Laboratories have managed to optimized and improved the previous computational algorithms and produced MMFF94 (Merck Molecular Force Field 94). One of the most prominent advantages of MMFF94 over other preceeding work is its enhanced prediction accuracy. The reason lies in the fact that MMFF94’s core parameterization utilizes an unprecedently large amount of computational data obtained from ab initio calculations1.

Subsequently after the development of MMFF94, a new “static” variant of the MMFF was introduced i.e. the MMFF94s. Unlike MMFF94 that was developed for the use of molecular dynamics simulations (which can be expensive), MMFF94s was developed with the purpose of energy minimization studies in mind. Although both systems provide identical results for most systems, they differ for amides and unsaturated amines which contain resonance-delocalized trigonal nitrogen atoms2.

In this computational exercise, MMFF94s is used predominantly as oppose to the alternative Universal Force Field (UFF). Although versatile across the entire periodic table, UFF is derived from simple rules and atomic parameters such as fixed hybridization that increases the likelihood of erroneous structural and energetic predictions3.

=== '''Forms of MMFF94s''' ===

Steric energy of a molecule is the energy arise due to its geometry or conformation. Energy minimization of steric energy process ensures that the molecule is in its lowest energy conformation.

MMFF94s assumes that the total steric energy of a molecule can be found by the sum of a few specific interactions in a molecule.

ES = EBS + EAB + E SB + ET + EOOP + EVdW + EEE

'''where the bonded interactions are:'''

ES = Total Steric energy

EBS = Total Bond Stretching energy

EAB = Total Angle Bending energy

ESB = Total Stretch Bending energy

ET = Total Torsional Energy

EOOP = Total Out-Of-Plane Bending energy, and

'''where the non-bonded interactions are:'''

EVdW = Total Van der Waals Energy

EEE = Total Electrostatic Energy

{| border="1" cellspacing="1" cellpadding="10"
|-
| width="300" align="center" | '''Types of Energies'''
! width="600" align="center" | '''Explanation'''
|-
| colspan="2" style="text-align: center;" | '''Bonded Interactions'''
|-
| width="300" align="center" | '''Total Bond Stretching Energy'''
! width="600" align="left" | The total bond stretching energy is related to the vibration energy of the molecules in comparison to the equilibrium bond length. Whenever a bond deviates from the equilibrium bond length, the energy value increases.

MMFF94s uses a quartic function that has the force constant term (relate to bond strength). The quartic function term is superior to the cubic function term (used in MM2) in the sense that it avoid the “cubic stretch catastrophe” where progressive elongation of molecule bond length leads to negative infinity.
|-
| width="300" align="center" | '''Total Angle Bending Energy'''
! width="600" align="left" | Similar to Total Bond Stretching Energy, the total angle bending energy is also related to the vibration energy of the molecules about the equilibrium bond length. However, unlike EBS that measures the bond strength, EAB is associated with the stiffness of the molecules based on the Hookiean potential. Whenever bond angles deviate from the norm during vibration, this energy term increases as well.
|-
| width="300" align="center" | '''Total Stretch-Bending Energy'''
! width="600" align="left" | This energy term takes into account of the energy due to increase in bond length when bond angle between two atoms changes.
|-
| width="300" align="center" | '''Total Torsional Energy'''
! width="600" align="left" | Total torsional energy is the energy required for intermolecular rotation about the bonds. In molecule mechanics, however, this term is often used as a correction that must be added or subtracted to the total energy of the molecule to fit a quantum mechanical calculation about the dihedral angles of bonds.
|-
| width="300" align="center" | '''Total Out-Of-Plane Bending Energy'''
! width="600" align="left" | This energy term refers to the energy needed to deform the dihedral angle (zero degrees) of a planar group of atoms such as carbonyl or amide functional groups.
|-
| colspan="2" style="text-align: center;" | '''Non-Bonded Interactions'''
|-
| width="300" align="center" | '''Total Van der Waals Energy'''
! width="600" align="left" | The total Van der Waals energy term examines the intramolecular interactions such as repulsion or attraction between non-bonded atoms in the molecule. This term is crucial in determining the preferred conformation of the molecule.

MMFF94s employs the novel “Buffered-14-7”. The name is derived from a buffering constant and the 14th and 7th power dependencies of the repulsive and attractive energy in the equation.
|-
| width="300" align="center" | '''Total Electrostatic Energy'''
! width="600" align="left" | The total electrostatic energy functions take into account of the Coulombic potential and partial charge/dipole/atomic point charges interactions within the molecule.
|-

|}

 

== '''Part 2 : Conformational Analysis Using Molecular Mechanics''' ==
=== '''The Hydrogenation of Cyclopentadiene Dimer''' ===

==== '''Endo and exo adduct from the Dimerization of Cyclopentadiene''' ====
Cyclopentadiene will undergo dimerization by Diels-alder reaction to form either an endo or exo adduct.

[[File:XcwDimerization of CP.png|500px|center]]

==== '''Stereoselectivity of Dimerization of Cyclopentadiene''' ====
Although the exo adduct is thermodynamically more stable than the endo adduct, the endo adduct is form preferentially. Using the QST2 method, the transition state of the Diels Alder dimerization was found. It was discovered that due to the secondary orbital interactions in the endo transition state, the endo dimer is formed preferentially (the kinetic product). Hence, it is proven that the Diels Alder dimerization between two cyclopentadiene are kinetically controlled.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Transition State of Dimerization of Cyclopentadiene'''
| '''Imaginary Stretch Frequency (-881.25) of the Endo Transition State (click to animate)'''
| '''Secondary Orbital Interaction (Red overlapping orbitals)'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<uploadedFileContents>EndotsDCPD2.mol
</uploadedFileContents>
</jmolApplet></jmol>
| [[File:Xcwendotsimaginary.gif|300px|center]]
| [[File:XcwSecondary orbital interaction1.jpg|300px|center]]
|-
|}

 

==== '''Asynchronous Bond Formation of Dimerization of Cyclopentadiene''' ====

The initial study of the molecular orbitals of the transition states seemed a bit peculiar. Instead of getting a LUMO with symmetrical orbitals, the calculations showed a HOMO that is asymetric at the carbons where the new sigma bonds will be formed. Running an IRC further, it soon became clear that the asymmetry of the HOMO leads to an asychronous bond formation before leading to the product.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''IRC plot following the Endo Transition State '''
| '''IRC following the Endo Transition State (click to animate)'''
| '''Asymmetry of orbitals at the carbons where the new sigma bonds will be formed'''
|- align="center"
| [[File:XcwendotscyclopentadieneIRC.png|300px|center]]
| [[File:XcwendotsIRC.gif|300px|center]]
| [[File:XcwAsynchronous mo.jpg|300px|center]]
|-
|}

 

==== '''Comparison of Energies between the Endo and Exo adduct of Dicyclopentadiene''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Adduct of Dicyclopentadiene dimerization'''
| '''Exo Adduct of Dicyclopentadiene dimerization'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=19,atomno=1,atomno=2; color green;measure 19 1;measure 19 2;</script>
<uploadedFileContents>XcwEndodimer3.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>Exodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=7,atomno=17; color green;measure 17 7;</script>
<uploadedFileContents>XcwExodimer1.mol</uploadedFileContents>
</jmolApplet></jmol>
|-
|}

 

Using MMFF94s ab initio calculations, the energies for the exo dimer and the endo dimer are derived.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Exodimer'''
| '''55.374'''
| 3.543
| 30.772
| -2.041
| -2.728
| 0.015
| 12.800
| 13.014
|-
| '''Endodimer'''
| '''58.191'''
| 3.468
| 33.187
| -2.082
| -2.950
| 0.023
| 12.360
| 14.186
|-
|}

 

The MMFF94s steric energy (after minimization) for the exo dimer is lower than that of the endo dimer. This is reflected by the large difference for the EEE between the endo dimer and the exo dimer due to unfavourable steric repulsion between the two “arched down” cyclopentene rings.

==== '''Hydrogenation of Dicyclopentadiene''' ====

Hydrogenation of the endo dicyclopentadiene (DCPD) would lead to two potential products: dihydro product 1 and dihydro product 2.

[[File:XcwFormation of Dihydro products.png|500px|center]]

Using MMFF94s, the energy of the two dihydro products are calculated.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Dihydro Product 1'''
| '''50.123'''
| 3.308
| 30.864
| -1.927
| 0.060
| 0.015(2)
| 13.281
| 5.121
|-
| '''Dihydro Product 2'''
| '''41.257'''
| 2.823
| 24.685
| -1.657
| -0.379
| 0.000(2)
| 10.639
| 5.147
|-
| '''Tetrahydro Product'''
| '''39.042'''
| 2.730
| 25.151
| -1.676
| 1.287
| 0.000
| 11.551
| 0.000
|}

 

From the MMFF94s calculation, it can be seen that dihydro product 2 has a lower steric energy than dihydro product 1. Therefore, dihydro product 2 is the thermodynamic product for the hydrogenation of dicylopentadiene. And indeed, this was what was observed by Skala et al.. He observed that the first hydrogenation occur at the norborene part of the molecule (rate of hydrogenation several times faster than that in the cyclopentene ring)6. The first heat of hydrogenation at the norborene is 138.8 kJ/mol while the second hydrogenation at the cyclopentene right is 109.5 kJ/mol6.

From the above results, it is also obvious that tetrahydro product is much more stable than either dihydro product. And yet, studies have shown that the tetrahydro product will only form after prolonged hydrogenation under high temperature. However, subjecting DCPD to high temperature leads to low yield due to cracking of DCPD.

Since thermodynamically it is predicted to form favourably, the fact that it does not could only mean that the hydrogenation of DCPD to tetrahydrodicyclopentadiene (TH-DCPD) is kinetically controlled. Most possibly, the transition state of the hydrogenation of DCPD is highly unstable hence it is unlikely to form.

=== '''Atropisomerism in an Intermediate related to the Synthesis of Taxol''' ===

Atropisomerism is a type of stereoisomerism that is form as a result of hindered rotation about a single bond.

[[File:XcwAtropisomerism example.png|500px|center]]

In the case of the 6,6’-dinitro-2,2’-diphenic acid, rotation about the bonds joining the two substituted phenyl rings would have to overcome large steric interaction between the bulky substituents. The barrier of rotation is high enough for the two conformers to be isolated individually.

In the synthesis of taxol, one of the key intermediates exhibit atropisomerism.

==== '''Atropisomerism in Taxol Synthesis''' ====

For the key intermediate, rotation about the carbon-carbon bonds would lead to two types of atropisomers, each with either the carbonyl group poining upwards or downwards in relative to the bridge.

[[File:XcwIntermediate 9 and Intermediate 10.png|500px|center]]

Once again by using MMFF94s ab initio calculations, the steric energies for the two intermediates are illustrated as below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 9'''
| '''70.571'''
| 7.743
| 28.356
| -0.062
| 0.004
| 0.949
| 33.293
| 0.288
|-
| '''Intermediate 10'''
| '''60.553'''
| 7.599
| 18.838
| -0.139
| 0.199
| 0.844
| 33.269
| -0.056
|-

|}

 

Analyzing the data above, the largest energy difference between Intermediate 9 and Intermediate 10 stems from the EAB which is related to the strain of the ring. Intermediate 9 has an excess of 9.518 kcal/mol EAB as compared to Intermediate 10. This comes as a surprise as intermediate 9 is predicted to be more stable alkene.

The rationale behind the prediction of the stability of intermediate 9 stems from the fact that the through-space distance of the upward-pointing carbonyl oxygen with the carbon-carbon is further than the through space distance between the downward-pointing carbonyl oxygen with the -CH2-CH2- fragment at the norbornene part in intermediate 10.

==== '''Hyperstable Olefins''' ====

Intermediate 9 and Intermediate 10 does not react readily with other reagents during functionalization. This is due to the hyperstability effect found in hyperstable olefins.

Hyperstable olefins are alkenes that contain less strain in the ring (i.e. negative olefin strain values) compared to the parent hydrocarbon. To study this further, further MMFF94s calculation was done to compare Intermediate 10 with the parent hydrocarbon.

[[File:XcwIntermediate10andPH.png|500px|center]]

The energies that we calculated are tabulated as shown below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 10'''
| '''44.878 '''
| 5.211
| 15.488
| -0.267
| -1.655
| 0.998
| 25.014
| 0.088
|-
| '''Parent Hydrocarbon'''
| '''50.564'''
| 4.692
| 21.979
| 0.109
| -0.958
| 0.247
| 24.495
| 0.000
|-

|}

 

Scrutinizing the results, the largest energy difference between intermediate 10 and the parent hydrocarbon stems from the Total Angle Bending Energy, EAB. Since the Total Angle bending energy is related to the angle strain in the molecules, it is apparent that the parent hydrocarbon has more ring strain as compared to the bridgehead olefin.

== '''Part 3 : Spectroscopic Simulation Using Quantum Mechanics''' ==
=== '''Spectroscopy of an Intermediate Related to the Synthesis of Taxol''' ===

Molecule 17 and 18 are derivatives of intermediate 9 and 10. In this exercise, MMFF94s is used to predict the 1H and 13C NMR of molecule 17 and molecule 18.

[[File:XcwIntermediate17&18.png|500px|center]]

==== '''NMR Spectra of Molecule 17''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 17.mol
</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwHNMRMolecule 17 Chair Overall NMR.png|500px|center]]
| [[File:XcwHNMRMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.1825
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| The first three results were fairly straight forward to be deduced and correlate wit experimental data.

The hydrogen atom that is geminally attached to the carbon of the double bonds is the most deshielded due to the ring current anisotropic effect of the ring current

The second most deshielded hydrogen atom is the hydrogen atom on the methyl group on the bridge. The hydrogen atom is pointing directly to the oxygen atom of the carbonyl functional group.

The peaks with an integration height of 4 is assigned to the hydrogen atoms in the 1,3-dithiolane ring fragment.

Subsequent analysis of the 1H NMR became very complicated very quickly for two reasons:

1. Gaussian calculations showed some atoms with an integration height of 3. Comparing their file atom number and checking their chemical environment, it is not possible to find any correlation between them.

2. Some of the peaks in the literature remains unresolved and are given as multiplets or grouped together.

|- align="center"
| 52
| 3.1775
| 1
| '''2.99'''
|- align="center"
| 53,52,50,51
| 3.0867
| 4
| '''3.40-3.10'''
|- align="center"
| 42,43,39
| 2.7445
| 3
| ''' '''
|- align="center"
| 49
| 2.6187
| 1
| ''' '''
|- align="center"
| 34
| 2.4371
| 1
| ''' '''
|- align="center"
| 35
| 2.3782
| 1
| ''' '''
|- align="center"
| 40,37,26
| 2.2730
| 3
| ''' '''
|- align="center"
| 30
| 2.1566
| 1
| ''' '''
|- align="center"
| 36
| 2.1033
| 1
| ''' '''
|- align="center"
| 32,28
| 2.0259
| 2
| ''' '''
|- align="center"
| 25
| 1.8535
| 2
| ''' '''
|- align="center"
| 38,46,27
| 1.5898
| 3
| '''1.25'''
|- align="center"
| 29
| 1.4557
| 1
| ''' '''
|- align="center"
| 31
| 1.0123
| 1
| ''' '''
|- align="center"
| 44,48,45
| 0.9087
| 3
| '''1.10'''
|- align="center"
| 47
| 0.8354
| 1
| ''' '''
|- align="center"
| 33
| 0.5790
| 1
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 17 Chair Overall NMR2.png|500px|center]]
| [[File:XcwMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 216.2725
| 1
| '''218.79'''
| rowspan="10" style="text-align:center;"| [[File:XcwMolecule 17 image for CNMR.jpg|600px|center]]
|- align="center"
| 13
| 144.8626
| 1
| '''144.63'''
|- align="center"
| 14
| 124.7193
| 1
| '''125.33'''
|- align="center"
| 3
| 91.3340
| 1
| '''72.88'''
|- align="center"
| 2
| 60.9568
| 1
| '''56.19'''
|- align="center"
| 1
| 57.0811
| 1
| '''52.52'''
|- align="center"
| 10
| 52.4663
| 1
| '''48.50'''
|- align="center"
| 16
| 51.4857
| 1
| '''46.80'''
|- align="center"
| 9
| 46.9196
| 1
| '''45.76'''
|- align="center"
| 23
| 43.8647
| 1
| '''39.80'''
|- align="center"
| 22
| 41.9450
| 1
| '''38.81'''
| Comments
|- align="center"
| 4
| 41.8724
| 1
| '''35.85'''
| rowspan="9" style="text-align:left;"| The carbon bonded to the oxygen atom is the most deshielded, as is shown in the predicted values and the experimental values. There is a deviation between the values. Quite possibly, this is due to the fact that in reality, the carbonyl functional group is pointing slightly towards the equatorial position rather than a lateral position relative to the ring (as is in the input for Gaussian calculation)

Most of the 1CNMR values that was predicted by Gaussian are all within an acceptable range of deviation. However, there is carbon 3 that has significant deviation between the predicted value and experimental value.

Carbon 3 is the carbon bonded to the two sulphurs in the 1,3-dithiolane ring fragment. Such a huge deviation would possibly mean that the conformer that was given as input to Gaussian differs from the literature.

The above NMR spectra was corrected with a level of theory B3LYP/6-31G(d,p) using TMS as reference and in chloroform.

|- align="center"
| 15
| 35.4348
| 1
| '''32.66'''
|- align="center"
| 11
| 31.1964
| 1
| '''28.79'''
|- align="center"
| 6
| 28.9432
| 1
| '''28.29'''
|- align="center"
| 7
| 28.3640
| 1
| '''26.88'''
|- align="center"
| 12
| 27.3767
| 1
| '''25.66'''
|- align="center"
| 17
| 26.3311
| 1
| '''23.86'''
|- align="center"
| 15
| 24.5483
| 1
| '''20.96'''
|- align="center"
| 18
| 19.7788
| 1
| '''18.71'''
|-
|}
 

==== '''NMR Spectra of Molecule 18''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 18 Boat for Image2.mol</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"-
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 18 Chair Overall NMR.png|500px|center]]
| [[File:Molecule 18 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.2832
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| ''' '''
|- align="center"
| 50
| 3.3175
| 1
| rowspan="4" style="text-align:centre;"| '''3.00-2.70'''
|- align="center"
| 52
| 3.2153
| 1
|- align="center"
| 51,53
| 3.1161
| 2
|- align="center"
| 34,43
| 2.8606
| 2
|- align="center"
| 38
| 2.4549
| 1
| ''' '''
|- align="center"
| 42
| 2.3968
| 1
| ''' '''
|- align="center"
| 25,29,26
| 2.2796
| 3
| ''' '''
|- align="center"
| 39
| 2.0844
| 1
| ''' '''
|- align="center"
| 40,36
| 1.9699
| 2
| ''' '''
|- align="center"
| 37,24
| 1.8519
| 2
| ''' '''
|- align="center"
| 31,27
| 1.6780
| 2
| ''' '''
|- align="center"
| 28
| 1.6175
| 1
| ''' '''
|- align="center"
| 46,49
| 1.4979
| 2
| ''' '''
|- align="center"
| 35
| 1.4150
| 1
| ''' '''
|- align="center"
| 32
| 1.3531
| 1
| ''' '''
|- align="center"
| 48
| 1.1606
| 1
| ''' '''
|- align="center"
| 33,30,47
| 1.0653
| 3
| '''1.03'''
|- align="center"
| 44,45
| 0.9643
| 2
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwMolecule 18 Boat Overall NMR.png|500px|center]]
| [[File:XcwMolecule 18 Boat zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 211.8325
| 1
| '''211.49'''
| rowspan="10" style="text-align:center;"| [[File:Molecule 18 Boat for 13 CNMR.jpg|600px|center]]
|- align="center"
| 13
| 148.6673
| 1
| '''148.72'''
|- align="center"
| 14
| 118.8373
| 1
| '''120.90'''
|- align="center"
| 3
| 89.0869
| 1
| '''74.61'''
|- align="center"
| 2
| 67.8886
| 1
| '''60.53'''
|- align="center"
| 1
| 56.1133
| 1
| '''51.30'''
|- align="center"
| 10
| 55.5998
| 1
| '''50.94'''
|- align="center"
| 16
| 50.1124
| 1
| '''45.53'''
|- align="center"
| 22
| 48.2030
| 1
| '''43.28'''
|- align="center"
| 23
| 44.2222
| 1
| '''40.82'''
|- align="center"
| 4
| 42.0354
| 1
| '''38.73'''
| Comments
|- align="center"
| 9
| 37.5865
| 1
| '''36.78'''
| rowspan="9" style="text-align:left;"| ''' '''
|- align="center"
| 6
| 35.3106
| 1
| '''35.47'''
|- align="center"
| 15
| 31.0459
| 1
| '''30.84'''
|- align="center"
| 7
| 28.8476
| 1
| '''30.00'''
|- align="center"
| 12
| 28.6623
| 1
| '''25.56'''
|- align="center"
| 17
| 25.7393
| 1
| '''25.35'''
|- align="center"
| 11
| 25.2603
| 1
| '''22.21'''
|- align="center"
| 18
| 23.3944
| 1
| '''21.39'''
|- align="center"
| 5
| 21.0478
| 1
| '''19.83'''
|-
|}
 

== '''Part 4 : Analysis of the Properties of the Synthesized Alkene Epoxides''' ==
=== '''The two catalytics systems''' ===

Assymmetric epoxidation of prochiral alkenes may lead to product with different stereochemical outcome as illustrated as below. To solve this problem, different types of asymmetric epoxidation catalyst have been synthesized. In this study, we shall be focusing on Shi asymmetric fructose catalyst as well as Jacobsen asymmetric catalyst.

[[File:Asymmetric catalyst.png|400px|center]]

==== ''' The Shi Asymmetric Fructose Catalyst''' ====

Molecule 21 is the stable precursor of molecule 22, the active catalyst. Molecule 21 can be converted to molecule 22 by using either persulfuric acid or potassium peroxymonosulphate.

[[File:Molecule 21 to 23.png|400px|center]]

The transition state of the Shi epoxidation was a subject of debate for a few moments. However, recent studies have led to the conclusion that the spiro transition state is more favored than the planar transition state. The spiro transition state is the transition that has its dioxirane perpendicularly bisecting the alkene double bond. This is thought to be more favourable due to interactions between the lone pairs of the oxygen with the LUMO of the alkene.

[[File:Spiro and planar ts.png|500px|center]]

==== ''' The Jacobsen Asymmetric Catalyst''' ====

Molecule 23 is the stable precursor of molecule 24, the active catalyst. Molecule 23 can be converted to molecule 24 by using sodium perchlorate.

[[File:Salen, 23 and 24.png|400px|center]]

Jacobsen catalyst is biphasic. The first phase involves the transfer of oxygen to molecule 23. Sodium perchlorate oxidizes Mn(III) to Mn(V).

In the second step, Jacobsen catalyst acts via a radical mechanism. It is thought to be so because epoxidation of trans-alkene by Jacobsen catalyst yield cis-alkene as well. A radical mechanism will lead to the lost of stereochemical information of the molecule.

=== ''' Crystal structure of the two catalyst''' ===
==== '''Molecule 21''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 21'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 21 strucutre.png|600px|center]]'''
|-
| style="text-align:center;" width="150" | ''' Bond '''
| style="text-align:center;" width="150"| ''' Bond Lenghts (Angstrom)'''
| style="text-align:center;" | ''' Evaluation'''
|-
| style="text-align:center;"| ''' O1-C1 '''
| style="text-align:center;"| ''' 1.400'''
| rowspan="10" style="text-align:left;"| [[File:Molecule 21 2.png|300px|center]]

The normal bond length of an C-O bond is 1.430 angstrom.

The most interesting aspect here is O4 and O2. The lone pair of O4 is antiperplanar to the sigma* orbital of the carbonyl group while the lone pair of O2 is anti periplanar to the carbonyl pi* orbital. Donation of electron can occur because of the correct symmetry. Due to the mixing of the orbitals, the C2-O2 and C4-O4 has been conferred with a certain degree of double bond character.

However, due to the lone pair on oxygen being now donated to the carbonyl antibonding orbitals, the O2 and O4 is slightly “electron deficient” and electron density will be pulled away from O2 and O4. That would explain why the bond length increase for O2-C7 and O4-C10. Increase in bond length is an indicator of the weakening of the bond.
|-
| style="text-align:center;"|'''O1-C7'''
| style="text-align:center;"|'''1.413'''
|-
| style="text-align:center;"|'''O2-C7'''
| style="text-align:center;"|'''1.441'''
|-
| style="text-align:center;"|'''O2-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O4-C4'''
| style="text-align:center;"|'''1.396'''
|-
| style="text-align:center;"|'''O4-C10'''
| style="text-align:center;"|'''1.439'''
|-
| style="text-align:center;"|'''O5-C10'''
| style="text-align:center;"|'''1.409'''
|-
| style="text-align:center;"|'''O5-C5'''
| style="text-align:center;"|'''1.416'''
|-
| style="text-align:center;"|'''O6-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O6-C6'''
| style="text-align:center;"|'''1.420'''
|-
|}
 

==== '''Molecule 23''' ====

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 23'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 23 struc.png|600px|center]]'''
|-
| The most outstanding feature from this molecule is the fact that is adopt a puckered form of the square base pyramidal form. This is no surprise that the molecule is almost planar due to the electron delocalization around each side of the salen ligand.

The tery-butyl hydrogen are oriented closely to one another. Non-covalent interaction studies indicated that repulsion would occur for H---H bond length that are less than 2.1 angstrom while favourable interaction may be dominant with bond length above 2.4 angstrom. It was discovered that all 4 hydrogens have bond length more than 2.4 angstrom hence there should not be any significant repulsion between them. Instead, certain amount of attractive force will ensue and that contributes to the overall stability of the molecule

|-
|}
 

=== ''' The calculated NMR properties of the product''' ===

=== ''' Assigning the absolute configuration of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="200" | '''(S)-Styrene'''
| width="200" | '''(R,R)-Trans-stilbene'''
| width="200" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''Predicted ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg'''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg '''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental conditions'''
| width="100" | '''1.00g/100ml, chloroform, 21 degree Celcisus, 589 nm wavelength '''
| width="100" | '''1.02g/100ml (99% ee), chloroform, 25 degree Celsius, 589 nm wavelength '''
| width="100" | '''1.01g/100ml, ethanol, 22 degree Celsius, 589 nm wavelength '''
| width="100" | '''0.6g/100ml, ethanol, 20 degree Celsius, 589 nm wavelength '''
|- align="left"
| width="100" | ''' Predicted VCD Spectrum'''
| width="100" | '''-1343.024742'''
| width="100" | '''-0.007701'''
| width="100" | '''2.88E-04'''
| width="100" | '''99.94'''
|-
|}

 

=== ''' Analysis of the Transition State for Reactions''' ===
==== '''Predicting Enantiomeric Excess based on Transition State energies''' ====

One of the energy output from Gaussian calculation is the “sum of electronic and thermal free energies”. This is Gibbs Free Energy at 298.15K and 1 atm.

Using this term and invoking a variant of the Curtin-Hammett Principle, it is possible to calculate a predicted enantiomeric excess of one enantiomer over the other.

[[File:Ee and transition state energy.png|800px|center]]

Using the derivations from above and equation (4), we analyze the enantiomeric excess of beta-methyl styrene and the results are tabulated as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1343.022970'''
| width="100" | '''-1343.017942'''
| width="150" | '''-0.005028'''
| width="150" | '''4.88E-03'''
| width="150" | '''99.03'''
|- align="center"
| width="100" | '''-1343.019233'''
| width="100" | '''-1343.015603'''
| width="150" | '''-0.003630'''
| width="150" | '''2.14E-02'''
| width="150" | '''95.80'''
|- align="center"
| width="100" | '''-1343.029272'''
| width="100" | '''-1343.023766'''
| width="150" | '''-0.005506'''
| width="150" | '''2.94E-03'''
| width="150" | '''99.41'''
|- align="center"
| width="100" | '''-1343.032443'''
| width="100" | '''-1343.024742'''
| width="150" | '''-0.007701'''
| width="150" | '''2.88E-04'''
| width="150" | '''99.94'''
|-
|}

 

The above hartree units are converted to J/mol for calculation of K where 1 hartress = 4.3597E-18

Studying all the free energies of the (R,R) series and compare them with the (S,S) series, it comes as no surprise that (R,R) product is favoured over (S,S) product as (R,R) is more stable. Indeed, this corresponds with the literature value reporting 92% ee of (R,R) products over that of (S,S).

==== '''Analysis of the Transition State of Epoxidation''' ====
==== '''Shi Fructose Catalyst''' ====
For this section, I will be analyzing the the transition state of 1) styrene and 2) trans-stilbene with the Shi fructose catalyst.

===== '''(R) and (S)-styrene transition state''' =====
The transition state for the formation of (R)-styrene oxide and (S)-styrene oxide are given as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R)-styrene oxide'''
| width="150" | '''(S)-styrene oxide'''
|- align="center"
| width="150" | ''' Structure of Catalyst '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide R.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide S ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| [[File:Steric shi fructose R.png|450px|center]]
| [[File:Steric shi fructose S.png|450px|center]]
|-
|}

 

In the transition state for (R)-styrene, it was discovered that the Re face is reacting with the oxygen of the dioxirane. The phenyl ring is oriented endo with respect to the fructose catalyst. However, the (S)-styrene is reacting at the Si face and the phenyl ring is oriented exo relative to the catalyst.

The approach taken by (R)-styrene and (S)-styrene are restricted to only one due to steric interactions. Therefore, the epoxidation of both styrenes by the Shi catalyst will be stereospecific and retains all the stereochemical information of the reactant. However, whether or not (R)-styrene oxide or (S)-styrene oxide is form is dependent on the relative energies of the transition state. The more stable the transition state, the more likely the product of the transition state will be formed.

So in order to examine this, an example of transition state of both styrenes with Shi catalyst are obtained and analyzed.
 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1303.736813'''
| width="100" | '''-1303.727673'''
| width="150" | '''-0.00914'''
| width="150" | '''6.28E-05'''
| width="150" | '''99.99'''

|-
|}

 

From the above, we can see the predicted high enantiopurity of the reaction favoring the (R) product because of the lower energy of the transition states. To understand the reason, we have to turn to non-covalent interaction (NCI) analysis.

[[File:NCI shi fructose styrene.png|700px|center]]

To complement the NCI analysis, a QTAIM (Quantum Theory of Atoms in Molecules) analysis is conducted as well.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''(R)-styrene transition state'''
| width="200" | '''(S)-styrene transition state'''
|- align="center"
| width="100" | '''[[File:QTAIM R.png|400px|center]]'''
| width="100" | '''[[File:QTAIM S.png|400px|center]]'''
|- align="center"
| colspan="2" width="100" | '''Comments'''
|-
| colspan="2" width="100" | '''Unsurprisingly, QTAIM analysis has also shown that (R)-styrene/Shi catalyst has more interactions with one another. While (R)-styrene has 2 strong interactions, (S)-styrene has only one with the catalyst. Besides, the phenyl ring of (R)-styrene also confers additional positive interaction with the catalyst. QTAIM analysis has also show several interactions between the C=C geminal hydrogen of (R)-styrene intreacting with the oxygen atoms on the dioxacyclopentane ring'''
|-
|}

 

===== '''(R,R) and (S,S)-Stilbene transition state''' =====

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R,R)-Stilbene oxide'''
| width="150" | '''(S,S)-Stilbene oxide'''
|- align="center"
| width="150" | ''' Structure of Transition State '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Stilbene RR ts.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>SS stilbene oxide ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| colspan="2" | [[File:Shi fructose stilbene.png|700px|center]]

|-
|}

 

However, unlike styrene, trans-stilbene seems to approach perpendicularly to the dioxirane. This is proposed to be due to the steric interactions (marked in purple). Based on first inspection, it seems that (S,S)-Stilbene oxide has more steric interactions than (R,R)-Stilbene oxide. Although unsubstantial, it seems like my guess was correct. The (R,R)-stilbene/Shi catalyst transition state is lower in energy.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1534.687808'''
| width="100" | '''-1534.683440'''
| width="150" | '''0.004368'''
| width="150" | '''9.08E-3'''
| width="150" | '''98.20'''

|-
|}

 

NCI Analysis is also done for trans-stilbene

[[File:NCI stilbene.png|700px|center]]

==== '''Jacobsen Catalyst''' ====

For this section, cis-beta methyl styrene transition state will be analyzed.

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-3383.259559'''
| width="100" | '''-3383.251060'''
| width="150" | '''-0.008499'''
| width="150" | '''1.24E-04'''
| width="150" | '''99.98'''
|- align="center"
| width="100" | '''-3383.253442'''
| width="100" | '''-3383.250270'''
| width="150" | '''-0.003172'''
| width="150" | '''3.48E-02'''
| width="150" | '''93.27'''
|-
|}

 

As is obvious from here, the (S,R) transition state is more stable than the (R,S) transition state. Both transition states are exo with respect to the catalyst.

It is not immediately apparent just by looking at the molecule to determine which spatial groups have interactions with one another. Therefore, an NCI analysis is conducted again.

[[File:NCI Jacobsen.png|700px|center]]

Rep:Mod:Computationalreport1C

2013-11-21T21:47:12Z

Xc2611: /* Assigning the absolute configuration of the product */

= '''Synthesis and Computational Lab: 1C''' =
== '''Part 1: Introduction to Molecular Mechanics''' ==
=== '''Introduction to MMFF94 and MMFF94s''' ===

With the improvement of computational data and computer processing power, the usage of molecular mechanics/dynamics forcefield has become very integrated in predicting properties of chemical molecules. A molecular mechanics/dynamics forcefield should be able to predict characteristics such as molecular geometries, conformational/stereoisomeric energies, vibrational frequencies etc. to a reasonable accuracy as compared to experimental-derived values.

Building on work from Kollman et al. s’ AMBER forcefield and Allinger et al. s’ MM1, MM2, MM3 and MM4, Merck Research Laboratories have managed to optimized and improved the previous computational algorithms and produced MMFF94 (Merck Molecular Force Field 94). One of the most prominent advantages of MMFF94 over other preceeding work is its enhanced prediction accuracy. The reason lies in the fact that MMFF94’s core parameterization utilizes an unprecedently large amount of computational data obtained from ab initio calculations1.

Subsequently after the development of MMFF94, a new “static” variant of the MMFF was introduced i.e. the MMFF94s. Unlike MMFF94 that was developed for the use of molecular dynamics simulations (which can be expensive), MMFF94s was developed with the purpose of energy minimization studies in mind. Although both systems provide identical results for most systems, they differ for amides and unsaturated amines which contain resonance-delocalized trigonal nitrogen atoms2.

In this computational exercise, MMFF94s is used predominantly as oppose to the alternative Universal Force Field (UFF). Although versatile across the entire periodic table, UFF is derived from simple rules and atomic parameters such as fixed hybridization that increases the likelihood of erroneous structural and energetic predictions3.

=== '''Forms of MMFF94s''' ===

Steric energy of a molecule is the energy arise due to its geometry or conformation. Energy minimization of steric energy process ensures that the molecule is in its lowest energy conformation.

MMFF94s assumes that the total steric energy of a molecule can be found by the sum of a few specific interactions in a molecule.

ES = EBS + EAB + E SB + ET + EOOP + EVdW + EEE

'''where the bonded interactions are:'''

ES = Total Steric energy

EBS = Total Bond Stretching energy

EAB = Total Angle Bending energy

ESB = Total Stretch Bending energy

ET = Total Torsional Energy

EOOP = Total Out-Of-Plane Bending energy, and

'''where the non-bonded interactions are:'''

EVdW = Total Van der Waals Energy

EEE = Total Electrostatic Energy

{| border="1" cellspacing="1" cellpadding="10"
|-
| width="300" align="center" | '''Types of Energies'''
! width="600" align="center" | '''Explanation'''
|-
| colspan="2" style="text-align: center;" | '''Bonded Interactions'''
|-
| width="300" align="center" | '''Total Bond Stretching Energy'''
! width="600" align="left" | The total bond stretching energy is related to the vibration energy of the molecules in comparison to the equilibrium bond length. Whenever a bond deviates from the equilibrium bond length, the energy value increases.

MMFF94s uses a quartic function that has the force constant term (relate to bond strength). The quartic function term is superior to the cubic function term (used in MM2) in the sense that it avoid the “cubic stretch catastrophe” where progressive elongation of molecule bond length leads to negative infinity.
|-
| width="300" align="center" | '''Total Angle Bending Energy'''
! width="600" align="left" | Similar to Total Bond Stretching Energy, the total angle bending energy is also related to the vibration energy of the molecules about the equilibrium bond length. However, unlike EBS that measures the bond strength, EAB is associated with the stiffness of the molecules based on the Hookiean potential. Whenever bond angles deviate from the norm during vibration, this energy term increases as well.
|-
| width="300" align="center" | '''Total Stretch-Bending Energy'''
! width="600" align="left" | This energy term takes into account of the energy due to increase in bond length when bond angle between two atoms changes.
|-
| width="300" align="center" | '''Total Torsional Energy'''
! width="600" align="left" | Total torsional energy is the energy required for intermolecular rotation about the bonds. In molecule mechanics, however, this term is often used as a correction that must be added or subtracted to the total energy of the molecule to fit a quantum mechanical calculation about the dihedral angles of bonds.
|-
| width="300" align="center" | '''Total Out-Of-Plane Bending Energy'''
! width="600" align="left" | This energy term refers to the energy needed to deform the dihedral angle (zero degrees) of a planar group of atoms such as carbonyl or amide functional groups.
|-
| colspan="2" style="text-align: center;" | '''Non-Bonded Interactions'''
|-
| width="300" align="center" | '''Total Van der Waals Energy'''
! width="600" align="left" | The total Van der Waals energy term examines the intramolecular interactions such as repulsion or attraction between non-bonded atoms in the molecule. This term is crucial in determining the preferred conformation of the molecule.

MMFF94s employs the novel “Buffered-14-7”. The name is derived from a buffering constant and the 14th and 7th power dependencies of the repulsive and attractive energy in the equation.
|-
| width="300" align="center" | '''Total Electrostatic Energy'''
! width="600" align="left" | The total electrostatic energy functions take into account of the Coulombic potential and partial charge/dipole/atomic point charges interactions within the molecule.
|-

|}

 

== '''Part 2 : Conformational Analysis Using Molecular Mechanics''' ==
=== '''The Hydrogenation of Cyclopentadiene Dimer''' ===

==== '''Endo and exo adduct from the Dimerization of Cyclopentadiene''' ====
Cyclopentadiene will undergo dimerization by Diels-alder reaction to form either an endo or exo adduct.

[[File:XcwDimerization of CP.png|500px|center]]

==== '''Stereoselectivity of Dimerization of Cyclopentadiene''' ====
Although the exo adduct is thermodynamically more stable than the endo adduct, the endo adduct is form preferentially. Using the QST2 method, the transition state of the Diels Alder dimerization was found. It was discovered that due to the secondary orbital interactions in the endo transition state, the endo dimer is formed preferentially (the kinetic product). Hence, it is proven that the Diels Alder dimerization between two cyclopentadiene are kinetically controlled.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Transition State of Dimerization of Cyclopentadiene'''
| '''Imaginary Stretch Frequency (-881.25) of the Endo Transition State (click to animate)'''
| '''Secondary Orbital Interaction (Red overlapping orbitals)'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<uploadedFileContents>EndotsDCPD2.mol
</uploadedFileContents>
</jmolApplet></jmol>
| [[File:Xcwendotsimaginary.gif|300px|center]]
| [[File:XcwSecondary orbital interaction1.jpg|300px|center]]
|-
|}

 

==== '''Asynchronous Bond Formation of Dimerization of Cyclopentadiene''' ====

The initial study of the molecular orbitals of the transition states seemed a bit peculiar. Instead of getting a LUMO with symmetrical orbitals, the calculations showed a HOMO that is asymetric at the carbons where the new sigma bonds will be formed. Running an IRC further, it soon became clear that the asymmetry of the HOMO leads to an asychronous bond formation before leading to the product.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''IRC plot following the Endo Transition State '''
| '''IRC following the Endo Transition State (click to animate)'''
| '''Asymmetry of orbitals at the carbons where the new sigma bonds will be formed'''
|- align="center"
| [[File:XcwendotscyclopentadieneIRC.png|300px|center]]
| [[File:XcwendotsIRC.gif|300px|center]]
| [[File:XcwAsynchronous mo.jpg|300px|center]]
|-
|}

 

==== '''Comparison of Energies between the Endo and Exo adduct of Dicyclopentadiene''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Adduct of Dicyclopentadiene dimerization'''
| '''Exo Adduct of Dicyclopentadiene dimerization'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=19,atomno=1,atomno=2; color green;measure 19 1;measure 19 2;</script>
<uploadedFileContents>XcwEndodimer3.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>Exodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=7,atomno=17; color green;measure 17 7;</script>
<uploadedFileContents>XcwExodimer1.mol</uploadedFileContents>
</jmolApplet></jmol>
|-
|}

 

Using MMFF94s ab initio calculations, the energies for the exo dimer and the endo dimer are derived.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Exodimer'''
| '''55.374'''
| 3.543
| 30.772
| -2.041
| -2.728
| 0.015
| 12.800
| 13.014
|-
| '''Endodimer'''
| '''58.191'''
| 3.468
| 33.187
| -2.082
| -2.950
| 0.023
| 12.360
| 14.186
|-
|}

 

The MMFF94s steric energy (after minimization) for the exo dimer is lower than that of the endo dimer. This is reflected by the large difference for the EEE between the endo dimer and the exo dimer due to unfavourable steric repulsion between the two “arched down” cyclopentene rings.

==== '''Hydrogenation of Dicyclopentadiene''' ====

Hydrogenation of the endo dicyclopentadiene (DCPD) would lead to two potential products: dihydro product 1 and dihydro product 2.

[[File:XcwFormation of Dihydro products.png|500px|center]]

Using MMFF94s, the energy of the two dihydro products are calculated.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Dihydro Product 1'''
| '''50.123'''
| 3.308
| 30.864
| -1.927
| 0.060
| 0.015(2)
| 13.281
| 5.121
|-
| '''Dihydro Product 2'''
| '''41.257'''
| 2.823
| 24.685
| -1.657
| -0.379
| 0.000(2)
| 10.639
| 5.147
|-
| '''Tetrahydro Product'''
| '''39.042'''
| 2.730
| 25.151
| -1.676
| 1.287
| 0.000
| 11.551
| 0.000
|}

 

From the MMFF94s calculation, it can be seen that dihydro product 2 has a lower steric energy than dihydro product 1. Therefore, dihydro product 2 is the thermodynamic product for the hydrogenation of dicylopentadiene. And indeed, this was what was observed by Skala et al.. He observed that the first hydrogenation occur at the norborene part of the molecule (rate of hydrogenation several times faster than that in the cyclopentene ring)6. The first heat of hydrogenation at the norborene is 138.8 kJ/mol while the second hydrogenation at the cyclopentene right is 109.5 kJ/mol6.

From the above results, it is also obvious that tetrahydro product is much more stable than either dihydro product. And yet, studies have shown that the tetrahydro product will only form after prolonged hydrogenation under high temperature. However, subjecting DCPD to high temperature leads to low yield due to cracking of DCPD.

Since thermodynamically it is predicted to form favourably, the fact that it does not could only mean that the hydrogenation of DCPD to tetrahydrodicyclopentadiene (TH-DCPD) is kinetically controlled. Most possibly, the transition state of the hydrogenation of DCPD is highly unstable hence it is unlikely to form.

=== '''Atropisomerism in an Intermediate related to the Synthesis of Taxol''' ===

Atropisomerism is a type of stereoisomerism that is form as a result of hindered rotation about a single bond.

[[File:XcwAtropisomerism example.png|500px|center]]

In the case of the 6,6’-dinitro-2,2’-diphenic acid, rotation about the bonds joining the two substituted phenyl rings would have to overcome large steric interaction between the bulky substituents. The barrier of rotation is high enough for the two conformers to be isolated individually.

In the synthesis of taxol, one of the key intermediates exhibit atropisomerism.

==== '''Atropisomerism in Taxol Synthesis''' ====

For the key intermediate, rotation about the carbon-carbon bonds would lead to two types of atropisomers, each with either the carbonyl group poining upwards or downwards in relative to the bridge.

[[File:XcwIntermediate 9 and Intermediate 10.png|500px|center]]

Once again by using MMFF94s ab initio calculations, the steric energies for the two intermediates are illustrated as below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 9'''
| '''70.571'''
| 7.743
| 28.356
| -0.062
| 0.004
| 0.949
| 33.293
| 0.288
|-
| '''Intermediate 10'''
| '''60.553'''
| 7.599
| 18.838
| -0.139
| 0.199
| 0.844
| 33.269
| -0.056
|-

|}

 

Analyzing the data above, the largest energy difference between Intermediate 9 and Intermediate 10 stems from the EAB which is related to the strain of the ring. Intermediate 9 has an excess of 9.518 kcal/mol EAB as compared to Intermediate 10. This comes as a surprise as intermediate 9 is predicted to be more stable alkene.

The rationale behind the prediction of the stability of intermediate 9 stems from the fact that the through-space distance of the upward-pointing carbonyl oxygen with the carbon-carbon is further than the through space distance between the downward-pointing carbonyl oxygen with the -CH2-CH2- fragment at the norbornene part in intermediate 10.

==== '''Hyperstable Olefins''' ====

Intermediate 9 and Intermediate 10 does not react readily with other reagents during functionalization. This is due to the hyperstability effect found in hyperstable olefins.

Hyperstable olefins are alkenes that contain less strain in the ring (i.e. negative olefin strain values) compared to the parent hydrocarbon. To study this further, further MMFF94s calculation was done to compare Intermediate 10 with the parent hydrocarbon.

[[File:XcwIntermediate10andPH.png|500px|center]]

The energies that we calculated are tabulated as shown below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 10'''
| '''44.878 '''
| 5.211
| 15.488
| -0.267
| -1.655
| 0.998
| 25.014
| 0.088
|-
| '''Parent Hydrocarbon'''
| '''50.564'''
| 4.692
| 21.979
| 0.109
| -0.958
| 0.247
| 24.495
| 0.000
|-

|}

 

Scrutinizing the results, the largest energy difference between intermediate 10 and the parent hydrocarbon stems from the Total Angle Bending Energy, EAB. Since the Total Angle bending energy is related to the angle strain in the molecules, it is apparent that the parent hydrocarbon has more ring strain as compared to the bridgehead olefin.

== '''Part 3 : Spectroscopic Simulation Using Quantum Mechanics''' ==
=== '''Spectroscopy of an Intermediate Related to the Synthesis of Taxol''' ===

Molecule 17 and 18 are derivatives of intermediate 9 and 10. In this exercise, MMFF94s is used to predict the 1H and 13C NMR of molecule 17 and molecule 18.

[[File:XcwIntermediate17&18.png|500px|center]]

==== '''NMR Spectra of Molecule 17''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 17.mol
</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwHNMRMolecule 17 Chair Overall NMR.png|500px|center]]
| [[File:XcwHNMRMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.1825
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| The first three results were fairly straight forward to be deduced and correlate wit experimental data.

The hydrogen atom that is geminally attached to the carbon of the double bonds is the most deshielded due to the ring current anisotropic effect of the ring current

The second most deshielded hydrogen atom is the hydrogen atom on the methyl group on the bridge. The hydrogen atom is pointing directly to the oxygen atom of the carbonyl functional group.

The peaks with an integration height of 4 is assigned to the hydrogen atoms in the 1,3-dithiolane ring fragment.

Subsequent analysis of the 1H NMR became very complicated very quickly for two reasons:

1. Gaussian calculations showed some atoms with an integration height of 3. Comparing their file atom number and checking their chemical environment, it is not possible to find any correlation between them.

2. Some of the peaks in the literature remains unresolved and are given as multiplets or grouped together.

|- align="center"
| 52
| 3.1775
| 1
| '''2.99'''
|- align="center"
| 53,52,50,51
| 3.0867
| 4
| '''3.40-3.10'''
|- align="center"
| 42,43,39
| 2.7445
| 3
| ''' '''
|- align="center"
| 49
| 2.6187
| 1
| ''' '''
|- align="center"
| 34
| 2.4371
| 1
| ''' '''
|- align="center"
| 35
| 2.3782
| 1
| ''' '''
|- align="center"
| 40,37,26
| 2.2730
| 3
| ''' '''
|- align="center"
| 30
| 2.1566
| 1
| ''' '''
|- align="center"
| 36
| 2.1033
| 1
| ''' '''
|- align="center"
| 32,28
| 2.0259
| 2
| ''' '''
|- align="center"
| 25
| 1.8535
| 2
| ''' '''
|- align="center"
| 38,46,27
| 1.5898
| 3
| '''1.25'''
|- align="center"
| 29
| 1.4557
| 1
| ''' '''
|- align="center"
| 31
| 1.0123
| 1
| ''' '''
|- align="center"
| 44,48,45
| 0.9087
| 3
| '''1.10'''
|- align="center"
| 47
| 0.8354
| 1
| ''' '''
|- align="center"
| 33
| 0.5790
| 1
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 17 Chair Overall NMR2.png|500px|center]]
| [[File:XcwMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 216.2725
| 1
| '''218.79'''
| rowspan="10" style="text-align:center;"| [[File:XcwMolecule 17 image for CNMR.jpg|600px|center]]
|- align="center"
| 13
| 144.8626
| 1
| '''144.63'''
|- align="center"
| 14
| 124.7193
| 1
| '''125.33'''
|- align="center"
| 3
| 91.3340
| 1
| '''72.88'''
|- align="center"
| 2
| 60.9568
| 1
| '''56.19'''
|- align="center"
| 1
| 57.0811
| 1
| '''52.52'''
|- align="center"
| 10
| 52.4663
| 1
| '''48.50'''
|- align="center"
| 16
| 51.4857
| 1
| '''46.80'''
|- align="center"
| 9
| 46.9196
| 1
| '''45.76'''
|- align="center"
| 23
| 43.8647
| 1
| '''39.80'''
|- align="center"
| 22
| 41.9450
| 1
| '''38.81'''
| Comments
|- align="center"
| 4
| 41.8724
| 1
| '''35.85'''
| rowspan="9" style="text-align:left;"| The carbon bonded to the oxygen atom is the most deshielded, as is shown in the predicted values and the experimental values. There is a deviation between the values. Quite possibly, this is due to the fact that in reality, the carbonyl functional group is pointing slightly towards the equatorial position rather than a lateral position relative to the ring (as is in the input for Gaussian calculation)

Most of the 1CNMR values that was predicted by Gaussian are all within an acceptable range of deviation. However, there is carbon 3 that has significant deviation between the predicted value and experimental value.

Carbon 3 is the carbon bonded to the two sulphurs in the 1,3-dithiolane ring fragment. Such a huge deviation would possibly mean that the conformer that was given as input to Gaussian differs from the literature.

The above NMR spectra was corrected with a level of theory B3LYP/6-31G(d,p) using TMS as reference and in chloroform.

|- align="center"
| 15
| 35.4348
| 1
| '''32.66'''
|- align="center"
| 11
| 31.1964
| 1
| '''28.79'''
|- align="center"
| 6
| 28.9432
| 1
| '''28.29'''
|- align="center"
| 7
| 28.3640
| 1
| '''26.88'''
|- align="center"
| 12
| 27.3767
| 1
| '''25.66'''
|- align="center"
| 17
| 26.3311
| 1
| '''23.86'''
|- align="center"
| 15
| 24.5483
| 1
| '''20.96'''
|- align="center"
| 18
| 19.7788
| 1
| '''18.71'''
|-
|}
 

==== '''NMR Spectra of Molecule 18''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 18 Boat for Image2.mol</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"-
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 18 Chair Overall NMR.png|500px|center]]
| [[File:Molecule 18 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.2832
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| ''' '''
|- align="center"
| 50
| 3.3175
| 1
| rowspan="4" style="text-align:centre;"| '''3.00-2.70'''
|- align="center"
| 52
| 3.2153
| 1
|- align="center"
| 51,53
| 3.1161
| 2
|- align="center"
| 34,43
| 2.8606
| 2
|- align="center"
| 38
| 2.4549
| 1
| ''' '''
|- align="center"
| 42
| 2.3968
| 1
| ''' '''
|- align="center"
| 25,29,26
| 2.2796
| 3
| ''' '''
|- align="center"
| 39
| 2.0844
| 1
| ''' '''
|- align="center"
| 40,36
| 1.9699
| 2
| ''' '''
|- align="center"
| 37,24
| 1.8519
| 2
| ''' '''
|- align="center"
| 31,27
| 1.6780
| 2
| ''' '''
|- align="center"
| 28
| 1.6175
| 1
| ''' '''
|- align="center"
| 46,49
| 1.4979
| 2
| ''' '''
|- align="center"
| 35
| 1.4150
| 1
| ''' '''
|- align="center"
| 32
| 1.3531
| 1
| ''' '''
|- align="center"
| 48
| 1.1606
| 1
| ''' '''
|- align="center"
| 33,30,47
| 1.0653
| 3
| '''1.03'''
|- align="center"
| 44,45
| 0.9643
| 2
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwMolecule 18 Boat Overall NMR.png|500px|center]]
| [[File:XcwMolecule 18 Boat zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 211.8325
| 1
| '''211.49'''
| rowspan="10" style="text-align:center;"| [[File:Molecule 18 Boat for 13 CNMR.jpg|600px|center]]
|- align="center"
| 13
| 148.6673
| 1
| '''148.72'''
|- align="center"
| 14
| 118.8373
| 1
| '''120.90'''
|- align="center"
| 3
| 89.0869
| 1
| '''74.61'''
|- align="center"
| 2
| 67.8886
| 1
| '''60.53'''
|- align="center"
| 1
| 56.1133
| 1
| '''51.30'''
|- align="center"
| 10
| 55.5998
| 1
| '''50.94'''
|- align="center"
| 16
| 50.1124
| 1
| '''45.53'''
|- align="center"
| 22
| 48.2030
| 1
| '''43.28'''
|- align="center"
| 23
| 44.2222
| 1
| '''40.82'''
|- align="center"
| 4
| 42.0354
| 1
| '''38.73'''
| Comments
|- align="center"
| 9
| 37.5865
| 1
| '''36.78'''
| rowspan="9" style="text-align:left;"| ''' '''
|- align="center"
| 6
| 35.3106
| 1
| '''35.47'''
|- align="center"
| 15
| 31.0459
| 1
| '''30.84'''
|- align="center"
| 7
| 28.8476
| 1
| '''30.00'''
|- align="center"
| 12
| 28.6623
| 1
| '''25.56'''
|- align="center"
| 17
| 25.7393
| 1
| '''25.35'''
|- align="center"
| 11
| 25.2603
| 1
| '''22.21'''
|- align="center"
| 18
| 23.3944
| 1
| '''21.39'''
|- align="center"
| 5
| 21.0478
| 1
| '''19.83'''
|-
|}
 

== '''Part 4 : Analysis of the Properties of the Synthesized Alkene Epoxides''' ==
=== '''The two catalytics systems''' ===

Assymmetric epoxidation of prochiral alkenes may lead to product with different stereochemical outcome as illustrated as below. To solve this problem, different types of asymmetric epoxidation catalyst have been synthesized. In this study, we shall be focusing on Shi asymmetric fructose catalyst as well as Jacobsen asymmetric catalyst.

[[File:Asymmetric catalyst.png|400px|center]]

==== ''' The Shi Asymmetric Fructose Catalyst''' ====

Molecule 21 is the stable precursor of molecule 22, the active catalyst. Molecule 21 can be converted to molecule 22 by using either persulfuric acid or potassium peroxymonosulphate.

[[File:Molecule 21 to 23.png|400px|center]]

The transition state of the Shi epoxidation was a subject of debate for a few moments. However, recent studies have led to the conclusion that the spiro transition state is more favored than the planar transition state. The spiro transition state is the transition that has its dioxirane perpendicularly bisecting the alkene double bond. This is thought to be more favourable due to interactions between the lone pairs of the oxygen with the LUMO of the alkene.

[[File:Spiro and planar ts.png|500px|center]]

==== ''' The Jacobsen Asymmetric Catalyst''' ====

Molecule 23 is the stable precursor of molecule 24, the active catalyst. Molecule 23 can be converted to molecule 24 by using sodium perchlorate.

[[File:Salen, 23 and 24.png|400px|center]]

Jacobsen catalyst is biphasic. The first phase involves the transfer of oxygen to molecule 23. Sodium perchlorate oxidizes Mn(III) to Mn(V).

In the second step, Jacobsen catalyst acts via a radical mechanism. It is thought to be so because epoxidation of trans-alkene by Jacobsen catalyst yield cis-alkene as well. A radical mechanism will lead to the lost of stereochemical information of the molecule.

=== ''' Crystal structure of the two catalyst''' ===
==== '''Molecule 21''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 21'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 21 strucutre.png|600px|center]]'''
|-
| style="text-align:center;" width="150" | ''' Bond '''
| style="text-align:center;" width="150"| ''' Bond Lenghts (Angstrom)'''
| style="text-align:center;" | ''' Evaluation'''
|-
| style="text-align:center;"| ''' O1-C1 '''
| style="text-align:center;"| ''' 1.400'''
| rowspan="10" style="text-align:left;"| [[File:Molecule 21 2.png|300px|center]]

The normal bond length of an C-O bond is 1.430 angstrom.

The most interesting aspect here is O4 and O2. The lone pair of O4 is antiperplanar to the sigma* orbital of the carbonyl group while the lone pair of O2 is anti periplanar to the carbonyl pi* orbital. Donation of electron can occur because of the correct symmetry. Due to the mixing of the orbitals, the C2-O2 and C4-O4 has been conferred with a certain degree of double bond character.

However, due to the lone pair on oxygen being now donated to the carbonyl antibonding orbitals, the O2 and O4 is slightly “electron deficient” and electron density will be pulled away from O2 and O4. That would explain why the bond length increase for O2-C7 and O4-C10. Increase in bond length is an indicator of the weakening of the bond.
|-
| style="text-align:center;"|'''O1-C7'''
| style="text-align:center;"|'''1.413'''
|-
| style="text-align:center;"|'''O2-C7'''
| style="text-align:center;"|'''1.441'''
|-
| style="text-align:center;"|'''O2-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O4-C4'''
| style="text-align:center;"|'''1.396'''
|-
| style="text-align:center;"|'''O4-C10'''
| style="text-align:center;"|'''1.439'''
|-
| style="text-align:center;"|'''O5-C10'''
| style="text-align:center;"|'''1.409'''
|-
| style="text-align:center;"|'''O5-C5'''
| style="text-align:center;"|'''1.416'''
|-
| style="text-align:center;"|'''O6-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O6-C6'''
| style="text-align:center;"|'''1.420'''
|-
|}
 

==== '''Molecule 23''' ====

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 23'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 23 struc.png|600px|center]]'''
|-
| The most outstanding feature from this molecule is the fact that is adopt a puckered form of the square base pyramidal form. This is no surprise that the molecule is almost planar due to the electron delocalization around each side of the salen ligand.

The tery-butyl hydrogen are oriented closely to one another. Non-covalent interaction studies indicated that repulsion would occur for H---H bond length that are less than 2.1 angstrom while favourable interaction may be dominant with bond length above 2.4 angstrom. It was discovered that all 4 hydrogens have bond length more than 2.4 angstrom hence there should not be any significant repulsion between them. Instead, certain amount of attractive force will ensue and that contributes to the overall stability of the molecule

|-
|}
 

=== ''' The calculated NMR properties of the product''' ===

=== ''' Assigning the absolute configuration of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="100" | ''' '''
| width="100" | '''(R)-Styrene'''
| width="100" | '''(S)-Styrene'''
| width="100" | '''(R,R)-Trans-stilbene'''
| width="150" | '''(S,S)-Trans-stilbene'''
|- align="left"
| width="100" | '''Predicted ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg'''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental ORP'''
| width="100" | '''-24 deg '''
| width="100" | '''32.1 deg '''
| width="100" | '''296 deg '''
| width="100" | '''-205.2 deg '''
|- align="left"
| width="100" | '''Experimental conditions'''
| width="100" | '''1.00g/100ml, chloroform, 21 degree Celcisus, 589 nm wavelength '''
| width="100" | '''1.02g/100ml (99% ee), chloroform, 25 degree Celsius, 589 nm wavelength '''
| width="100" | '''1.01g/100ml, ethanol, 22 degree Celsius, 589 nm wavelength '''
| width="100" | '''0.6g/100ml, ethanol, 20 degree Celsius, 589 nm wavelength '''
|- align="left"
| width="100" | ''' Predicted VCD Spectrum'''
| width="100" | '''-1343.024742'''
| width="100" | '''-0.007701'''
| width="100" | '''2.88E-04'''
| width="100" | '''99.94'''
|-
|}

 

=== ''' Analysis of the Transition State for Reactions''' ===
==== '''Predicting Enantiomeric Excess based on Transition State energies''' ====

One of the energy output from Gaussian calculation is the “sum of electronic and thermal free energies”. This is Gibbs Free Energy at 298.15K and 1 atm.

Using this term and invoking a variant of the Curtin-Hammett Principle, it is possible to calculate a predicted enantiomeric excess of one enantiomer over the other.

[[File:Ee and transition state energy.png|800px|center]]

Using the derivations from above and equation (4), we analyze the enantiomeric excess of beta-methyl styrene and the results are tabulated as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1343.022970'''
| width="100" | '''-1343.017942'''
| width="150" | '''-0.005028'''
| width="150" | '''4.88E-03'''
| width="150" | '''99.03'''
|- align="center"
| width="100" | '''-1343.019233'''
| width="100" | '''-1343.015603'''
| width="150" | '''-0.003630'''
| width="150" | '''2.14E-02'''
| width="150" | '''95.80'''
|- align="center"
| width="100" | '''-1343.029272'''
| width="100" | '''-1343.023766'''
| width="150" | '''-0.005506'''
| width="150" | '''2.94E-03'''
| width="150" | '''99.41'''
|- align="center"
| width="100" | '''-1343.032443'''
| width="100" | '''-1343.024742'''
| width="150" | '''-0.007701'''
| width="150" | '''2.88E-04'''
| width="150" | '''99.94'''
|-
|}

 

The above hartree units are converted to J/mol for calculation of K where 1 hartress = 4.3597E-18

Studying all the free energies of the (R,R) series and compare them with the (S,S) series, it comes as no surprise that (R,R) product is favoured over (S,S) product as (R,R) is more stable. Indeed, this corresponds with the literature value reporting 92% ee of (R,R) products over that of (S,S).

==== '''Analysis of the Transition State of Epoxidation''' ====
==== '''Shi Fructose Catalyst''' ====
For this section, I will be analyzing the the transition state of 1) styrene and 2) trans-stilbene with the Shi fructose catalyst.

===== '''(R) and (S)-styrene transition state''' =====
The transition state for the formation of (R)-styrene oxide and (S)-styrene oxide are given as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R)-styrene oxide'''
| width="150" | '''(S)-styrene oxide'''
|- align="center"
| width="150" | ''' Structure of Catalyst '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide R.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide S ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| [[File:Steric shi fructose R.png|450px|center]]
| [[File:Steric shi fructose S.png|450px|center]]
|-
|}

 

In the transition state for (R)-styrene, it was discovered that the Re face is reacting with the oxygen of the dioxirane. The phenyl ring is oriented endo with respect to the fructose catalyst. However, the (S)-styrene is reacting at the Si face and the phenyl ring is oriented exo relative to the catalyst.

The approach taken by (R)-styrene and (S)-styrene are restricted to only one due to steric interactions. Therefore, the epoxidation of both styrenes by the Shi catalyst will be stereospecific and retains all the stereochemical information of the reactant. However, whether or not (R)-styrene oxide or (S)-styrene oxide is form is dependent on the relative energies of the transition state. The more stable the transition state, the more likely the product of the transition state will be formed.

So in order to examine this, an example of transition state of both styrenes with Shi catalyst are obtained and analyzed.
 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1303.736813'''
| width="100" | '''-1303.727673'''
| width="150" | '''-0.00914'''
| width="150" | '''6.28E-05'''
| width="150" | '''99.99'''

|-
|}

 

From the above, we can see the predicted high enantiopurity of the reaction favoring the (R) product because of the lower energy of the transition states. To understand the reason, we have to turn to non-covalent interaction (NCI) analysis.

[[File:NCI shi fructose styrene.png|700px|center]]

To complement the NCI analysis, a QTAIM (Quantum Theory of Atoms in Molecules) analysis is conducted as well.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''(R)-styrene transition state'''
| width="200" | '''(S)-styrene transition state'''
|- align="center"
| width="100" | '''[[File:QTAIM R.png|400px|center]]'''
| width="100" | '''[[File:QTAIM S.png|400px|center]]'''
|- align="center"
| colspan="2" width="100" | '''Comments'''
|-
| colspan="2" width="100" | '''Unsurprisingly, QTAIM analysis has also shown that (R)-styrene/Shi catalyst has more interactions with one another. While (R)-styrene has 2 strong interactions, (S)-styrene has only one with the catalyst. Besides, the phenyl ring of (R)-styrene also confers additional positive interaction with the catalyst. QTAIM analysis has also show several interactions between the C=C geminal hydrogen of (R)-styrene intreacting with the oxygen atoms on the dioxacyclopentane ring'''
|-
|}

 

===== '''(R,R) and (S,S)-Stilbene transition state''' =====

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R,R)-Stilbene oxide'''
| width="150" | '''(S,S)-Stilbene oxide'''
|- align="center"
| width="150" | ''' Structure of Transition State '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Stilbene RR ts.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>SS stilbene oxide ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| colspan="2" | [[File:Shi fructose stilbene.png|700px|center]]

|-
|}

 

However, unlike styrene, trans-stilbene seems to approach perpendicularly to the dioxirane. This is proposed to be due to the steric interactions (marked in purple). Based on first inspection, it seems that (S,S)-Stilbene oxide has more steric interactions than (R,R)-Stilbene oxide. Although unsubstantial, it seems like my guess was correct. The (R,R)-stilbene/Shi catalyst transition state is lower in energy.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1534.687808'''
| width="100" | '''-1534.683440'''
| width="150" | '''0.004368'''
| width="150" | '''9.08E-3'''
| width="150" | '''98.20'''

|-
|}

 

NCI Analysis is also done for trans-stilbene

[[File:NCI stilbene.png|700px|center]]

==== '''Jacobsen Catalyst''' ====

For this section, cis-beta methyl styrene transition state will be analyzed.

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-3383.259559'''
| width="100" | '''-3383.251060'''
| width="150" | '''-0.008499'''
| width="150" | '''1.24E-04'''
| width="150" | '''99.98'''
|- align="center"
| width="100" | '''-3383.253442'''
| width="100" | '''-3383.250270'''
| width="150" | '''-0.003172'''
| width="150" | '''3.48E-02'''
| width="150" | '''93.27'''
|-
|}

 

As is obvious from here, the (S,R) transition state is more stable than the (R,S) transition state. Both transition states are exo with respect to the catalyst.

It is not immediately apparent just by looking at the molecule to determine which spatial groups have interactions with one another. Therefore, an NCI analysis is conducted again.

[[File:NCI Jacobsen.png|700px|center]]

Rep:Mod:Computationalreport1C

2013-11-21T21:44:28Z

Xc2611: /* Assigning the absolute configuration of the product */

= '''Synthesis and Computational Lab: 1C''' =
== '''Part 1: Introduction to Molecular Mechanics''' ==
=== '''Introduction to MMFF94 and MMFF94s''' ===

With the improvement of computational data and computer processing power, the usage of molecular mechanics/dynamics forcefield has become very integrated in predicting properties of chemical molecules. A molecular mechanics/dynamics forcefield should be able to predict characteristics such as molecular geometries, conformational/stereoisomeric energies, vibrational frequencies etc. to a reasonable accuracy as compared to experimental-derived values.

Building on work from Kollman et al. s’ AMBER forcefield and Allinger et al. s’ MM1, MM2, MM3 and MM4, Merck Research Laboratories have managed to optimized and improved the previous computational algorithms and produced MMFF94 (Merck Molecular Force Field 94). One of the most prominent advantages of MMFF94 over other preceeding work is its enhanced prediction accuracy. The reason lies in the fact that MMFF94’s core parameterization utilizes an unprecedently large amount of computational data obtained from ab initio calculations1.

Subsequently after the development of MMFF94, a new “static” variant of the MMFF was introduced i.e. the MMFF94s. Unlike MMFF94 that was developed for the use of molecular dynamics simulations (which can be expensive), MMFF94s was developed with the purpose of energy minimization studies in mind. Although both systems provide identical results for most systems, they differ for amides and unsaturated amines which contain resonance-delocalized trigonal nitrogen atoms2.

In this computational exercise, MMFF94s is used predominantly as oppose to the alternative Universal Force Field (UFF). Although versatile across the entire periodic table, UFF is derived from simple rules and atomic parameters such as fixed hybridization that increases the likelihood of erroneous structural and energetic predictions3.

=== '''Forms of MMFF94s''' ===

Steric energy of a molecule is the energy arise due to its geometry or conformation. Energy minimization of steric energy process ensures that the molecule is in its lowest energy conformation.

MMFF94s assumes that the total steric energy of a molecule can be found by the sum of a few specific interactions in a molecule.

ES = EBS + EAB + E SB + ET + EOOP + EVdW + EEE

'''where the bonded interactions are:'''

ES = Total Steric energy

EBS = Total Bond Stretching energy

EAB = Total Angle Bending energy

ESB = Total Stretch Bending energy

ET = Total Torsional Energy

EOOP = Total Out-Of-Plane Bending energy, and

'''where the non-bonded interactions are:'''

EVdW = Total Van der Waals Energy

EEE = Total Electrostatic Energy

{| border="1" cellspacing="1" cellpadding="10"
|-
| width="300" align="center" | '''Types of Energies'''
! width="600" align="center" | '''Explanation'''
|-
| colspan="2" style="text-align: center;" | '''Bonded Interactions'''
|-
| width="300" align="center" | '''Total Bond Stretching Energy'''
! width="600" align="left" | The total bond stretching energy is related to the vibration energy of the molecules in comparison to the equilibrium bond length. Whenever a bond deviates from the equilibrium bond length, the energy value increases.

MMFF94s uses a quartic function that has the force constant term (relate to bond strength). The quartic function term is superior to the cubic function term (used in MM2) in the sense that it avoid the “cubic stretch catastrophe” where progressive elongation of molecule bond length leads to negative infinity.
|-
| width="300" align="center" | '''Total Angle Bending Energy'''
! width="600" align="left" | Similar to Total Bond Stretching Energy, the total angle bending energy is also related to the vibration energy of the molecules about the equilibrium bond length. However, unlike EBS that measures the bond strength, EAB is associated with the stiffness of the molecules based on the Hookiean potential. Whenever bond angles deviate from the norm during vibration, this energy term increases as well.
|-
| width="300" align="center" | '''Total Stretch-Bending Energy'''
! width="600" align="left" | This energy term takes into account of the energy due to increase in bond length when bond angle between two atoms changes.
|-
| width="300" align="center" | '''Total Torsional Energy'''
! width="600" align="left" | Total torsional energy is the energy required for intermolecular rotation about the bonds. In molecule mechanics, however, this term is often used as a correction that must be added or subtracted to the total energy of the molecule to fit a quantum mechanical calculation about the dihedral angles of bonds.
|-
| width="300" align="center" | '''Total Out-Of-Plane Bending Energy'''
! width="600" align="left" | This energy term refers to the energy needed to deform the dihedral angle (zero degrees) of a planar group of atoms such as carbonyl or amide functional groups.
|-
| colspan="2" style="text-align: center;" | '''Non-Bonded Interactions'''
|-
| width="300" align="center" | '''Total Van der Waals Energy'''
! width="600" align="left" | The total Van der Waals energy term examines the intramolecular interactions such as repulsion or attraction between non-bonded atoms in the molecule. This term is crucial in determining the preferred conformation of the molecule.

MMFF94s employs the novel “Buffered-14-7”. The name is derived from a buffering constant and the 14th and 7th power dependencies of the repulsive and attractive energy in the equation.
|-
| width="300" align="center" | '''Total Electrostatic Energy'''
! width="600" align="left" | The total electrostatic energy functions take into account of the Coulombic potential and partial charge/dipole/atomic point charges interactions within the molecule.
|-

|}

 

== '''Part 2 : Conformational Analysis Using Molecular Mechanics''' ==
=== '''The Hydrogenation of Cyclopentadiene Dimer''' ===

==== '''Endo and exo adduct from the Dimerization of Cyclopentadiene''' ====
Cyclopentadiene will undergo dimerization by Diels-alder reaction to form either an endo or exo adduct.

[[File:XcwDimerization of CP.png|500px|center]]

==== '''Stereoselectivity of Dimerization of Cyclopentadiene''' ====
Although the exo adduct is thermodynamically more stable than the endo adduct, the endo adduct is form preferentially. Using the QST2 method, the transition state of the Diels Alder dimerization was found. It was discovered that due to the secondary orbital interactions in the endo transition state, the endo dimer is formed preferentially (the kinetic product). Hence, it is proven that the Diels Alder dimerization between two cyclopentadiene are kinetically controlled.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Transition State of Dimerization of Cyclopentadiene'''
| '''Imaginary Stretch Frequency (-881.25) of the Endo Transition State (click to animate)'''
| '''Secondary Orbital Interaction (Red overlapping orbitals)'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<uploadedFileContents>EndotsDCPD2.mol
</uploadedFileContents>
</jmolApplet></jmol>
| [[File:Xcwendotsimaginary.gif|300px|center]]
| [[File:XcwSecondary orbital interaction1.jpg|300px|center]]
|-
|}

 

==== '''Asynchronous Bond Formation of Dimerization of Cyclopentadiene''' ====

The initial study of the molecular orbitals of the transition states seemed a bit peculiar. Instead of getting a LUMO with symmetrical orbitals, the calculations showed a HOMO that is asymetric at the carbons where the new sigma bonds will be formed. Running an IRC further, it soon became clear that the asymmetry of the HOMO leads to an asychronous bond formation before leading to the product.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''IRC plot following the Endo Transition State '''
| '''IRC following the Endo Transition State (click to animate)'''
| '''Asymmetry of orbitals at the carbons where the new sigma bonds will be formed'''
|- align="center"
| [[File:XcwendotscyclopentadieneIRC.png|300px|center]]
| [[File:XcwendotsIRC.gif|300px|center]]
| [[File:XcwAsynchronous mo.jpg|300px|center]]
|-
|}

 

==== '''Comparison of Energies between the Endo and Exo adduct of Dicyclopentadiene''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Adduct of Dicyclopentadiene dimerization'''
| '''Exo Adduct of Dicyclopentadiene dimerization'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=19,atomno=1,atomno=2; color green;measure 19 1;measure 19 2;</script>
<uploadedFileContents>XcwEndodimer3.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>Exodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=7,atomno=17; color green;measure 17 7;</script>
<uploadedFileContents>XcwExodimer1.mol</uploadedFileContents>
</jmolApplet></jmol>
|-
|}

 

Using MMFF94s ab initio calculations, the energies for the exo dimer and the endo dimer are derived.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Exodimer'''
| '''55.374'''
| 3.543
| 30.772
| -2.041
| -2.728
| 0.015
| 12.800
| 13.014
|-
| '''Endodimer'''
| '''58.191'''
| 3.468
| 33.187
| -2.082
| -2.950
| 0.023
| 12.360
| 14.186
|-
|}

 

The MMFF94s steric energy (after minimization) for the exo dimer is lower than that of the endo dimer. This is reflected by the large difference for the EEE between the endo dimer and the exo dimer due to unfavourable steric repulsion between the two “arched down” cyclopentene rings.

==== '''Hydrogenation of Dicyclopentadiene''' ====

Hydrogenation of the endo dicyclopentadiene (DCPD) would lead to two potential products: dihydro product 1 and dihydro product 2.

[[File:XcwFormation of Dihydro products.png|500px|center]]

Using MMFF94s, the energy of the two dihydro products are calculated.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Dihydro Product 1'''
| '''50.123'''
| 3.308
| 30.864
| -1.927
| 0.060
| 0.015(2)
| 13.281
| 5.121
|-
| '''Dihydro Product 2'''
| '''41.257'''
| 2.823
| 24.685
| -1.657
| -0.379
| 0.000(2)
| 10.639
| 5.147
|-
| '''Tetrahydro Product'''
| '''39.042'''
| 2.730
| 25.151
| -1.676
| 1.287
| 0.000
| 11.551
| 0.000
|}

 

From the MMFF94s calculation, it can be seen that dihydro product 2 has a lower steric energy than dihydro product 1. Therefore, dihydro product 2 is the thermodynamic product for the hydrogenation of dicylopentadiene. And indeed, this was what was observed by Skala et al.. He observed that the first hydrogenation occur at the norborene part of the molecule (rate of hydrogenation several times faster than that in the cyclopentene ring)6. The first heat of hydrogenation at the norborene is 138.8 kJ/mol while the second hydrogenation at the cyclopentene right is 109.5 kJ/mol6.

From the above results, it is also obvious that tetrahydro product is much more stable than either dihydro product. And yet, studies have shown that the tetrahydro product will only form after prolonged hydrogenation under high temperature. However, subjecting DCPD to high temperature leads to low yield due to cracking of DCPD.

Since thermodynamically it is predicted to form favourably, the fact that it does not could only mean that the hydrogenation of DCPD to tetrahydrodicyclopentadiene (TH-DCPD) is kinetically controlled. Most possibly, the transition state of the hydrogenation of DCPD is highly unstable hence it is unlikely to form.

=== '''Atropisomerism in an Intermediate related to the Synthesis of Taxol''' ===

Atropisomerism is a type of stereoisomerism that is form as a result of hindered rotation about a single bond.

[[File:XcwAtropisomerism example.png|500px|center]]

In the case of the 6,6’-dinitro-2,2’-diphenic acid, rotation about the bonds joining the two substituted phenyl rings would have to overcome large steric interaction between the bulky substituents. The barrier of rotation is high enough for the two conformers to be isolated individually.

In the synthesis of taxol, one of the key intermediates exhibit atropisomerism.

==== '''Atropisomerism in Taxol Synthesis''' ====

For the key intermediate, rotation about the carbon-carbon bonds would lead to two types of atropisomers, each with either the carbonyl group poining upwards or downwards in relative to the bridge.

[[File:XcwIntermediate 9 and Intermediate 10.png|500px|center]]

Once again by using MMFF94s ab initio calculations, the steric energies for the two intermediates are illustrated as below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 9'''
| '''70.571'''
| 7.743
| 28.356
| -0.062
| 0.004
| 0.949
| 33.293
| 0.288
|-
| '''Intermediate 10'''
| '''60.553'''
| 7.599
| 18.838
| -0.139
| 0.199
| 0.844
| 33.269
| -0.056
|-

|}

 

Analyzing the data above, the largest energy difference between Intermediate 9 and Intermediate 10 stems from the EAB which is related to the strain of the ring. Intermediate 9 has an excess of 9.518 kcal/mol EAB as compared to Intermediate 10. This comes as a surprise as intermediate 9 is predicted to be more stable alkene.

The rationale behind the prediction of the stability of intermediate 9 stems from the fact that the through-space distance of the upward-pointing carbonyl oxygen with the carbon-carbon is further than the through space distance between the downward-pointing carbonyl oxygen with the -CH2-CH2- fragment at the norbornene part in intermediate 10.

==== '''Hyperstable Olefins''' ====

Intermediate 9 and Intermediate 10 does not react readily with other reagents during functionalization. This is due to the hyperstability effect found in hyperstable olefins.

Hyperstable olefins are alkenes that contain less strain in the ring (i.e. negative olefin strain values) compared to the parent hydrocarbon. To study this further, further MMFF94s calculation was done to compare Intermediate 10 with the parent hydrocarbon.

[[File:XcwIntermediate10andPH.png|500px|center]]

The energies that we calculated are tabulated as shown below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 10'''
| '''44.878 '''
| 5.211
| 15.488
| -0.267
| -1.655
| 0.998
| 25.014
| 0.088
|-
| '''Parent Hydrocarbon'''
| '''50.564'''
| 4.692
| 21.979
| 0.109
| -0.958
| 0.247
| 24.495
| 0.000
|-

|}

 

Scrutinizing the results, the largest energy difference between intermediate 10 and the parent hydrocarbon stems from the Total Angle Bending Energy, EAB. Since the Total Angle bending energy is related to the angle strain in the molecules, it is apparent that the parent hydrocarbon has more ring strain as compared to the bridgehead olefin.

== '''Part 3 : Spectroscopic Simulation Using Quantum Mechanics''' ==
=== '''Spectroscopy of an Intermediate Related to the Synthesis of Taxol''' ===

Molecule 17 and 18 are derivatives of intermediate 9 and 10. In this exercise, MMFF94s is used to predict the 1H and 13C NMR of molecule 17 and molecule 18.

[[File:XcwIntermediate17&18.png|500px|center]]

==== '''NMR Spectra of Molecule 17''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 17.mol
</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwHNMRMolecule 17 Chair Overall NMR.png|500px|center]]
| [[File:XcwHNMRMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.1825
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| The first three results were fairly straight forward to be deduced and correlate wit experimental data.

The hydrogen atom that is geminally attached to the carbon of the double bonds is the most deshielded due to the ring current anisotropic effect of the ring current

The second most deshielded hydrogen atom is the hydrogen atom on the methyl group on the bridge. The hydrogen atom is pointing directly to the oxygen atom of the carbonyl functional group.

The peaks with an integration height of 4 is assigned to the hydrogen atoms in the 1,3-dithiolane ring fragment.

Subsequent analysis of the 1H NMR became very complicated very quickly for two reasons:

1. Gaussian calculations showed some atoms with an integration height of 3. Comparing their file atom number and checking their chemical environment, it is not possible to find any correlation between them.

2. Some of the peaks in the literature remains unresolved and are given as multiplets or grouped together.

|- align="center"
| 52
| 3.1775
| 1
| '''2.99'''
|- align="center"
| 53,52,50,51
| 3.0867
| 4
| '''3.40-3.10'''
|- align="center"
| 42,43,39
| 2.7445
| 3
| ''' '''
|- align="center"
| 49
| 2.6187
| 1
| ''' '''
|- align="center"
| 34
| 2.4371
| 1
| ''' '''
|- align="center"
| 35
| 2.3782
| 1
| ''' '''
|- align="center"
| 40,37,26
| 2.2730
| 3
| ''' '''
|- align="center"
| 30
| 2.1566
| 1
| ''' '''
|- align="center"
| 36
| 2.1033
| 1
| ''' '''
|- align="center"
| 32,28
| 2.0259
| 2
| ''' '''
|- align="center"
| 25
| 1.8535
| 2
| ''' '''
|- align="center"
| 38,46,27
| 1.5898
| 3
| '''1.25'''
|- align="center"
| 29
| 1.4557
| 1
| ''' '''
|- align="center"
| 31
| 1.0123
| 1
| ''' '''
|- align="center"
| 44,48,45
| 0.9087
| 3
| '''1.10'''
|- align="center"
| 47
| 0.8354
| 1
| ''' '''
|- align="center"
| 33
| 0.5790
| 1
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 17 Chair Overall NMR2.png|500px|center]]
| [[File:XcwMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 216.2725
| 1
| '''218.79'''
| rowspan="10" style="text-align:center;"| [[File:XcwMolecule 17 image for CNMR.jpg|600px|center]]
|- align="center"
| 13
| 144.8626
| 1
| '''144.63'''
|- align="center"
| 14
| 124.7193
| 1
| '''125.33'''
|- align="center"
| 3
| 91.3340
| 1
| '''72.88'''
|- align="center"
| 2
| 60.9568
| 1
| '''56.19'''
|- align="center"
| 1
| 57.0811
| 1
| '''52.52'''
|- align="center"
| 10
| 52.4663
| 1
| '''48.50'''
|- align="center"
| 16
| 51.4857
| 1
| '''46.80'''
|- align="center"
| 9
| 46.9196
| 1
| '''45.76'''
|- align="center"
| 23
| 43.8647
| 1
| '''39.80'''
|- align="center"
| 22
| 41.9450
| 1
| '''38.81'''
| Comments
|- align="center"
| 4
| 41.8724
| 1
| '''35.85'''
| rowspan="9" style="text-align:left;"| The carbon bonded to the oxygen atom is the most deshielded, as is shown in the predicted values and the experimental values. There is a deviation between the values. Quite possibly, this is due to the fact that in reality, the carbonyl functional group is pointing slightly towards the equatorial position rather than a lateral position relative to the ring (as is in the input for Gaussian calculation)

Most of the 1CNMR values that was predicted by Gaussian are all within an acceptable range of deviation. However, there is carbon 3 that has significant deviation between the predicted value and experimental value.

Carbon 3 is the carbon bonded to the two sulphurs in the 1,3-dithiolane ring fragment. Such a huge deviation would possibly mean that the conformer that was given as input to Gaussian differs from the literature.

The above NMR spectra was corrected with a level of theory B3LYP/6-31G(d,p) using TMS as reference and in chloroform.

|- align="center"
| 15
| 35.4348
| 1
| '''32.66'''
|- align="center"
| 11
| 31.1964
| 1
| '''28.79'''
|- align="center"
| 6
| 28.9432
| 1
| '''28.29'''
|- align="center"
| 7
| 28.3640
| 1
| '''26.88'''
|- align="center"
| 12
| 27.3767
| 1
| '''25.66'''
|- align="center"
| 17
| 26.3311
| 1
| '''23.86'''
|- align="center"
| 15
| 24.5483
| 1
| '''20.96'''
|- align="center"
| 18
| 19.7788
| 1
| '''18.71'''
|-
|}
 

==== '''NMR Spectra of Molecule 18''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 18 Boat for Image2.mol</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"-
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 18 Chair Overall NMR.png|500px|center]]
| [[File:Molecule 18 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.2832
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| ''' '''
|- align="center"
| 50
| 3.3175
| 1
| rowspan="4" style="text-align:centre;"| '''3.00-2.70'''
|- align="center"
| 52
| 3.2153
| 1
|- align="center"
| 51,53
| 3.1161
| 2
|- align="center"
| 34,43
| 2.8606
| 2
|- align="center"
| 38
| 2.4549
| 1
| ''' '''
|- align="center"
| 42
| 2.3968
| 1
| ''' '''
|- align="center"
| 25,29,26
| 2.2796
| 3
| ''' '''
|- align="center"
| 39
| 2.0844
| 1
| ''' '''
|- align="center"
| 40,36
| 1.9699
| 2
| ''' '''
|- align="center"
| 37,24
| 1.8519
| 2
| ''' '''
|- align="center"
| 31,27
| 1.6780
| 2
| ''' '''
|- align="center"
| 28
| 1.6175
| 1
| ''' '''
|- align="center"
| 46,49
| 1.4979
| 2
| ''' '''
|- align="center"
| 35
| 1.4150
| 1
| ''' '''
|- align="center"
| 32
| 1.3531
| 1
| ''' '''
|- align="center"
| 48
| 1.1606
| 1
| ''' '''
|- align="center"
| 33,30,47
| 1.0653
| 3
| '''1.03'''
|- align="center"
| 44,45
| 0.9643
| 2
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwMolecule 18 Boat Overall NMR.png|500px|center]]
| [[File:XcwMolecule 18 Boat zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 211.8325
| 1
| '''211.49'''
| rowspan="10" style="text-align:center;"| [[File:Molecule 18 Boat for 13 CNMR.jpg|600px|center]]
|- align="center"
| 13
| 148.6673
| 1
| '''148.72'''
|- align="center"
| 14
| 118.8373
| 1
| '''120.90'''
|- align="center"
| 3
| 89.0869
| 1
| '''74.61'''
|- align="center"
| 2
| 67.8886
| 1
| '''60.53'''
|- align="center"
| 1
| 56.1133
| 1
| '''51.30'''
|- align="center"
| 10
| 55.5998
| 1
| '''50.94'''
|- align="center"
| 16
| 50.1124
| 1
| '''45.53'''
|- align="center"
| 22
| 48.2030
| 1
| '''43.28'''
|- align="center"
| 23
| 44.2222
| 1
| '''40.82'''
|- align="center"
| 4
| 42.0354
| 1
| '''38.73'''
| Comments
|- align="center"
| 9
| 37.5865
| 1
| '''36.78'''
| rowspan="9" style="text-align:left;"| ''' '''
|- align="center"
| 6
| 35.3106
| 1
| '''35.47'''
|- align="center"
| 15
| 31.0459
| 1
| '''30.84'''
|- align="center"
| 7
| 28.8476
| 1
| '''30.00'''
|- align="center"
| 12
| 28.6623
| 1
| '''25.56'''
|- align="center"
| 17
| 25.7393
| 1
| '''25.35'''
|- align="center"
| 11
| 25.2603
| 1
| '''22.21'''
|- align="center"
| 18
| 23.3944
| 1
| '''21.39'''
|- align="center"
| 5
| 21.0478
| 1
| '''19.83'''
|-
|}
 

== '''Part 4 : Analysis of the Properties of the Synthesized Alkene Epoxides''' ==
=== '''The two catalytics systems''' ===

Assymmetric epoxidation of prochiral alkenes may lead to product with different stereochemical outcome as illustrated as below. To solve this problem, different types of asymmetric epoxidation catalyst have been synthesized. In this study, we shall be focusing on Shi asymmetric fructose catalyst as well as Jacobsen asymmetric catalyst.

[[File:Asymmetric catalyst.png|400px|center]]

==== ''' The Shi Asymmetric Fructose Catalyst''' ====

Molecule 21 is the stable precursor of molecule 22, the active catalyst. Molecule 21 can be converted to molecule 22 by using either persulfuric acid or potassium peroxymonosulphate.

[[File:Molecule 21 to 23.png|400px|center]]

The transition state of the Shi epoxidation was a subject of debate for a few moments. However, recent studies have led to the conclusion that the spiro transition state is more favored than the planar transition state. The spiro transition state is the transition that has its dioxirane perpendicularly bisecting the alkene double bond. This is thought to be more favourable due to interactions between the lone pairs of the oxygen with the LUMO of the alkene.

[[File:Spiro and planar ts.png|500px|center]]

==== ''' The Jacobsen Asymmetric Catalyst''' ====

Molecule 23 is the stable precursor of molecule 24, the active catalyst. Molecule 23 can be converted to molecule 24 by using sodium perchlorate.

[[File:Salen, 23 and 24.png|400px|center]]

Jacobsen catalyst is biphasic. The first phase involves the transfer of oxygen to molecule 23. Sodium perchlorate oxidizes Mn(III) to Mn(V).

In the second step, Jacobsen catalyst acts via a radical mechanism. It is thought to be so because epoxidation of trans-alkene by Jacobsen catalyst yield cis-alkene as well. A radical mechanism will lead to the lost of stereochemical information of the molecule.

=== ''' Crystal structure of the two catalyst''' ===
==== '''Molecule 21''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 21'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 21 strucutre.png|600px|center]]'''
|-
| style="text-align:center;" width="150" | ''' Bond '''
| style="text-align:center;" width="150"| ''' Bond Lenghts (Angstrom)'''
| style="text-align:center;" | ''' Evaluation'''
|-
| style="text-align:center;"| ''' O1-C1 '''
| style="text-align:center;"| ''' 1.400'''
| rowspan="10" style="text-align:left;"| [[File:Molecule 21 2.png|300px|center]]

The normal bond length of an C-O bond is 1.430 angstrom.

The most interesting aspect here is O4 and O2. The lone pair of O4 is antiperplanar to the sigma* orbital of the carbonyl group while the lone pair of O2 is anti periplanar to the carbonyl pi* orbital. Donation of electron can occur because of the correct symmetry. Due to the mixing of the orbitals, the C2-O2 and C4-O4 has been conferred with a certain degree of double bond character.

However, due to the lone pair on oxygen being now donated to the carbonyl antibonding orbitals, the O2 and O4 is slightly “electron deficient” and electron density will be pulled away from O2 and O4. That would explain why the bond length increase for O2-C7 and O4-C10. Increase in bond length is an indicator of the weakening of the bond.
|-
| style="text-align:center;"|'''O1-C7'''
| style="text-align:center;"|'''1.413'''
|-
| style="text-align:center;"|'''O2-C7'''
| style="text-align:center;"|'''1.441'''
|-
| style="text-align:center;"|'''O2-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O4-C4'''
| style="text-align:center;"|'''1.396'''
|-
| style="text-align:center;"|'''O4-C10'''
| style="text-align:center;"|'''1.439'''
|-
| style="text-align:center;"|'''O5-C10'''
| style="text-align:center;"|'''1.409'''
|-
| style="text-align:center;"|'''O5-C5'''
| style="text-align:center;"|'''1.416'''
|-
| style="text-align:center;"|'''O6-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O6-C6'''
| style="text-align:center;"|'''1.420'''
|-
|}
 

==== '''Molecule 23''' ====

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 23'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 23 struc.png|600px|center]]'''
|-
| The most outstanding feature from this molecule is the fact that is adopt a puckered form of the square base pyramidal form. This is no surprise that the molecule is almost planar due to the electron delocalization around each side of the salen ligand.

The tery-butyl hydrogen are oriented closely to one another. Non-covalent interaction studies indicated that repulsion would occur for H---H bond length that are less than 2.1 angstrom while favourable interaction may be dominant with bond length above 2.4 angstrom. It was discovered that all 4 hydrogens have bond length more than 2.4 angstrom hence there should not be any significant repulsion between them. Instead, certain amount of attractive force will ensue and that contributes to the overall stability of the molecule

|-
|}
 

=== ''' The calculated NMR properties of the product''' ===

=== ''' Assigning the absolute configuration of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | ''' '''
| width="200" | '''(R)-Styrene'''
| width="300" | '''(S)-Styrene'''
| width="100" | '''(R,R)-Trans-stilbene'''
| width="150" | '''(S,S)-Trans-stilbene'''
|- align="center"
| width="100" | '''Predicted ORP'''
| width="100" | '''-24 deg '''
| width="150" | '''32.1 deg '''
| width="150" | '''296 deg'''
| width="150" | '''-205.2 deg '''
|- align="center"
| width="100" | '''Experimental ORP'''
| width="100" | '''-24 deg '''
| width="150" | '''32.1 deg '''
| width="150" | '''296 deg '''
| width="150" | '''-205.2 deg '''
|- align="center"
| width="100" | '''Experimental conditions'''
| width="100" | '''1.00g/100ml, chloroform, 21 degree Celcisus, 589 nm wavelength '''
| width="150" | '''1.02g/100ml (99% ee), chloroform, 25 degree Celsius, 589 nm wavelength '''
| width="150" | '''1.01g/100ml, ethanol, 22 degree Celsius, 589 nm wavelength '''
| width="150" | '''0.6g/100ml, ethanol, 20 degree Celsius, 589 nm wavelength '''
|- align="center"
| width="100" | ''' Predicted VCD Spectrum'''
| width="100" | '''-1343.024742'''
| width="150" | '''-0.007701'''
| width="150" | '''2.88E-04'''
| width="150" | '''99.94'''
|-
|}

 

=== ''' Analysis of the Transition State for Reactions''' ===
==== '''Predicting Enantiomeric Excess based on Transition State energies''' ====

One of the energy output from Gaussian calculation is the “sum of electronic and thermal free energies”. This is Gibbs Free Energy at 298.15K and 1 atm.

Using this term and invoking a variant of the Curtin-Hammett Principle, it is possible to calculate a predicted enantiomeric excess of one enantiomer over the other.

[[File:Ee and transition state energy.png|800px|center]]

Using the derivations from above and equation (4), we analyze the enantiomeric excess of beta-methyl styrene and the results are tabulated as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1343.022970'''
| width="100" | '''-1343.017942'''
| width="150" | '''-0.005028'''
| width="150" | '''4.88E-03'''
| width="150" | '''99.03'''
|- align="center"
| width="100" | '''-1343.019233'''
| width="100" | '''-1343.015603'''
| width="150" | '''-0.003630'''
| width="150" | '''2.14E-02'''
| width="150" | '''95.80'''
|- align="center"
| width="100" | '''-1343.029272'''
| width="100" | '''-1343.023766'''
| width="150" | '''-0.005506'''
| width="150" | '''2.94E-03'''
| width="150" | '''99.41'''
|- align="center"
| width="100" | '''-1343.032443'''
| width="100" | '''-1343.024742'''
| width="150" | '''-0.007701'''
| width="150" | '''2.88E-04'''
| width="150" | '''99.94'''
|-
|}

 

The above hartree units are converted to J/mol for calculation of K where 1 hartress = 4.3597E-18

Studying all the free energies of the (R,R) series and compare them with the (S,S) series, it comes as no surprise that (R,R) product is favoured over (S,S) product as (R,R) is more stable. Indeed, this corresponds with the literature value reporting 92% ee of (R,R) products over that of (S,S).

==== '''Analysis of the Transition State of Epoxidation''' ====
==== '''Shi Fructose Catalyst''' ====
For this section, I will be analyzing the the transition state of 1) styrene and 2) trans-stilbene with the Shi fructose catalyst.

===== '''(R) and (S)-styrene transition state''' =====
The transition state for the formation of (R)-styrene oxide and (S)-styrene oxide are given as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R)-styrene oxide'''
| width="150" | '''(S)-styrene oxide'''
|- align="center"
| width="150" | ''' Structure of Catalyst '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide R.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide S ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| [[File:Steric shi fructose R.png|450px|center]]
| [[File:Steric shi fructose S.png|450px|center]]
|-
|}

 

In the transition state for (R)-styrene, it was discovered that the Re face is reacting with the oxygen of the dioxirane. The phenyl ring is oriented endo with respect to the fructose catalyst. However, the (S)-styrene is reacting at the Si face and the phenyl ring is oriented exo relative to the catalyst.

The approach taken by (R)-styrene and (S)-styrene are restricted to only one due to steric interactions. Therefore, the epoxidation of both styrenes by the Shi catalyst will be stereospecific and retains all the stereochemical information of the reactant. However, whether or not (R)-styrene oxide or (S)-styrene oxide is form is dependent on the relative energies of the transition state. The more stable the transition state, the more likely the product of the transition state will be formed.

So in order to examine this, an example of transition state of both styrenes with Shi catalyst are obtained and analyzed.
 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1303.736813'''
| width="100" | '''-1303.727673'''
| width="150" | '''-0.00914'''
| width="150" | '''6.28E-05'''
| width="150" | '''99.99'''

|-
|}

 

From the above, we can see the predicted high enantiopurity of the reaction favoring the (R) product because of the lower energy of the transition states. To understand the reason, we have to turn to non-covalent interaction (NCI) analysis.

[[File:NCI shi fructose styrene.png|700px|center]]

To complement the NCI analysis, a QTAIM (Quantum Theory of Atoms in Molecules) analysis is conducted as well.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''(R)-styrene transition state'''
| width="200" | '''(S)-styrene transition state'''
|- align="center"
| width="100" | '''[[File:QTAIM R.png|400px|center]]'''
| width="100" | '''[[File:QTAIM S.png|400px|center]]'''
|- align="center"
| colspan="2" width="100" | '''Comments'''
|-
| colspan="2" width="100" | '''Unsurprisingly, QTAIM analysis has also shown that (R)-styrene/Shi catalyst has more interactions with one another. While (R)-styrene has 2 strong interactions, (S)-styrene has only one with the catalyst. Besides, the phenyl ring of (R)-styrene also confers additional positive interaction with the catalyst. QTAIM analysis has also show several interactions between the C=C geminal hydrogen of (R)-styrene intreacting with the oxygen atoms on the dioxacyclopentane ring'''
|-
|}

 

===== '''(R,R) and (S,S)-Stilbene transition state''' =====

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R,R)-Stilbene oxide'''
| width="150" | '''(S,S)-Stilbene oxide'''
|- align="center"
| width="150" | ''' Structure of Transition State '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Stilbene RR ts.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>SS stilbene oxide ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| colspan="2" | [[File:Shi fructose stilbene.png|700px|center]]

|-
|}

 

However, unlike styrene, trans-stilbene seems to approach perpendicularly to the dioxirane. This is proposed to be due to the steric interactions (marked in purple). Based on first inspection, it seems that (S,S)-Stilbene oxide has more steric interactions than (R,R)-Stilbene oxide. Although unsubstantial, it seems like my guess was correct. The (R,R)-stilbene/Shi catalyst transition state is lower in energy.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1534.687808'''
| width="100" | '''-1534.683440'''
| width="150" | '''0.004368'''
| width="150" | '''9.08E-3'''
| width="150" | '''98.20'''

|-
|}

 

NCI Analysis is also done for trans-stilbene

[[File:NCI stilbene.png|700px|center]]

==== '''Jacobsen Catalyst''' ====

For this section, cis-beta methyl styrene transition state will be analyzed.

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-3383.259559'''
| width="100" | '''-3383.251060'''
| width="150" | '''-0.008499'''
| width="150" | '''1.24E-04'''
| width="150" | '''99.98'''
|- align="center"
| width="100" | '''-3383.253442'''
| width="100" | '''-3383.250270'''
| width="150" | '''-0.003172'''
| width="150" | '''3.48E-02'''
| width="150" | '''93.27'''
|-
|}

 

As is obvious from here, the (S,R) transition state is more stable than the (R,S) transition state. Both transition states are exo with respect to the catalyst.

It is not immediately apparent just by looking at the molecule to determine which spatial groups have interactions with one another. Therefore, an NCI analysis is conducted again.

[[File:NCI Jacobsen.png|700px|center]]

Rep:Mod:Computationalreport1C

2013-11-21T20:29:46Z

Xc2611: /* Assigning the absolute configuration of the product */

= '''Synthesis and Computational Lab: 1C''' =
== '''Part 1: Introduction to Molecular Mechanics''' ==
=== '''Introduction to MMFF94 and MMFF94s''' ===

With the improvement of computational data and computer processing power, the usage of molecular mechanics/dynamics forcefield has become very integrated in predicting properties of chemical molecules. A molecular mechanics/dynamics forcefield should be able to predict characteristics such as molecular geometries, conformational/stereoisomeric energies, vibrational frequencies etc. to a reasonable accuracy as compared to experimental-derived values.

Building on work from Kollman et al. s’ AMBER forcefield and Allinger et al. s’ MM1, MM2, MM3 and MM4, Merck Research Laboratories have managed to optimized and improved the previous computational algorithms and produced MMFF94 (Merck Molecular Force Field 94). One of the most prominent advantages of MMFF94 over other preceeding work is its enhanced prediction accuracy. The reason lies in the fact that MMFF94’s core parameterization utilizes an unprecedently large amount of computational data obtained from ab initio calculations1.

Subsequently after the development of MMFF94, a new “static” variant of the MMFF was introduced i.e. the MMFF94s. Unlike MMFF94 that was developed for the use of molecular dynamics simulations (which can be expensive), MMFF94s was developed with the purpose of energy minimization studies in mind. Although both systems provide identical results for most systems, they differ for amides and unsaturated amines which contain resonance-delocalized trigonal nitrogen atoms2.

In this computational exercise, MMFF94s is used predominantly as oppose to the alternative Universal Force Field (UFF). Although versatile across the entire periodic table, UFF is derived from simple rules and atomic parameters such as fixed hybridization that increases the likelihood of erroneous structural and energetic predictions3.

=== '''Forms of MMFF94s''' ===

Steric energy of a molecule is the energy arise due to its geometry or conformation. Energy minimization of steric energy process ensures that the molecule is in its lowest energy conformation.

MMFF94s assumes that the total steric energy of a molecule can be found by the sum of a few specific interactions in a molecule.

ES = EBS + EAB + E SB + ET + EOOP + EVdW + EEE

'''where the bonded interactions are:'''

ES = Total Steric energy

EBS = Total Bond Stretching energy

EAB = Total Angle Bending energy

ESB = Total Stretch Bending energy

ET = Total Torsional Energy

EOOP = Total Out-Of-Plane Bending energy, and

'''where the non-bonded interactions are:'''

EVdW = Total Van der Waals Energy

EEE = Total Electrostatic Energy

{| border="1" cellspacing="1" cellpadding="10"
|-
| width="300" align="center" | '''Types of Energies'''
! width="600" align="center" | '''Explanation'''
|-
| colspan="2" style="text-align: center;" | '''Bonded Interactions'''
|-
| width="300" align="center" | '''Total Bond Stretching Energy'''
! width="600" align="left" | The total bond stretching energy is related to the vibration energy of the molecules in comparison to the equilibrium bond length. Whenever a bond deviates from the equilibrium bond length, the energy value increases.

MMFF94s uses a quartic function that has the force constant term (relate to bond strength). The quartic function term is superior to the cubic function term (used in MM2) in the sense that it avoid the “cubic stretch catastrophe” where progressive elongation of molecule bond length leads to negative infinity.
|-
| width="300" align="center" | '''Total Angle Bending Energy'''
! width="600" align="left" | Similar to Total Bond Stretching Energy, the total angle bending energy is also related to the vibration energy of the molecules about the equilibrium bond length. However, unlike EBS that measures the bond strength, EAB is associated with the stiffness of the molecules based on the Hookiean potential. Whenever bond angles deviate from the norm during vibration, this energy term increases as well.
|-
| width="300" align="center" | '''Total Stretch-Bending Energy'''
! width="600" align="left" | This energy term takes into account of the energy due to increase in bond length when bond angle between two atoms changes.
|-
| width="300" align="center" | '''Total Torsional Energy'''
! width="600" align="left" | Total torsional energy is the energy required for intermolecular rotation about the bonds. In molecule mechanics, however, this term is often used as a correction that must be added or subtracted to the total energy of the molecule to fit a quantum mechanical calculation about the dihedral angles of bonds.
|-
| width="300" align="center" | '''Total Out-Of-Plane Bending Energy'''
! width="600" align="left" | This energy term refers to the energy needed to deform the dihedral angle (zero degrees) of a planar group of atoms such as carbonyl or amide functional groups.
|-
| colspan="2" style="text-align: center;" | '''Non-Bonded Interactions'''
|-
| width="300" align="center" | '''Total Van der Waals Energy'''
! width="600" align="left" | The total Van der Waals energy term examines the intramolecular interactions such as repulsion or attraction between non-bonded atoms in the molecule. This term is crucial in determining the preferred conformation of the molecule.

MMFF94s employs the novel “Buffered-14-7”. The name is derived from a buffering constant and the 14th and 7th power dependencies of the repulsive and attractive energy in the equation.
|-
| width="300" align="center" | '''Total Electrostatic Energy'''
! width="600" align="left" | The total electrostatic energy functions take into account of the Coulombic potential and partial charge/dipole/atomic point charges interactions within the molecule.
|-

|}

 

== '''Part 2 : Conformational Analysis Using Molecular Mechanics''' ==
=== '''The Hydrogenation of Cyclopentadiene Dimer''' ===

==== '''Endo and exo adduct from the Dimerization of Cyclopentadiene''' ====
Cyclopentadiene will undergo dimerization by Diels-alder reaction to form either an endo or exo adduct.

[[File:XcwDimerization of CP.png|500px|center]]

==== '''Stereoselectivity of Dimerization of Cyclopentadiene''' ====
Although the exo adduct is thermodynamically more stable than the endo adduct, the endo adduct is form preferentially. Using the QST2 method, the transition state of the Diels Alder dimerization was found. It was discovered that due to the secondary orbital interactions in the endo transition state, the endo dimer is formed preferentially (the kinetic product). Hence, it is proven that the Diels Alder dimerization between two cyclopentadiene are kinetically controlled.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Transition State of Dimerization of Cyclopentadiene'''
| '''Imaginary Stretch Frequency (-881.25) of the Endo Transition State (click to animate)'''
| '''Secondary Orbital Interaction (Red overlapping orbitals)'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<uploadedFileContents>EndotsDCPD2.mol
</uploadedFileContents>
</jmolApplet></jmol>
| [[File:Xcwendotsimaginary.gif|300px|center]]
| [[File:XcwSecondary orbital interaction1.jpg|300px|center]]
|-
|}

 

==== '''Asynchronous Bond Formation of Dimerization of Cyclopentadiene''' ====

The initial study of the molecular orbitals of the transition states seemed a bit peculiar. Instead of getting a LUMO with symmetrical orbitals, the calculations showed a HOMO that is asymetric at the carbons where the new sigma bonds will be formed. Running an IRC further, it soon became clear that the asymmetry of the HOMO leads to an asychronous bond formation before leading to the product.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''IRC plot following the Endo Transition State '''
| '''IRC following the Endo Transition State (click to animate)'''
| '''Asymmetry of orbitals at the carbons where the new sigma bonds will be formed'''
|- align="center"
| [[File:XcwendotscyclopentadieneIRC.png|300px|center]]
| [[File:XcwendotsIRC.gif|300px|center]]
| [[File:XcwAsynchronous mo.jpg|300px|center]]
|-
|}

 

==== '''Comparison of Energies between the Endo and Exo adduct of Dicyclopentadiene''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Adduct of Dicyclopentadiene dimerization'''
| '''Exo Adduct of Dicyclopentadiene dimerization'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=19,atomno=1,atomno=2; color green;measure 19 1;measure 19 2;</script>
<uploadedFileContents>XcwEndodimer3.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>Exodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=7,atomno=17; color green;measure 17 7;</script>
<uploadedFileContents>XcwExodimer1.mol</uploadedFileContents>
</jmolApplet></jmol>
|-
|}

 

Using MMFF94s ab initio calculations, the energies for the exo dimer and the endo dimer are derived.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Exodimer'''
| '''55.374'''
| 3.543
| 30.772
| -2.041
| -2.728
| 0.015
| 12.800
| 13.014
|-
| '''Endodimer'''
| '''58.191'''
| 3.468
| 33.187
| -2.082
| -2.950
| 0.023
| 12.360
| 14.186
|-
|}

 

The MMFF94s steric energy (after minimization) for the exo dimer is lower than that of the endo dimer. This is reflected by the large difference for the EEE between the endo dimer and the exo dimer due to unfavourable steric repulsion between the two “arched down” cyclopentene rings.

==== '''Hydrogenation of Dicyclopentadiene''' ====

Hydrogenation of the endo dicyclopentadiene (DCPD) would lead to two potential products: dihydro product 1 and dihydro product 2.

[[File:XcwFormation of Dihydro products.png|500px|center]]

Using MMFF94s, the energy of the two dihydro products are calculated.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Dihydro Product 1'''
| '''50.123'''
| 3.308
| 30.864
| -1.927
| 0.060
| 0.015(2)
| 13.281
| 5.121
|-
| '''Dihydro Product 2'''
| '''41.257'''
| 2.823
| 24.685
| -1.657
| -0.379
| 0.000(2)
| 10.639
| 5.147
|-
| '''Tetrahydro Product'''
| '''39.042'''
| 2.730
| 25.151
| -1.676
| 1.287
| 0.000
| 11.551
| 0.000
|}

 

From the MMFF94s calculation, it can be seen that dihydro product 2 has a lower steric energy than dihydro product 1. Therefore, dihydro product 2 is the thermodynamic product for the hydrogenation of dicylopentadiene. And indeed, this was what was observed by Skala et al.. He observed that the first hydrogenation occur at the norborene part of the molecule (rate of hydrogenation several times faster than that in the cyclopentene ring)6. The first heat of hydrogenation at the norborene is 138.8 kJ/mol while the second hydrogenation at the cyclopentene right is 109.5 kJ/mol6.

From the above results, it is also obvious that tetrahydro product is much more stable than either dihydro product. And yet, studies have shown that the tetrahydro product will only form after prolonged hydrogenation under high temperature. However, subjecting DCPD to high temperature leads to low yield due to cracking of DCPD.

Since thermodynamically it is predicted to form favourably, the fact that it does not could only mean that the hydrogenation of DCPD to tetrahydrodicyclopentadiene (TH-DCPD) is kinetically controlled. Most possibly, the transition state of the hydrogenation of DCPD is highly unstable hence it is unlikely to form.

=== '''Atropisomerism in an Intermediate related to the Synthesis of Taxol''' ===

Atropisomerism is a type of stereoisomerism that is form as a result of hindered rotation about a single bond.

[[File:XcwAtropisomerism example.png|500px|center]]

In the case of the 6,6’-dinitro-2,2’-diphenic acid, rotation about the bonds joining the two substituted phenyl rings would have to overcome large steric interaction between the bulky substituents. The barrier of rotation is high enough for the two conformers to be isolated individually.

In the synthesis of taxol, one of the key intermediates exhibit atropisomerism.

==== '''Atropisomerism in Taxol Synthesis''' ====

For the key intermediate, rotation about the carbon-carbon bonds would lead to two types of atropisomers, each with either the carbonyl group poining upwards or downwards in relative to the bridge.

[[File:XcwIntermediate 9 and Intermediate 10.png|500px|center]]

Once again by using MMFF94s ab initio calculations, the steric energies for the two intermediates are illustrated as below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 9'''
| '''70.571'''
| 7.743
| 28.356
| -0.062
| 0.004
| 0.949
| 33.293
| 0.288
|-
| '''Intermediate 10'''
| '''60.553'''
| 7.599
| 18.838
| -0.139
| 0.199
| 0.844
| 33.269
| -0.056
|-

|}

 

Analyzing the data above, the largest energy difference between Intermediate 9 and Intermediate 10 stems from the EAB which is related to the strain of the ring. Intermediate 9 has an excess of 9.518 kcal/mol EAB as compared to Intermediate 10. This comes as a surprise as intermediate 9 is predicted to be more stable alkene.

The rationale behind the prediction of the stability of intermediate 9 stems from the fact that the through-space distance of the upward-pointing carbonyl oxygen with the carbon-carbon is further than the through space distance between the downward-pointing carbonyl oxygen with the -CH2-CH2- fragment at the norbornene part in intermediate 10.

==== '''Hyperstable Olefins''' ====

Intermediate 9 and Intermediate 10 does not react readily with other reagents during functionalization. This is due to the hyperstability effect found in hyperstable olefins.

Hyperstable olefins are alkenes that contain less strain in the ring (i.e. negative olefin strain values) compared to the parent hydrocarbon. To study this further, further MMFF94s calculation was done to compare Intermediate 10 with the parent hydrocarbon.

[[File:XcwIntermediate10andPH.png|500px|center]]

The energies that we calculated are tabulated as shown below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 10'''
| '''44.878 '''
| 5.211
| 15.488
| -0.267
| -1.655
| 0.998
| 25.014
| 0.088
|-
| '''Parent Hydrocarbon'''
| '''50.564'''
| 4.692
| 21.979
| 0.109
| -0.958
| 0.247
| 24.495
| 0.000
|-

|}

 

Scrutinizing the results, the largest energy difference between intermediate 10 and the parent hydrocarbon stems from the Total Angle Bending Energy, EAB. Since the Total Angle bending energy is related to the angle strain in the molecules, it is apparent that the parent hydrocarbon has more ring strain as compared to the bridgehead olefin.

== '''Part 3 : Spectroscopic Simulation Using Quantum Mechanics''' ==
=== '''Spectroscopy of an Intermediate Related to the Synthesis of Taxol''' ===

Molecule 17 and 18 are derivatives of intermediate 9 and 10. In this exercise, MMFF94s is used to predict the 1H and 13C NMR of molecule 17 and molecule 18.

[[File:XcwIntermediate17&18.png|500px|center]]

==== '''NMR Spectra of Molecule 17''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 17.mol
</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwHNMRMolecule 17 Chair Overall NMR.png|500px|center]]
| [[File:XcwHNMRMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.1825
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| The first three results were fairly straight forward to be deduced and correlate wit experimental data.

The hydrogen atom that is geminally attached to the carbon of the double bonds is the most deshielded due to the ring current anisotropic effect of the ring current

The second most deshielded hydrogen atom is the hydrogen atom on the methyl group on the bridge. The hydrogen atom is pointing directly to the oxygen atom of the carbonyl functional group.

The peaks with an integration height of 4 is assigned to the hydrogen atoms in the 1,3-dithiolane ring fragment.

Subsequent analysis of the 1H NMR became very complicated very quickly for two reasons:

1. Gaussian calculations showed some atoms with an integration height of 3. Comparing their file atom number and checking their chemical environment, it is not possible to find any correlation between them.

2. Some of the peaks in the literature remains unresolved and are given as multiplets or grouped together.

|- align="center"
| 52
| 3.1775
| 1
| '''2.99'''
|- align="center"
| 53,52,50,51
| 3.0867
| 4
| '''3.40-3.10'''
|- align="center"
| 42,43,39
| 2.7445
| 3
| ''' '''
|- align="center"
| 49
| 2.6187
| 1
| ''' '''
|- align="center"
| 34
| 2.4371
| 1
| ''' '''
|- align="center"
| 35
| 2.3782
| 1
| ''' '''
|- align="center"
| 40,37,26
| 2.2730
| 3
| ''' '''
|- align="center"
| 30
| 2.1566
| 1
| ''' '''
|- align="center"
| 36
| 2.1033
| 1
| ''' '''
|- align="center"
| 32,28
| 2.0259
| 2
| ''' '''
|- align="center"
| 25
| 1.8535
| 2
| ''' '''
|- align="center"
| 38,46,27
| 1.5898
| 3
| '''1.25'''
|- align="center"
| 29
| 1.4557
| 1
| ''' '''
|- align="center"
| 31
| 1.0123
| 1
| ''' '''
|- align="center"
| 44,48,45
| 0.9087
| 3
| '''1.10'''
|- align="center"
| 47
| 0.8354
| 1
| ''' '''
|- align="center"
| 33
| 0.5790
| 1
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 17 Chair Overall NMR2.png|500px|center]]
| [[File:XcwMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 216.2725
| 1
| '''218.79'''
| rowspan="10" style="text-align:center;"| [[File:XcwMolecule 17 image for CNMR.jpg|600px|center]]
|- align="center"
| 13
| 144.8626
| 1
| '''144.63'''
|- align="center"
| 14
| 124.7193
| 1
| '''125.33'''
|- align="center"
| 3
| 91.3340
| 1
| '''72.88'''
|- align="center"
| 2
| 60.9568
| 1
| '''56.19'''
|- align="center"
| 1
| 57.0811
| 1
| '''52.52'''
|- align="center"
| 10
| 52.4663
| 1
| '''48.50'''
|- align="center"
| 16
| 51.4857
| 1
| '''46.80'''
|- align="center"
| 9
| 46.9196
| 1
| '''45.76'''
|- align="center"
| 23
| 43.8647
| 1
| '''39.80'''
|- align="center"
| 22
| 41.9450
| 1
| '''38.81'''
| Comments
|- align="center"
| 4
| 41.8724
| 1
| '''35.85'''
| rowspan="9" style="text-align:left;"| The carbon bonded to the oxygen atom is the most deshielded, as is shown in the predicted values and the experimental values. There is a deviation between the values. Quite possibly, this is due to the fact that in reality, the carbonyl functional group is pointing slightly towards the equatorial position rather than a lateral position relative to the ring (as is in the input for Gaussian calculation)

Most of the 1CNMR values that was predicted by Gaussian are all within an acceptable range of deviation. However, there is carbon 3 that has significant deviation between the predicted value and experimental value.

Carbon 3 is the carbon bonded to the two sulphurs in the 1,3-dithiolane ring fragment. Such a huge deviation would possibly mean that the conformer that was given as input to Gaussian differs from the literature.

The above NMR spectra was corrected with a level of theory B3LYP/6-31G(d,p) using TMS as reference and in chloroform.

|- align="center"
| 15
| 35.4348
| 1
| '''32.66'''
|- align="center"
| 11
| 31.1964
| 1
| '''28.79'''
|- align="center"
| 6
| 28.9432
| 1
| '''28.29'''
|- align="center"
| 7
| 28.3640
| 1
| '''26.88'''
|- align="center"
| 12
| 27.3767
| 1
| '''25.66'''
|- align="center"
| 17
| 26.3311
| 1
| '''23.86'''
|- align="center"
| 15
| 24.5483
| 1
| '''20.96'''
|- align="center"
| 18
| 19.7788
| 1
| '''18.71'''
|-
|}
 

==== '''NMR Spectra of Molecule 18''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 18 Boat for Image2.mol</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"-
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 18 Chair Overall NMR.png|500px|center]]
| [[File:Molecule 18 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.2832
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| ''' '''
|- align="center"
| 50
| 3.3175
| 1
| rowspan="4" style="text-align:centre;"| '''3.00-2.70'''
|- align="center"
| 52
| 3.2153
| 1
|- align="center"
| 51,53
| 3.1161
| 2
|- align="center"
| 34,43
| 2.8606
| 2
|- align="center"
| 38
| 2.4549
| 1
| ''' '''
|- align="center"
| 42
| 2.3968
| 1
| ''' '''
|- align="center"
| 25,29,26
| 2.2796
| 3
| ''' '''
|- align="center"
| 39
| 2.0844
| 1
| ''' '''
|- align="center"
| 40,36
| 1.9699
| 2
| ''' '''
|- align="center"
| 37,24
| 1.8519
| 2
| ''' '''
|- align="center"
| 31,27
| 1.6780
| 2
| ''' '''
|- align="center"
| 28
| 1.6175
| 1
| ''' '''
|- align="center"
| 46,49
| 1.4979
| 2
| ''' '''
|- align="center"
| 35
| 1.4150
| 1
| ''' '''
|- align="center"
| 32
| 1.3531
| 1
| ''' '''
|- align="center"
| 48
| 1.1606
| 1
| ''' '''
|- align="center"
| 33,30,47
| 1.0653
| 3
| '''1.03'''
|- align="center"
| 44,45
| 0.9643
| 2
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwMolecule 18 Boat Overall NMR.png|500px|center]]
| [[File:XcwMolecule 18 Boat zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 211.8325
| 1
| '''211.49'''
| rowspan="10" style="text-align:center;"| [[File:Molecule 18 Boat for 13 CNMR.jpg|600px|center]]
|- align="center"
| 13
| 148.6673
| 1
| '''148.72'''
|- align="center"
| 14
| 118.8373
| 1
| '''120.90'''
|- align="center"
| 3
| 89.0869
| 1
| '''74.61'''
|- align="center"
| 2
| 67.8886
| 1
| '''60.53'''
|- align="center"
| 1
| 56.1133
| 1
| '''51.30'''
|- align="center"
| 10
| 55.5998
| 1
| '''50.94'''
|- align="center"
| 16
| 50.1124
| 1
| '''45.53'''
|- align="center"
| 22
| 48.2030
| 1
| '''43.28'''
|- align="center"
| 23
| 44.2222
| 1
| '''40.82'''
|- align="center"
| 4
| 42.0354
| 1
| '''38.73'''
| Comments
|- align="center"
| 9
| 37.5865
| 1
| '''36.78'''
| rowspan="9" style="text-align:left;"| ''' '''
|- align="center"
| 6
| 35.3106
| 1
| '''35.47'''
|- align="center"
| 15
| 31.0459
| 1
| '''30.84'''
|- align="center"
| 7
| 28.8476
| 1
| '''30.00'''
|- align="center"
| 12
| 28.6623
| 1
| '''25.56'''
|- align="center"
| 17
| 25.7393
| 1
| '''25.35'''
|- align="center"
| 11
| 25.2603
| 1
| '''22.21'''
|- align="center"
| 18
| 23.3944
| 1
| '''21.39'''
|- align="center"
| 5
| 21.0478
| 1
| '''19.83'''
|-
|}
 

== '''Part 4 : Analysis of the Properties of the Synthesized Alkene Epoxides''' ==
=== '''The two catalytics systems''' ===

Assymmetric epoxidation of prochiral alkenes may lead to product with different stereochemical outcome as illustrated as below. To solve this problem, different types of asymmetric epoxidation catalyst have been synthesized. In this study, we shall be focusing on Shi asymmetric fructose catalyst as well as Jacobsen asymmetric catalyst.

[[File:Asymmetric catalyst.png|400px|center]]

==== ''' The Shi Asymmetric Fructose Catalyst''' ====

Molecule 21 is the stable precursor of molecule 22, the active catalyst. Molecule 21 can be converted to molecule 22 by using either persulfuric acid or potassium peroxymonosulphate.

[[File:Molecule 21 to 23.png|400px|center]]

The transition state of the Shi epoxidation was a subject of debate for a few moments. However, recent studies have led to the conclusion that the spiro transition state is more favored than the planar transition state. The spiro transition state is the transition that has its dioxirane perpendicularly bisecting the alkene double bond. This is thought to be more favourable due to interactions between the lone pairs of the oxygen with the LUMO of the alkene.

[[File:Spiro and planar ts.png|500px|center]]

==== ''' The Jacobsen Asymmetric Catalyst''' ====

Molecule 23 is the stable precursor of molecule 24, the active catalyst. Molecule 23 can be converted to molecule 24 by using sodium perchlorate.

[[File:Salen, 23 and 24.png|400px|center]]

Jacobsen catalyst is biphasic. The first phase involves the transfer of oxygen to molecule 23. Sodium perchlorate oxidizes Mn(III) to Mn(V).

In the second step, Jacobsen catalyst acts via a radical mechanism. It is thought to be so because epoxidation of trans-alkene by Jacobsen catalyst yield cis-alkene as well. A radical mechanism will lead to the lost of stereochemical information of the molecule.

=== ''' Crystal structure of the two catalyst''' ===
==== '''Molecule 21''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 21'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 21 strucutre.png|600px|center]]'''
|-
| style="text-align:center;" width="150" | ''' Bond '''
| style="text-align:center;" width="150"| ''' Bond Lenghts (Angstrom)'''
| style="text-align:center;" | ''' Evaluation'''
|-
| style="text-align:center;"| ''' O1-C1 '''
| style="text-align:center;"| ''' 1.400'''
| rowspan="10" style="text-align:left;"| [[File:Molecule 21 2.png|300px|center]]

The normal bond length of an C-O bond is 1.430 angstrom.

The most interesting aspect here is O4 and O2. The lone pair of O4 is antiperplanar to the sigma* orbital of the carbonyl group while the lone pair of O2 is anti periplanar to the carbonyl pi* orbital. Donation of electron can occur because of the correct symmetry. Due to the mixing of the orbitals, the C2-O2 and C4-O4 has been conferred with a certain degree of double bond character.

However, due to the lone pair on oxygen being now donated to the carbonyl antibonding orbitals, the O2 and O4 is slightly “electron deficient” and electron density will be pulled away from O2 and O4. That would explain why the bond length increase for O2-C7 and O4-C10. Increase in bond length is an indicator of the weakening of the bond.
|-
| style="text-align:center;"|'''O1-C7'''
| style="text-align:center;"|'''1.413'''
|-
| style="text-align:center;"|'''O2-C7'''
| style="text-align:center;"|'''1.441'''
|-
| style="text-align:center;"|'''O2-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O4-C4'''
| style="text-align:center;"|'''1.396'''
|-
| style="text-align:center;"|'''O4-C10'''
| style="text-align:center;"|'''1.439'''
|-
| style="text-align:center;"|'''O5-C10'''
| style="text-align:center;"|'''1.409'''
|-
| style="text-align:center;"|'''O5-C5'''
| style="text-align:center;"|'''1.416'''
|-
| style="text-align:center;"|'''O6-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O6-C6'''
| style="text-align:center;"|'''1.420'''
|-
|}
 

==== '''Molecule 23''' ====

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 23'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 23 struc.png|600px|center]]'''
|-
| The most outstanding feature from this molecule is the fact that is adopt a puckered form of the square base pyramidal form. This is no surprise that the molecule is almost planar due to the electron delocalization around each side of the salen ligand.

The tery-butyl hydrogen are oriented closely to one another. Non-covalent interaction studies indicated that repulsion would occur for H---H bond length that are less than 2.1 angstrom while favourable interaction may be dominant with bond length above 2.4 angstrom. It was discovered that all 4 hydrogens have bond length more than 2.4 angstrom hence there should not be any significant repulsion between them. Instead, certain amount of attractive force will ensue and that contributes to the overall stability of the molecule

|-
|}
 

=== ''' The calculated NMR properties of the product''' ===

=== ''' Assigning the absolute configuration of the product''' ===

The two products that have been chosen are styrene and trans-stilbene.

=== ''' Analysis of the Transition State for Reactions''' ===
==== '''Predicting Enantiomeric Excess based on Transition State energies''' ====

One of the energy output from Gaussian calculation is the “sum of electronic and thermal free energies”. This is Gibbs Free Energy at 298.15K and 1 atm.

Using this term and invoking a variant of the Curtin-Hammett Principle, it is possible to calculate a predicted enantiomeric excess of one enantiomer over the other.

[[File:Ee and transition state energy.png|800px|center]]

Using the derivations from above and equation (4), we analyze the enantiomeric excess of beta-methyl styrene and the results are tabulated as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1343.022970'''
| width="100" | '''-1343.017942'''
| width="150" | '''-0.005028'''
| width="150" | '''4.88E-03'''
| width="150" | '''99.03'''
|- align="center"
| width="100" | '''-1343.019233'''
| width="100" | '''-1343.015603'''
| width="150" | '''-0.003630'''
| width="150" | '''2.14E-02'''
| width="150" | '''95.80'''
|- align="center"
| width="100" | '''-1343.029272'''
| width="100" | '''-1343.023766'''
| width="150" | '''-0.005506'''
| width="150" | '''2.94E-03'''
| width="150" | '''99.41'''
|- align="center"
| width="100" | '''-1343.032443'''
| width="100" | '''-1343.024742'''
| width="150" | '''-0.007701'''
| width="150" | '''2.88E-04'''
| width="150" | '''99.94'''
|-
|}

 

The above hartree units are converted to J/mol for calculation of K where 1 hartress = 4.3597E-18

Studying all the free energies of the (R,R) series and compare them with the (S,S) series, it comes as no surprise that (R,R) product is favoured over (S,S) product as (R,R) is more stable. Indeed, this corresponds with the literature value reporting 92% ee of (R,R) products over that of (S,S).

==== '''Analysis of the Transition State of Epoxidation''' ====
==== '''Shi Fructose Catalyst''' ====
For this section, I will be analyzing the the transition state of 1) styrene and 2) trans-stilbene with the Shi fructose catalyst.

===== '''(R) and (S)-styrene transition state''' =====
The transition state for the formation of (R)-styrene oxide and (S)-styrene oxide are given as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R)-styrene oxide'''
| width="150" | '''(S)-styrene oxide'''
|- align="center"
| width="150" | ''' Structure of Catalyst '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide R.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide S ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| [[File:Steric shi fructose R.png|450px|center]]
| [[File:Steric shi fructose S.png|450px|center]]
|-
|}

 

In the transition state for (R)-styrene, it was discovered that the Re face is reacting with the oxygen of the dioxirane. The phenyl ring is oriented endo with respect to the fructose catalyst. However, the (S)-styrene is reacting at the Si face and the phenyl ring is oriented exo relative to the catalyst.

The approach taken by (R)-styrene and (S)-styrene are restricted to only one due to steric interactions. Therefore, the epoxidation of both styrenes by the Shi catalyst will be stereospecific and retains all the stereochemical information of the reactant. However, whether or not (R)-styrene oxide or (S)-styrene oxide is form is dependent on the relative energies of the transition state. The more stable the transition state, the more likely the product of the transition state will be formed.

So in order to examine this, an example of transition state of both styrenes with Shi catalyst are obtained and analyzed.
 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1303.736813'''
| width="100" | '''-1303.727673'''
| width="150" | '''-0.00914'''
| width="150" | '''6.28E-05'''
| width="150" | '''99.99'''

|-
|}

 

From the above, we can see the predicted high enantiopurity of the reaction favoring the (R) product because of the lower energy of the transition states. To understand the reason, we have to turn to non-covalent interaction (NCI) analysis.

[[File:NCI shi fructose styrene.png|700px|center]]

To complement the NCI analysis, a QTAIM (Quantum Theory of Atoms in Molecules) analysis is conducted as well.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''(R)-styrene transition state'''
| width="200" | '''(S)-styrene transition state'''
|- align="center"
| width="100" | '''[[File:QTAIM R.png|400px|center]]'''
| width="100" | '''[[File:QTAIM S.png|400px|center]]'''
|- align="center"
| colspan="2" width="100" | '''Comments'''
|-
| colspan="2" width="100" | '''Unsurprisingly, QTAIM analysis has also shown that (R)-styrene/Shi catalyst has more interactions with one another. While (R)-styrene has 2 strong interactions, (S)-styrene has only one with the catalyst. Besides, the phenyl ring of (R)-styrene also confers additional positive interaction with the catalyst. QTAIM analysis has also show several interactions between the C=C geminal hydrogen of (R)-styrene intreacting with the oxygen atoms on the dioxacyclopentane ring'''
|-
|}

 

===== '''(R,R) and (S,S)-Stilbene transition state''' =====

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R,R)-Stilbene oxide'''
| width="150" | '''(S,S)-Stilbene oxide'''
|- align="center"
| width="150" | ''' Structure of Transition State '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Stilbene RR ts.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>SS stilbene oxide ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| colspan="2" | [[File:Shi fructose stilbene.png|700px|center]]

|-
|}

 

However, unlike styrene, trans-stilbene seems to approach perpendicularly to the dioxirane. This is proposed to be due to the steric interactions (marked in purple). Based on first inspection, it seems that (S,S)-Stilbene oxide has more steric interactions than (R,R)-Stilbene oxide. Although unsubstantial, it seems like my guess was correct. The (R,R)-stilbene/Shi catalyst transition state is lower in energy.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1534.687808'''
| width="100" | '''-1534.683440'''
| width="150" | '''0.004368'''
| width="150" | '''9.08E-3'''
| width="150" | '''98.20'''

|-
|}

 

NCI Analysis is also done for trans-stilbene

[[File:NCI stilbene.png|700px|center]]

==== '''Jacobsen Catalyst''' ====

For this section, cis-beta methyl styrene transition state will be analyzed.

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-3383.259559'''
| width="100" | '''-3383.251060'''
| width="150" | '''-0.008499'''
| width="150" | '''1.24E-04'''
| width="150" | '''99.98'''
|- align="center"
| width="100" | '''-3383.253442'''
| width="100" | '''-3383.250270'''
| width="150" | '''-0.003172'''
| width="150" | '''3.48E-02'''
| width="150" | '''93.27'''
|-
|}

 

As is obvious from here, the (S,R) transition state is more stable than the (R,S) transition state. Both transition states are exo with respect to the catalyst.

It is not immediately apparent just by looking at the molecule to determine which spatial groups have interactions with one another. Therefore, an NCI analysis is conducted again.

[[File:NCI Jacobsen.png|700px|center]]

Rep:Mod:Computationalreport1C

2013-11-21T20:28:45Z

Xc2611: /* Assigning the absolute configuration of the product */

= '''Synthesis and Computational Lab: 1C''' =
== '''Part 1: Introduction to Molecular Mechanics''' ==
=== '''Introduction to MMFF94 and MMFF94s''' ===

With the improvement of computational data and computer processing power, the usage of molecular mechanics/dynamics forcefield has become very integrated in predicting properties of chemical molecules. A molecular mechanics/dynamics forcefield should be able to predict characteristics such as molecular geometries, conformational/stereoisomeric energies, vibrational frequencies etc. to a reasonable accuracy as compared to experimental-derived values.

Building on work from Kollman et al. s’ AMBER forcefield and Allinger et al. s’ MM1, MM2, MM3 and MM4, Merck Research Laboratories have managed to optimized and improved the previous computational algorithms and produced MMFF94 (Merck Molecular Force Field 94). One of the most prominent advantages of MMFF94 over other preceeding work is its enhanced prediction accuracy. The reason lies in the fact that MMFF94’s core parameterization utilizes an unprecedently large amount of computational data obtained from ab initio calculations1.

Subsequently after the development of MMFF94, a new “static” variant of the MMFF was introduced i.e. the MMFF94s. Unlike MMFF94 that was developed for the use of molecular dynamics simulations (which can be expensive), MMFF94s was developed with the purpose of energy minimization studies in mind. Although both systems provide identical results for most systems, they differ for amides and unsaturated amines which contain resonance-delocalized trigonal nitrogen atoms2.

In this computational exercise, MMFF94s is used predominantly as oppose to the alternative Universal Force Field (UFF). Although versatile across the entire periodic table, UFF is derived from simple rules and atomic parameters such as fixed hybridization that increases the likelihood of erroneous structural and energetic predictions3.

=== '''Forms of MMFF94s''' ===

Steric energy of a molecule is the energy arise due to its geometry or conformation. Energy minimization of steric energy process ensures that the molecule is in its lowest energy conformation.

MMFF94s assumes that the total steric energy of a molecule can be found by the sum of a few specific interactions in a molecule.

ES = EBS + EAB + E SB + ET + EOOP + EVdW + EEE

'''where the bonded interactions are:'''

ES = Total Steric energy

EBS = Total Bond Stretching energy

EAB = Total Angle Bending energy

ESB = Total Stretch Bending energy

ET = Total Torsional Energy

EOOP = Total Out-Of-Plane Bending energy, and

'''where the non-bonded interactions are:'''

EVdW = Total Van der Waals Energy

EEE = Total Electrostatic Energy

{| border="1" cellspacing="1" cellpadding="10"
|-
| width="300" align="center" | '''Types of Energies'''
! width="600" align="center" | '''Explanation'''
|-
| colspan="2" style="text-align: center;" | '''Bonded Interactions'''
|-
| width="300" align="center" | '''Total Bond Stretching Energy'''
! width="600" align="left" | The total bond stretching energy is related to the vibration energy of the molecules in comparison to the equilibrium bond length. Whenever a bond deviates from the equilibrium bond length, the energy value increases.

MMFF94s uses a quartic function that has the force constant term (relate to bond strength). The quartic function term is superior to the cubic function term (used in MM2) in the sense that it avoid the “cubic stretch catastrophe” where progressive elongation of molecule bond length leads to negative infinity.
|-
| width="300" align="center" | '''Total Angle Bending Energy'''
! width="600" align="left" | Similar to Total Bond Stretching Energy, the total angle bending energy is also related to the vibration energy of the molecules about the equilibrium bond length. However, unlike EBS that measures the bond strength, EAB is associated with the stiffness of the molecules based on the Hookiean potential. Whenever bond angles deviate from the norm during vibration, this energy term increases as well.
|-
| width="300" align="center" | '''Total Stretch-Bending Energy'''
! width="600" align="left" | This energy term takes into account of the energy due to increase in bond length when bond angle between two atoms changes.
|-
| width="300" align="center" | '''Total Torsional Energy'''
! width="600" align="left" | Total torsional energy is the energy required for intermolecular rotation about the bonds. In molecule mechanics, however, this term is often used as a correction that must be added or subtracted to the total energy of the molecule to fit a quantum mechanical calculation about the dihedral angles of bonds.
|-
| width="300" align="center" | '''Total Out-Of-Plane Bending Energy'''
! width="600" align="left" | This energy term refers to the energy needed to deform the dihedral angle (zero degrees) of a planar group of atoms such as carbonyl or amide functional groups.
|-
| colspan="2" style="text-align: center;" | '''Non-Bonded Interactions'''
|-
| width="300" align="center" | '''Total Van der Waals Energy'''
! width="600" align="left" | The total Van der Waals energy term examines the intramolecular interactions such as repulsion or attraction between non-bonded atoms in the molecule. This term is crucial in determining the preferred conformation of the molecule.

MMFF94s employs the novel “Buffered-14-7”. The name is derived from a buffering constant and the 14th and 7th power dependencies of the repulsive and attractive energy in the equation.
|-
| width="300" align="center" | '''Total Electrostatic Energy'''
! width="600" align="left" | The total electrostatic energy functions take into account of the Coulombic potential and partial charge/dipole/atomic point charges interactions within the molecule.
|-

|}

 

== '''Part 2 : Conformational Analysis Using Molecular Mechanics''' ==
=== '''The Hydrogenation of Cyclopentadiene Dimer''' ===

==== '''Endo and exo adduct from the Dimerization of Cyclopentadiene''' ====
Cyclopentadiene will undergo dimerization by Diels-alder reaction to form either an endo or exo adduct.

[[File:XcwDimerization of CP.png|500px|center]]

==== '''Stereoselectivity of Dimerization of Cyclopentadiene''' ====
Although the exo adduct is thermodynamically more stable than the endo adduct, the endo adduct is form preferentially. Using the QST2 method, the transition state of the Diels Alder dimerization was found. It was discovered that due to the secondary orbital interactions in the endo transition state, the endo dimer is formed preferentially (the kinetic product). Hence, it is proven that the Diels Alder dimerization between two cyclopentadiene are kinetically controlled.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Transition State of Dimerization of Cyclopentadiene'''
| '''Imaginary Stretch Frequency (-881.25) of the Endo Transition State (click to animate)'''
| '''Secondary Orbital Interaction (Red overlapping orbitals)'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<uploadedFileContents>EndotsDCPD2.mol
</uploadedFileContents>
</jmolApplet></jmol>
| [[File:Xcwendotsimaginary.gif|300px|center]]
| [[File:XcwSecondary orbital interaction1.jpg|300px|center]]
|-
|}

 

==== '''Asynchronous Bond Formation of Dimerization of Cyclopentadiene''' ====

The initial study of the molecular orbitals of the transition states seemed a bit peculiar. Instead of getting a LUMO with symmetrical orbitals, the calculations showed a HOMO that is asymetric at the carbons where the new sigma bonds will be formed. Running an IRC further, it soon became clear that the asymmetry of the HOMO leads to an asychronous bond formation before leading to the product.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''IRC plot following the Endo Transition State '''
| '''IRC following the Endo Transition State (click to animate)'''
| '''Asymmetry of orbitals at the carbons where the new sigma bonds will be formed'''
|- align="center"
| [[File:XcwendotscyclopentadieneIRC.png|300px|center]]
| [[File:XcwendotsIRC.gif|300px|center]]
| [[File:XcwAsynchronous mo.jpg|300px|center]]
|-
|}

 

==== '''Comparison of Energies between the Endo and Exo adduct of Dicyclopentadiene''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Adduct of Dicyclopentadiene dimerization'''
| '''Exo Adduct of Dicyclopentadiene dimerization'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=19,atomno=1,atomno=2; color green;measure 19 1;measure 19 2;</script>
<uploadedFileContents>XcwEndodimer3.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>Exodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=7,atomno=17; color green;measure 17 7;</script>
<uploadedFileContents>XcwExodimer1.mol</uploadedFileContents>
</jmolApplet></jmol>
|-
|}

 

Using MMFF94s ab initio calculations, the energies for the exo dimer and the endo dimer are derived.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Exodimer'''
| '''55.374'''
| 3.543
| 30.772
| -2.041
| -2.728
| 0.015
| 12.800
| 13.014
|-
| '''Endodimer'''
| '''58.191'''
| 3.468
| 33.187
| -2.082
| -2.950
| 0.023
| 12.360
| 14.186
|-
|}

 

The MMFF94s steric energy (after minimization) for the exo dimer is lower than that of the endo dimer. This is reflected by the large difference for the EEE between the endo dimer and the exo dimer due to unfavourable steric repulsion between the two “arched down” cyclopentene rings.

==== '''Hydrogenation of Dicyclopentadiene''' ====

Hydrogenation of the endo dicyclopentadiene (DCPD) would lead to two potential products: dihydro product 1 and dihydro product 2.

[[File:XcwFormation of Dihydro products.png|500px|center]]

Using MMFF94s, the energy of the two dihydro products are calculated.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Dihydro Product 1'''
| '''50.123'''
| 3.308
| 30.864
| -1.927
| 0.060
| 0.015(2)
| 13.281
| 5.121
|-
| '''Dihydro Product 2'''
| '''41.257'''
| 2.823
| 24.685
| -1.657
| -0.379
| 0.000(2)
| 10.639
| 5.147
|-
| '''Tetrahydro Product'''
| '''39.042'''
| 2.730
| 25.151
| -1.676
| 1.287
| 0.000
| 11.551
| 0.000
|}

 

From the MMFF94s calculation, it can be seen that dihydro product 2 has a lower steric energy than dihydro product 1. Therefore, dihydro product 2 is the thermodynamic product for the hydrogenation of dicylopentadiene. And indeed, this was what was observed by Skala et al.. He observed that the first hydrogenation occur at the norborene part of the molecule (rate of hydrogenation several times faster than that in the cyclopentene ring)6. The first heat of hydrogenation at the norborene is 138.8 kJ/mol while the second hydrogenation at the cyclopentene right is 109.5 kJ/mol6.

From the above results, it is also obvious that tetrahydro product is much more stable than either dihydro product. And yet, studies have shown that the tetrahydro product will only form after prolonged hydrogenation under high temperature. However, subjecting DCPD to high temperature leads to low yield due to cracking of DCPD.

Since thermodynamically it is predicted to form favourably, the fact that it does not could only mean that the hydrogenation of DCPD to tetrahydrodicyclopentadiene (TH-DCPD) is kinetically controlled. Most possibly, the transition state of the hydrogenation of DCPD is highly unstable hence it is unlikely to form.

=== '''Atropisomerism in an Intermediate related to the Synthesis of Taxol''' ===

Atropisomerism is a type of stereoisomerism that is form as a result of hindered rotation about a single bond.

[[File:XcwAtropisomerism example.png|500px|center]]

In the case of the 6,6’-dinitro-2,2’-diphenic acid, rotation about the bonds joining the two substituted phenyl rings would have to overcome large steric interaction between the bulky substituents. The barrier of rotation is high enough for the two conformers to be isolated individually.

In the synthesis of taxol, one of the key intermediates exhibit atropisomerism.

==== '''Atropisomerism in Taxol Synthesis''' ====

For the key intermediate, rotation about the carbon-carbon bonds would lead to two types of atropisomers, each with either the carbonyl group poining upwards or downwards in relative to the bridge.

[[File:XcwIntermediate 9 and Intermediate 10.png|500px|center]]

Once again by using MMFF94s ab initio calculations, the steric energies for the two intermediates are illustrated as below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 9'''
| '''70.571'''
| 7.743
| 28.356
| -0.062
| 0.004
| 0.949
| 33.293
| 0.288
|-
| '''Intermediate 10'''
| '''60.553'''
| 7.599
| 18.838
| -0.139
| 0.199
| 0.844
| 33.269
| -0.056
|-

|}

 

Analyzing the data above, the largest energy difference between Intermediate 9 and Intermediate 10 stems from the EAB which is related to the strain of the ring. Intermediate 9 has an excess of 9.518 kcal/mol EAB as compared to Intermediate 10. This comes as a surprise as intermediate 9 is predicted to be more stable alkene.

The rationale behind the prediction of the stability of intermediate 9 stems from the fact that the through-space distance of the upward-pointing carbonyl oxygen with the carbon-carbon is further than the through space distance between the downward-pointing carbonyl oxygen with the -CH2-CH2- fragment at the norbornene part in intermediate 10.

==== '''Hyperstable Olefins''' ====

Intermediate 9 and Intermediate 10 does not react readily with other reagents during functionalization. This is due to the hyperstability effect found in hyperstable olefins.

Hyperstable olefins are alkenes that contain less strain in the ring (i.e. negative olefin strain values) compared to the parent hydrocarbon. To study this further, further MMFF94s calculation was done to compare Intermediate 10 with the parent hydrocarbon.

[[File:XcwIntermediate10andPH.png|500px|center]]

The energies that we calculated are tabulated as shown below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 10'''
| '''44.878 '''
| 5.211
| 15.488
| -0.267
| -1.655
| 0.998
| 25.014
| 0.088
|-
| '''Parent Hydrocarbon'''
| '''50.564'''
| 4.692
| 21.979
| 0.109
| -0.958
| 0.247
| 24.495
| 0.000
|-

|}

 

Scrutinizing the results, the largest energy difference between intermediate 10 and the parent hydrocarbon stems from the Total Angle Bending Energy, EAB. Since the Total Angle bending energy is related to the angle strain in the molecules, it is apparent that the parent hydrocarbon has more ring strain as compared to the bridgehead olefin.

== '''Part 3 : Spectroscopic Simulation Using Quantum Mechanics''' ==
=== '''Spectroscopy of an Intermediate Related to the Synthesis of Taxol''' ===

Molecule 17 and 18 are derivatives of intermediate 9 and 10. In this exercise, MMFF94s is used to predict the 1H and 13C NMR of molecule 17 and molecule 18.

[[File:XcwIntermediate17&18.png|500px|center]]

==== '''NMR Spectra of Molecule 17''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 17.mol
</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwHNMRMolecule 17 Chair Overall NMR.png|500px|center]]
| [[File:XcwHNMRMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.1825
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| The first three results were fairly straight forward to be deduced and correlate wit experimental data.

The hydrogen atom that is geminally attached to the carbon of the double bonds is the most deshielded due to the ring current anisotropic effect of the ring current

The second most deshielded hydrogen atom is the hydrogen atom on the methyl group on the bridge. The hydrogen atom is pointing directly to the oxygen atom of the carbonyl functional group.

The peaks with an integration height of 4 is assigned to the hydrogen atoms in the 1,3-dithiolane ring fragment.

Subsequent analysis of the 1H NMR became very complicated very quickly for two reasons:

1. Gaussian calculations showed some atoms with an integration height of 3. Comparing their file atom number and checking their chemical environment, it is not possible to find any correlation between them.

2. Some of the peaks in the literature remains unresolved and are given as multiplets or grouped together.

|- align="center"
| 52
| 3.1775
| 1
| '''2.99'''
|- align="center"
| 53,52,50,51
| 3.0867
| 4
| '''3.40-3.10'''
|- align="center"
| 42,43,39
| 2.7445
| 3
| ''' '''
|- align="center"
| 49
| 2.6187
| 1
| ''' '''
|- align="center"
| 34
| 2.4371
| 1
| ''' '''
|- align="center"
| 35
| 2.3782
| 1
| ''' '''
|- align="center"
| 40,37,26
| 2.2730
| 3
| ''' '''
|- align="center"
| 30
| 2.1566
| 1
| ''' '''
|- align="center"
| 36
| 2.1033
| 1
| ''' '''
|- align="center"
| 32,28
| 2.0259
| 2
| ''' '''
|- align="center"
| 25
| 1.8535
| 2
| ''' '''
|- align="center"
| 38,46,27
| 1.5898
| 3
| '''1.25'''
|- align="center"
| 29
| 1.4557
| 1
| ''' '''
|- align="center"
| 31
| 1.0123
| 1
| ''' '''
|- align="center"
| 44,48,45
| 0.9087
| 3
| '''1.10'''
|- align="center"
| 47
| 0.8354
| 1
| ''' '''
|- align="center"
| 33
| 0.5790
| 1
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 17 Chair Overall NMR2.png|500px|center]]
| [[File:XcwMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 216.2725
| 1
| '''218.79'''
| rowspan="10" style="text-align:center;"| [[File:XcwMolecule 17 image for CNMR.jpg|600px|center]]
|- align="center"
| 13
| 144.8626
| 1
| '''144.63'''
|- align="center"
| 14
| 124.7193
| 1
| '''125.33'''
|- align="center"
| 3
| 91.3340
| 1
| '''72.88'''
|- align="center"
| 2
| 60.9568
| 1
| '''56.19'''
|- align="center"
| 1
| 57.0811
| 1
| '''52.52'''
|- align="center"
| 10
| 52.4663
| 1
| '''48.50'''
|- align="center"
| 16
| 51.4857
| 1
| '''46.80'''
|- align="center"
| 9
| 46.9196
| 1
| '''45.76'''
|- align="center"
| 23
| 43.8647
| 1
| '''39.80'''
|- align="center"
| 22
| 41.9450
| 1
| '''38.81'''
| Comments
|- align="center"
| 4
| 41.8724
| 1
| '''35.85'''
| rowspan="9" style="text-align:left;"| The carbon bonded to the oxygen atom is the most deshielded, as is shown in the predicted values and the experimental values. There is a deviation between the values. Quite possibly, this is due to the fact that in reality, the carbonyl functional group is pointing slightly towards the equatorial position rather than a lateral position relative to the ring (as is in the input for Gaussian calculation)

Most of the 1CNMR values that was predicted by Gaussian are all within an acceptable range of deviation. However, there is carbon 3 that has significant deviation between the predicted value and experimental value.

Carbon 3 is the carbon bonded to the two sulphurs in the 1,3-dithiolane ring fragment. Such a huge deviation would possibly mean that the conformer that was given as input to Gaussian differs from the literature.

The above NMR spectra was corrected with a level of theory B3LYP/6-31G(d,p) using TMS as reference and in chloroform.

|- align="center"
| 15
| 35.4348
| 1
| '''32.66'''
|- align="center"
| 11
| 31.1964
| 1
| '''28.79'''
|- align="center"
| 6
| 28.9432
| 1
| '''28.29'''
|- align="center"
| 7
| 28.3640
| 1
| '''26.88'''
|- align="center"
| 12
| 27.3767
| 1
| '''25.66'''
|- align="center"
| 17
| 26.3311
| 1
| '''23.86'''
|- align="center"
| 15
| 24.5483
| 1
| '''20.96'''
|- align="center"
| 18
| 19.7788
| 1
| '''18.71'''
|-
|}
 

==== '''NMR Spectra of Molecule 18''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 18 Boat for Image2.mol</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"-
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 18 Chair Overall NMR.png|500px|center]]
| [[File:Molecule 18 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.2832
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| ''' '''
|- align="center"
| 50
| 3.3175
| 1
| rowspan="4" style="text-align:centre;"| '''3.00-2.70'''
|- align="center"
| 52
| 3.2153
| 1
|- align="center"
| 51,53
| 3.1161
| 2
|- align="center"
| 34,43
| 2.8606
| 2
|- align="center"
| 38
| 2.4549
| 1
| ''' '''
|- align="center"
| 42
| 2.3968
| 1
| ''' '''
|- align="center"
| 25,29,26
| 2.2796
| 3
| ''' '''
|- align="center"
| 39
| 2.0844
| 1
| ''' '''
|- align="center"
| 40,36
| 1.9699
| 2
| ''' '''
|- align="center"
| 37,24
| 1.8519
| 2
| ''' '''
|- align="center"
| 31,27
| 1.6780
| 2
| ''' '''
|- align="center"
| 28
| 1.6175
| 1
| ''' '''
|- align="center"
| 46,49
| 1.4979
| 2
| ''' '''
|- align="center"
| 35
| 1.4150
| 1
| ''' '''
|- align="center"
| 32
| 1.3531
| 1
| ''' '''
|- align="center"
| 48
| 1.1606
| 1
| ''' '''
|- align="center"
| 33,30,47
| 1.0653
| 3
| '''1.03'''
|- align="center"
| 44,45
| 0.9643
| 2
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwMolecule 18 Boat Overall NMR.png|500px|center]]
| [[File:XcwMolecule 18 Boat zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 211.8325
| 1
| '''211.49'''
| rowspan="10" style="text-align:center;"| [[File:Molecule 18 Boat for 13 CNMR.jpg|600px|center]]
|- align="center"
| 13
| 148.6673
| 1
| '''148.72'''
|- align="center"
| 14
| 118.8373
| 1
| '''120.90'''
|- align="center"
| 3
| 89.0869
| 1
| '''74.61'''
|- align="center"
| 2
| 67.8886
| 1
| '''60.53'''
|- align="center"
| 1
| 56.1133
| 1
| '''51.30'''
|- align="center"
| 10
| 55.5998
| 1
| '''50.94'''
|- align="center"
| 16
| 50.1124
| 1
| '''45.53'''
|- align="center"
| 22
| 48.2030
| 1
| '''43.28'''
|- align="center"
| 23
| 44.2222
| 1
| '''40.82'''
|- align="center"
| 4
| 42.0354
| 1
| '''38.73'''
| Comments
|- align="center"
| 9
| 37.5865
| 1
| '''36.78'''
| rowspan="9" style="text-align:left;"| ''' '''
|- align="center"
| 6
| 35.3106
| 1
| '''35.47'''
|- align="center"
| 15
| 31.0459
| 1
| '''30.84'''
|- align="center"
| 7
| 28.8476
| 1
| '''30.00'''
|- align="center"
| 12
| 28.6623
| 1
| '''25.56'''
|- align="center"
| 17
| 25.7393
| 1
| '''25.35'''
|- align="center"
| 11
| 25.2603
| 1
| '''22.21'''
|- align="center"
| 18
| 23.3944
| 1
| '''21.39'''
|- align="center"
| 5
| 21.0478
| 1
| '''19.83'''
|-
|}
 

== '''Part 4 : Analysis of the Properties of the Synthesized Alkene Epoxides''' ==
=== '''The two catalytics systems''' ===

Assymmetric epoxidation of prochiral alkenes may lead to product with different stereochemical outcome as illustrated as below. To solve this problem, different types of asymmetric epoxidation catalyst have been synthesized. In this study, we shall be focusing on Shi asymmetric fructose catalyst as well as Jacobsen asymmetric catalyst.

[[File:Asymmetric catalyst.png|400px|center]]

==== ''' The Shi Asymmetric Fructose Catalyst''' ====

Molecule 21 is the stable precursor of molecule 22, the active catalyst. Molecule 21 can be converted to molecule 22 by using either persulfuric acid or potassium peroxymonosulphate.

[[File:Molecule 21 to 23.png|400px|center]]

The transition state of the Shi epoxidation was a subject of debate for a few moments. However, recent studies have led to the conclusion that the spiro transition state is more favored than the planar transition state. The spiro transition state is the transition that has its dioxirane perpendicularly bisecting the alkene double bond. This is thought to be more favourable due to interactions between the lone pairs of the oxygen with the LUMO of the alkene.

[[File:Spiro and planar ts.png|500px|center]]

==== ''' The Jacobsen Asymmetric Catalyst''' ====

Molecule 23 is the stable precursor of molecule 24, the active catalyst. Molecule 23 can be converted to molecule 24 by using sodium perchlorate.

[[File:Salen, 23 and 24.png|400px|center]]

Jacobsen catalyst is biphasic. The first phase involves the transfer of oxygen to molecule 23. Sodium perchlorate oxidizes Mn(III) to Mn(V).

In the second step, Jacobsen catalyst acts via a radical mechanism. It is thought to be so because epoxidation of trans-alkene by Jacobsen catalyst yield cis-alkene as well. A radical mechanism will lead to the lost of stereochemical information of the molecule.

=== ''' Crystal structure of the two catalyst''' ===
==== '''Molecule 21''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 21'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 21 strucutre.png|600px|center]]'''
|-
| style="text-align:center;" width="150" | ''' Bond '''
| style="text-align:center;" width="150"| ''' Bond Lenghts (Angstrom)'''
| style="text-align:center;" | ''' Evaluation'''
|-
| style="text-align:center;"| ''' O1-C1 '''
| style="text-align:center;"| ''' 1.400'''
| rowspan="10" style="text-align:left;"| [[File:Molecule 21 2.png|300px|center]]

The normal bond length of an C-O bond is 1.430 angstrom.

The most interesting aspect here is O4 and O2. The lone pair of O4 is antiperplanar to the sigma* orbital of the carbonyl group while the lone pair of O2 is anti periplanar to the carbonyl pi* orbital. Donation of electron can occur because of the correct symmetry. Due to the mixing of the orbitals, the C2-O2 and C4-O4 has been conferred with a certain degree of double bond character.

However, due to the lone pair on oxygen being now donated to the carbonyl antibonding orbitals, the O2 and O4 is slightly “electron deficient” and electron density will be pulled away from O2 and O4. That would explain why the bond length increase for O2-C7 and O4-C10. Increase in bond length is an indicator of the weakening of the bond.
|-
| style="text-align:center;"|'''O1-C7'''
| style="text-align:center;"|'''1.413'''
|-
| style="text-align:center;"|'''O2-C7'''
| style="text-align:center;"|'''1.441'''
|-
| style="text-align:center;"|'''O2-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O4-C4'''
| style="text-align:center;"|'''1.396'''
|-
| style="text-align:center;"|'''O4-C10'''
| style="text-align:center;"|'''1.439'''
|-
| style="text-align:center;"|'''O5-C10'''
| style="text-align:center;"|'''1.409'''
|-
| style="text-align:center;"|'''O5-C5'''
| style="text-align:center;"|'''1.416'''
|-
| style="text-align:center;"|'''O6-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O6-C6'''
| style="text-align:center;"|'''1.420'''
|-
|}
 

==== '''Molecule 23''' ====

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 23'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 23 struc.png|600px|center]]'''
|-
| The most outstanding feature from this molecule is the fact that is adopt a puckered form of the square base pyramidal form. This is no surprise that the molecule is almost planar due to the electron delocalization around each side of the salen ligand.

The tery-butyl hydrogen are oriented closely to one another. Non-covalent interaction studies indicated that repulsion would occur for H---H bond length that are less than 2.1 angstrom while favourable interaction may be dominant with bond length above 2.4 angstrom. It was discovered that all 4 hydrogens have bond length more than 2.4 angstrom hence there should not be any significant repulsion between them. Instead, certain amount of attractive force will ensue and that contributes to the overall stability of the molecule

|-
|}
 

=== ''' The calculated NMR properties of the product''' ===

=== ''' Assigning the absolute configuration of the product''' ===

Normal 0 false false false EN-US JA X-NONE The two products that have been chosen are styrene and trans-stilbene

=== ''' Analysis of the Transition State for Reactions''' ===
==== '''Predicting Enantiomeric Excess based on Transition State energies''' ====

One of the energy output from Gaussian calculation is the “sum of electronic and thermal free energies”. This is Gibbs Free Energy at 298.15K and 1 atm.

Using this term and invoking a variant of the Curtin-Hammett Principle, it is possible to calculate a predicted enantiomeric excess of one enantiomer over the other.

[[File:Ee and transition state energy.png|800px|center]]

Using the derivations from above and equation (4), we analyze the enantiomeric excess of beta-methyl styrene and the results are tabulated as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1343.022970'''
| width="100" | '''-1343.017942'''
| width="150" | '''-0.005028'''
| width="150" | '''4.88E-03'''
| width="150" | '''99.03'''
|- align="center"
| width="100" | '''-1343.019233'''
| width="100" | '''-1343.015603'''
| width="150" | '''-0.003630'''
| width="150" | '''2.14E-02'''
| width="150" | '''95.80'''
|- align="center"
| width="100" | '''-1343.029272'''
| width="100" | '''-1343.023766'''
| width="150" | '''-0.005506'''
| width="150" | '''2.94E-03'''
| width="150" | '''99.41'''
|- align="center"
| width="100" | '''-1343.032443'''
| width="100" | '''-1343.024742'''
| width="150" | '''-0.007701'''
| width="150" | '''2.88E-04'''
| width="150" | '''99.94'''
|-
|}

 

The above hartree units are converted to J/mol for calculation of K where 1 hartress = 4.3597E-18

Studying all the free energies of the (R,R) series and compare them with the (S,S) series, it comes as no surprise that (R,R) product is favoured over (S,S) product as (R,R) is more stable. Indeed, this corresponds with the literature value reporting 92% ee of (R,R) products over that of (S,S).

==== '''Analysis of the Transition State of Epoxidation''' ====
==== '''Shi Fructose Catalyst''' ====
For this section, I will be analyzing the the transition state of 1) styrene and 2) trans-stilbene with the Shi fructose catalyst.

===== '''(R) and (S)-styrene transition state''' =====
The transition state for the formation of (R)-styrene oxide and (S)-styrene oxide are given as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R)-styrene oxide'''
| width="150" | '''(S)-styrene oxide'''
|- align="center"
| width="150" | ''' Structure of Catalyst '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide R.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide S ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| [[File:Steric shi fructose R.png|450px|center]]
| [[File:Steric shi fructose S.png|450px|center]]
|-
|}

 

In the transition state for (R)-styrene, it was discovered that the Re face is reacting with the oxygen of the dioxirane. The phenyl ring is oriented endo with respect to the fructose catalyst. However, the (S)-styrene is reacting at the Si face and the phenyl ring is oriented exo relative to the catalyst.

The approach taken by (R)-styrene and (S)-styrene are restricted to only one due to steric interactions. Therefore, the epoxidation of both styrenes by the Shi catalyst will be stereospecific and retains all the stereochemical information of the reactant. However, whether or not (R)-styrene oxide or (S)-styrene oxide is form is dependent on the relative energies of the transition state. The more stable the transition state, the more likely the product of the transition state will be formed.

So in order to examine this, an example of transition state of both styrenes with Shi catalyst are obtained and analyzed.
 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1303.736813'''
| width="100" | '''-1303.727673'''
| width="150" | '''-0.00914'''
| width="150" | '''6.28E-05'''
| width="150" | '''99.99'''

|-
|}

 

From the above, we can see the predicted high enantiopurity of the reaction favoring the (R) product because of the lower energy of the transition states. To understand the reason, we have to turn to non-covalent interaction (NCI) analysis.

[[File:NCI shi fructose styrene.png|700px|center]]

To complement the NCI analysis, a QTAIM (Quantum Theory of Atoms in Molecules) analysis is conducted as well.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''(R)-styrene transition state'''
| width="200" | '''(S)-styrene transition state'''
|- align="center"
| width="100" | '''[[File:QTAIM R.png|400px|center]]'''
| width="100" | '''[[File:QTAIM S.png|400px|center]]'''
|- align="center"
| colspan="2" width="100" | '''Comments'''
|-
| colspan="2" width="100" | '''Unsurprisingly, QTAIM analysis has also shown that (R)-styrene/Shi catalyst has more interactions with one another. While (R)-styrene has 2 strong interactions, (S)-styrene has only one with the catalyst. Besides, the phenyl ring of (R)-styrene also confers additional positive interaction with the catalyst. QTAIM analysis has also show several interactions between the C=C geminal hydrogen of (R)-styrene intreacting with the oxygen atoms on the dioxacyclopentane ring'''
|-
|}

 

===== '''(R,R) and (S,S)-Stilbene transition state''' =====

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R,R)-Stilbene oxide'''
| width="150" | '''(S,S)-Stilbene oxide'''
|- align="center"
| width="150" | ''' Structure of Transition State '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Stilbene RR ts.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>SS stilbene oxide ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| colspan="2" | [[File:Shi fructose stilbene.png|700px|center]]

|-
|}

 

However, unlike styrene, trans-stilbene seems to approach perpendicularly to the dioxirane. This is proposed to be due to the steric interactions (marked in purple). Based on first inspection, it seems that (S,S)-Stilbene oxide has more steric interactions than (R,R)-Stilbene oxide. Although unsubstantial, it seems like my guess was correct. The (R,R)-stilbene/Shi catalyst transition state is lower in energy.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1534.687808'''
| width="100" | '''-1534.683440'''
| width="150" | '''0.004368'''
| width="150" | '''9.08E-3'''
| width="150" | '''98.20'''

|-
|}

 

NCI Analysis is also done for trans-stilbene

[[File:NCI stilbene.png|700px|center]]

==== '''Jacobsen Catalyst''' ====

For this section, cis-beta methyl styrene transition state will be analyzed.

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-3383.259559'''
| width="100" | '''-3383.251060'''
| width="150" | '''-0.008499'''
| width="150" | '''1.24E-04'''
| width="150" | '''99.98'''
|- align="center"
| width="100" | '''-3383.253442'''
| width="100" | '''-3383.250270'''
| width="150" | '''-0.003172'''
| width="150" | '''3.48E-02'''
| width="150" | '''93.27'''
|-
|}

 

As is obvious from here, the (S,R) transition state is more stable than the (R,S) transition state. Both transition states are exo with respect to the catalyst.

It is not immediately apparent just by looking at the molecule to determine which spatial groups have interactions with one another. Therefore, an NCI analysis is conducted again.

[[File:NCI Jacobsen.png|700px|center]]

Rep:Mod:Computationalreport1C

2013-11-21T19:34:21Z

Xc2611: /* Molecule 23 */

= '''Synthesis and Computational Lab: 1C''' =
== '''Part 1: Introduction to Molecular Mechanics''' ==
=== '''Introduction to MMFF94 and MMFF94s''' ===

With the improvement of computational data and computer processing power, the usage of molecular mechanics/dynamics forcefield has become very integrated in predicting properties of chemical molecules. A molecular mechanics/dynamics forcefield should be able to predict characteristics such as molecular geometries, conformational/stereoisomeric energies, vibrational frequencies etc. to a reasonable accuracy as compared to experimental-derived values.

Building on work from Kollman et al. s’ AMBER forcefield and Allinger et al. s’ MM1, MM2, MM3 and MM4, Merck Research Laboratories have managed to optimized and improved the previous computational algorithms and produced MMFF94 (Merck Molecular Force Field 94). One of the most prominent advantages of MMFF94 over other preceeding work is its enhanced prediction accuracy. The reason lies in the fact that MMFF94’s core parameterization utilizes an unprecedently large amount of computational data obtained from ab initio calculations1.

Subsequently after the development of MMFF94, a new “static” variant of the MMFF was introduced i.e. the MMFF94s. Unlike MMFF94 that was developed for the use of molecular dynamics simulations (which can be expensive), MMFF94s was developed with the purpose of energy minimization studies in mind. Although both systems provide identical results for most systems, they differ for amides and unsaturated amines which contain resonance-delocalized trigonal nitrogen atoms2.

In this computational exercise, MMFF94s is used predominantly as oppose to the alternative Universal Force Field (UFF). Although versatile across the entire periodic table, UFF is derived from simple rules and atomic parameters such as fixed hybridization that increases the likelihood of erroneous structural and energetic predictions3.

=== '''Forms of MMFF94s''' ===

Steric energy of a molecule is the energy arise due to its geometry or conformation. Energy minimization of steric energy process ensures that the molecule is in its lowest energy conformation.

MMFF94s assumes that the total steric energy of a molecule can be found by the sum of a few specific interactions in a molecule.

ES = EBS + EAB + E SB + ET + EOOP + EVdW + EEE

'''where the bonded interactions are:'''

ES = Total Steric energy

EBS = Total Bond Stretching energy

EAB = Total Angle Bending energy

ESB = Total Stretch Bending energy

ET = Total Torsional Energy

EOOP = Total Out-Of-Plane Bending energy, and

'''where the non-bonded interactions are:'''

EVdW = Total Van der Waals Energy

EEE = Total Electrostatic Energy

{| border="1" cellspacing="1" cellpadding="10"
|-
| width="300" align="center" | '''Types of Energies'''
! width="600" align="center" | '''Explanation'''
|-
| colspan="2" style="text-align: center;" | '''Bonded Interactions'''
|-
| width="300" align="center" | '''Total Bond Stretching Energy'''
! width="600" align="left" | The total bond stretching energy is related to the vibration energy of the molecules in comparison to the equilibrium bond length. Whenever a bond deviates from the equilibrium bond length, the energy value increases.

MMFF94s uses a quartic function that has the force constant term (relate to bond strength). The quartic function term is superior to the cubic function term (used in MM2) in the sense that it avoid the “cubic stretch catastrophe” where progressive elongation of molecule bond length leads to negative infinity.
|-
| width="300" align="center" | '''Total Angle Bending Energy'''
! width="600" align="left" | Similar to Total Bond Stretching Energy, the total angle bending energy is also related to the vibration energy of the molecules about the equilibrium bond length. However, unlike EBS that measures the bond strength, EAB is associated with the stiffness of the molecules based on the Hookiean potential. Whenever bond angles deviate from the norm during vibration, this energy term increases as well.
|-
| width="300" align="center" | '''Total Stretch-Bending Energy'''
! width="600" align="left" | This energy term takes into account of the energy due to increase in bond length when bond angle between two atoms changes.
|-
| width="300" align="center" | '''Total Torsional Energy'''
! width="600" align="left" | Total torsional energy is the energy required for intermolecular rotation about the bonds. In molecule mechanics, however, this term is often used as a correction that must be added or subtracted to the total energy of the molecule to fit a quantum mechanical calculation about the dihedral angles of bonds.
|-
| width="300" align="center" | '''Total Out-Of-Plane Bending Energy'''
! width="600" align="left" | This energy term refers to the energy needed to deform the dihedral angle (zero degrees) of a planar group of atoms such as carbonyl or amide functional groups.
|-
| colspan="2" style="text-align: center;" | '''Non-Bonded Interactions'''
|-
| width="300" align="center" | '''Total Van der Waals Energy'''
! width="600" align="left" | The total Van der Waals energy term examines the intramolecular interactions such as repulsion or attraction between non-bonded atoms in the molecule. This term is crucial in determining the preferred conformation of the molecule.

MMFF94s employs the novel “Buffered-14-7”. The name is derived from a buffering constant and the 14th and 7th power dependencies of the repulsive and attractive energy in the equation.
|-
| width="300" align="center" | '''Total Electrostatic Energy'''
! width="600" align="left" | The total electrostatic energy functions take into account of the Coulombic potential and partial charge/dipole/atomic point charges interactions within the molecule.
|-

|}

 

== '''Part 2 : Conformational Analysis Using Molecular Mechanics''' ==
=== '''The Hydrogenation of Cyclopentadiene Dimer''' ===

==== '''Endo and exo adduct from the Dimerization of Cyclopentadiene''' ====
Cyclopentadiene will undergo dimerization by Diels-alder reaction to form either an endo or exo adduct.

[[File:XcwDimerization of CP.png|500px|center]]

==== '''Stereoselectivity of Dimerization of Cyclopentadiene''' ====
Although the exo adduct is thermodynamically more stable than the endo adduct, the endo adduct is form preferentially. Using the QST2 method, the transition state of the Diels Alder dimerization was found. It was discovered that due to the secondary orbital interactions in the endo transition state, the endo dimer is formed preferentially (the kinetic product). Hence, it is proven that the Diels Alder dimerization between two cyclopentadiene are kinetically controlled.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Transition State of Dimerization of Cyclopentadiene'''
| '''Imaginary Stretch Frequency (-881.25) of the Endo Transition State (click to animate)'''
| '''Secondary Orbital Interaction (Red overlapping orbitals)'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<uploadedFileContents>EndotsDCPD2.mol
</uploadedFileContents>
</jmolApplet></jmol>
| [[File:Xcwendotsimaginary.gif|300px|center]]
| [[File:XcwSecondary orbital interaction1.jpg|300px|center]]
|-
|}

 

==== '''Asynchronous Bond Formation of Dimerization of Cyclopentadiene''' ====

The initial study of the molecular orbitals of the transition states seemed a bit peculiar. Instead of getting a LUMO with symmetrical orbitals, the calculations showed a HOMO that is asymetric at the carbons where the new sigma bonds will be formed. Running an IRC further, it soon became clear that the asymmetry of the HOMO leads to an asychronous bond formation before leading to the product.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''IRC plot following the Endo Transition State '''
| '''IRC following the Endo Transition State (click to animate)'''
| '''Asymmetry of orbitals at the carbons where the new sigma bonds will be formed'''
|- align="center"
| [[File:XcwendotscyclopentadieneIRC.png|300px|center]]
| [[File:XcwendotsIRC.gif|300px|center]]
| [[File:XcwAsynchronous mo.jpg|300px|center]]
|-
|}

 

==== '''Comparison of Energies between the Endo and Exo adduct of Dicyclopentadiene''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Adduct of Dicyclopentadiene dimerization'''
| '''Exo Adduct of Dicyclopentadiene dimerization'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=19,atomno=1,atomno=2; color green;measure 19 1;measure 19 2;</script>
<uploadedFileContents>XcwEndodimer3.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>Exodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=7,atomno=17; color green;measure 17 7;</script>
<uploadedFileContents>XcwExodimer1.mol</uploadedFileContents>
</jmolApplet></jmol>
|-
|}

 

Using MMFF94s ab initio calculations, the energies for the exo dimer and the endo dimer are derived.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Exodimer'''
| '''55.374'''
| 3.543
| 30.772
| -2.041
| -2.728
| 0.015
| 12.800
| 13.014
|-
| '''Endodimer'''
| '''58.191'''
| 3.468
| 33.187
| -2.082
| -2.950
| 0.023
| 12.360
| 14.186
|-
|}

 

The MMFF94s steric energy (after minimization) for the exo dimer is lower than that of the endo dimer. This is reflected by the large difference for the EEE between the endo dimer and the exo dimer due to unfavourable steric repulsion between the two “arched down” cyclopentene rings.

==== '''Hydrogenation of Dicyclopentadiene''' ====

Hydrogenation of the endo dicyclopentadiene (DCPD) would lead to two potential products: dihydro product 1 and dihydro product 2.

[[File:XcwFormation of Dihydro products.png|500px|center]]

Using MMFF94s, the energy of the two dihydro products are calculated.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Dihydro Product 1'''
| '''50.123'''
| 3.308
| 30.864
| -1.927
| 0.060
| 0.015(2)
| 13.281
| 5.121
|-
| '''Dihydro Product 2'''
| '''41.257'''
| 2.823
| 24.685
| -1.657
| -0.379
| 0.000(2)
| 10.639
| 5.147
|-
| '''Tetrahydro Product'''
| '''39.042'''
| 2.730
| 25.151
| -1.676
| 1.287
| 0.000
| 11.551
| 0.000
|}

 

From the MMFF94s calculation, it can be seen that dihydro product 2 has a lower steric energy than dihydro product 1. Therefore, dihydro product 2 is the thermodynamic product for the hydrogenation of dicylopentadiene. And indeed, this was what was observed by Skala et al.. He observed that the first hydrogenation occur at the norborene part of the molecule (rate of hydrogenation several times faster than that in the cyclopentene ring)6. The first heat of hydrogenation at the norborene is 138.8 kJ/mol while the second hydrogenation at the cyclopentene right is 109.5 kJ/mol6.

From the above results, it is also obvious that tetrahydro product is much more stable than either dihydro product. And yet, studies have shown that the tetrahydro product will only form after prolonged hydrogenation under high temperature. However, subjecting DCPD to high temperature leads to low yield due to cracking of DCPD.

Since thermodynamically it is predicted to form favourably, the fact that it does not could only mean that the hydrogenation of DCPD to tetrahydrodicyclopentadiene (TH-DCPD) is kinetically controlled. Most possibly, the transition state of the hydrogenation of DCPD is highly unstable hence it is unlikely to form.

=== '''Atropisomerism in an Intermediate related to the Synthesis of Taxol''' ===

Atropisomerism is a type of stereoisomerism that is form as a result of hindered rotation about a single bond.

[[File:XcwAtropisomerism example.png|500px|center]]

In the case of the 6,6’-dinitro-2,2’-diphenic acid, rotation about the bonds joining the two substituted phenyl rings would have to overcome large steric interaction between the bulky substituents. The barrier of rotation is high enough for the two conformers to be isolated individually.

In the synthesis of taxol, one of the key intermediates exhibit atropisomerism.

==== '''Atropisomerism in Taxol Synthesis''' ====

For the key intermediate, rotation about the carbon-carbon bonds would lead to two types of atropisomers, each with either the carbonyl group poining upwards or downwards in relative to the bridge.

[[File:XcwIntermediate 9 and Intermediate 10.png|500px|center]]

Once again by using MMFF94s ab initio calculations, the steric energies for the two intermediates are illustrated as below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 9'''
| '''70.571'''
| 7.743
| 28.356
| -0.062
| 0.004
| 0.949
| 33.293
| 0.288
|-
| '''Intermediate 10'''
| '''60.553'''
| 7.599
| 18.838
| -0.139
| 0.199
| 0.844
| 33.269
| -0.056
|-

|}

 

Analyzing the data above, the largest energy difference between Intermediate 9 and Intermediate 10 stems from the EAB which is related to the strain of the ring. Intermediate 9 has an excess of 9.518 kcal/mol EAB as compared to Intermediate 10. This comes as a surprise as intermediate 9 is predicted to be more stable alkene.

The rationale behind the prediction of the stability of intermediate 9 stems from the fact that the through-space distance of the upward-pointing carbonyl oxygen with the carbon-carbon is further than the through space distance between the downward-pointing carbonyl oxygen with the -CH2-CH2- fragment at the norbornene part in intermediate 10.

==== '''Hyperstable Olefins''' ====

Intermediate 9 and Intermediate 10 does not react readily with other reagents during functionalization. This is due to the hyperstability effect found in hyperstable olefins.

Hyperstable olefins are alkenes that contain less strain in the ring (i.e. negative olefin strain values) compared to the parent hydrocarbon. To study this further, further MMFF94s calculation was done to compare Intermediate 10 with the parent hydrocarbon.

[[File:XcwIntermediate10andPH.png|500px|center]]

The energies that we calculated are tabulated as shown below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 10'''
| '''44.878 '''
| 5.211
| 15.488
| -0.267
| -1.655
| 0.998
| 25.014
| 0.088
|-
| '''Parent Hydrocarbon'''
| '''50.564'''
| 4.692
| 21.979
| 0.109
| -0.958
| 0.247
| 24.495
| 0.000
|-

|}

 

Scrutinizing the results, the largest energy difference between intermediate 10 and the parent hydrocarbon stems from the Total Angle Bending Energy, EAB. Since the Total Angle bending energy is related to the angle strain in the molecules, it is apparent that the parent hydrocarbon has more ring strain as compared to the bridgehead olefin.

== '''Part 3 : Spectroscopic Simulation Using Quantum Mechanics''' ==
=== '''Spectroscopy of an Intermediate Related to the Synthesis of Taxol''' ===

Molecule 17 and 18 are derivatives of intermediate 9 and 10. In this exercise, MMFF94s is used to predict the 1H and 13C NMR of molecule 17 and molecule 18.

[[File:XcwIntermediate17&18.png|500px|center]]

==== '''NMR Spectra of Molecule 17''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 17.mol
</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwHNMRMolecule 17 Chair Overall NMR.png|500px|center]]
| [[File:XcwHNMRMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.1825
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| The first three results were fairly straight forward to be deduced and correlate wit experimental data.

The hydrogen atom that is geminally attached to the carbon of the double bonds is the most deshielded due to the ring current anisotropic effect of the ring current

The second most deshielded hydrogen atom is the hydrogen atom on the methyl group on the bridge. The hydrogen atom is pointing directly to the oxygen atom of the carbonyl functional group.

The peaks with an integration height of 4 is assigned to the hydrogen atoms in the 1,3-dithiolane ring fragment.

Subsequent analysis of the 1H NMR became very complicated very quickly for two reasons:

1. Gaussian calculations showed some atoms with an integration height of 3. Comparing their file atom number and checking their chemical environment, it is not possible to find any correlation between them.

2. Some of the peaks in the literature remains unresolved and are given as multiplets or grouped together.

|- align="center"
| 52
| 3.1775
| 1
| '''2.99'''
|- align="center"
| 53,52,50,51
| 3.0867
| 4
| '''3.40-3.10'''
|- align="center"
| 42,43,39
| 2.7445
| 3
| ''' '''
|- align="center"
| 49
| 2.6187
| 1
| ''' '''
|- align="center"
| 34
| 2.4371
| 1
| ''' '''
|- align="center"
| 35
| 2.3782
| 1
| ''' '''
|- align="center"
| 40,37,26
| 2.2730
| 3
| ''' '''
|- align="center"
| 30
| 2.1566
| 1
| ''' '''
|- align="center"
| 36
| 2.1033
| 1
| ''' '''
|- align="center"
| 32,28
| 2.0259
| 2
| ''' '''
|- align="center"
| 25
| 1.8535
| 2
| ''' '''
|- align="center"
| 38,46,27
| 1.5898
| 3
| '''1.25'''
|- align="center"
| 29
| 1.4557
| 1
| ''' '''
|- align="center"
| 31
| 1.0123
| 1
| ''' '''
|- align="center"
| 44,48,45
| 0.9087
| 3
| '''1.10'''
|- align="center"
| 47
| 0.8354
| 1
| ''' '''
|- align="center"
| 33
| 0.5790
| 1
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 17 Chair Overall NMR2.png|500px|center]]
| [[File:XcwMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 216.2725
| 1
| '''218.79'''
| rowspan="10" style="text-align:center;"| [[File:XcwMolecule 17 image for CNMR.jpg|600px|center]]
|- align="center"
| 13
| 144.8626
| 1
| '''144.63'''
|- align="center"
| 14
| 124.7193
| 1
| '''125.33'''
|- align="center"
| 3
| 91.3340
| 1
| '''72.88'''
|- align="center"
| 2
| 60.9568
| 1
| '''56.19'''
|- align="center"
| 1
| 57.0811
| 1
| '''52.52'''
|- align="center"
| 10
| 52.4663
| 1
| '''48.50'''
|- align="center"
| 16
| 51.4857
| 1
| '''46.80'''
|- align="center"
| 9
| 46.9196
| 1
| '''45.76'''
|- align="center"
| 23
| 43.8647
| 1
| '''39.80'''
|- align="center"
| 22
| 41.9450
| 1
| '''38.81'''
| Comments
|- align="center"
| 4
| 41.8724
| 1
| '''35.85'''
| rowspan="9" style="text-align:left;"| The carbon bonded to the oxygen atom is the most deshielded, as is shown in the predicted values and the experimental values. There is a deviation between the values. Quite possibly, this is due to the fact that in reality, the carbonyl functional group is pointing slightly towards the equatorial position rather than a lateral position relative to the ring (as is in the input for Gaussian calculation)

Most of the 1CNMR values that was predicted by Gaussian are all within an acceptable range of deviation. However, there is carbon 3 that has significant deviation between the predicted value and experimental value.

Carbon 3 is the carbon bonded to the two sulphurs in the 1,3-dithiolane ring fragment. Such a huge deviation would possibly mean that the conformer that was given as input to Gaussian differs from the literature.

The above NMR spectra was corrected with a level of theory B3LYP/6-31G(d,p) using TMS as reference and in chloroform.

|- align="center"
| 15
| 35.4348
| 1
| '''32.66'''
|- align="center"
| 11
| 31.1964
| 1
| '''28.79'''
|- align="center"
| 6
| 28.9432
| 1
| '''28.29'''
|- align="center"
| 7
| 28.3640
| 1
| '''26.88'''
|- align="center"
| 12
| 27.3767
| 1
| '''25.66'''
|- align="center"
| 17
| 26.3311
| 1
| '''23.86'''
|- align="center"
| 15
| 24.5483
| 1
| '''20.96'''
|- align="center"
| 18
| 19.7788
| 1
| '''18.71'''
|-
|}
 

==== '''NMR Spectra of Molecule 18''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 18 Boat for Image2.mol</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"-
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 18 Chair Overall NMR.png|500px|center]]
| [[File:Molecule 18 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.2832
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| ''' '''
|- align="center"
| 50
| 3.3175
| 1
| rowspan="4" style="text-align:centre;"| '''3.00-2.70'''
|- align="center"
| 52
| 3.2153
| 1
|- align="center"
| 51,53
| 3.1161
| 2
|- align="center"
| 34,43
| 2.8606
| 2
|- align="center"
| 38
| 2.4549
| 1
| ''' '''
|- align="center"
| 42
| 2.3968
| 1
| ''' '''
|- align="center"
| 25,29,26
| 2.2796
| 3
| ''' '''
|- align="center"
| 39
| 2.0844
| 1
| ''' '''
|- align="center"
| 40,36
| 1.9699
| 2
| ''' '''
|- align="center"
| 37,24
| 1.8519
| 2
| ''' '''
|- align="center"
| 31,27
| 1.6780
| 2
| ''' '''
|- align="center"
| 28
| 1.6175
| 1
| ''' '''
|- align="center"
| 46,49
| 1.4979
| 2
| ''' '''
|- align="center"
| 35
| 1.4150
| 1
| ''' '''
|- align="center"
| 32
| 1.3531
| 1
| ''' '''
|- align="center"
| 48
| 1.1606
| 1
| ''' '''
|- align="center"
| 33,30,47
| 1.0653
| 3
| '''1.03'''
|- align="center"
| 44,45
| 0.9643
| 2
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwMolecule 18 Boat Overall NMR.png|500px|center]]
| [[File:XcwMolecule 18 Boat zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 211.8325
| 1
| '''211.49'''
| rowspan="10" style="text-align:center;"| [[File:Molecule 18 Boat for 13 CNMR.jpg|600px|center]]
|- align="center"
| 13
| 148.6673
| 1
| '''148.72'''
|- align="center"
| 14
| 118.8373
| 1
| '''120.90'''
|- align="center"
| 3
| 89.0869
| 1
| '''74.61'''
|- align="center"
| 2
| 67.8886
| 1
| '''60.53'''
|- align="center"
| 1
| 56.1133
| 1
| '''51.30'''
|- align="center"
| 10
| 55.5998
| 1
| '''50.94'''
|- align="center"
| 16
| 50.1124
| 1
| '''45.53'''
|- align="center"
| 22
| 48.2030
| 1
| '''43.28'''
|- align="center"
| 23
| 44.2222
| 1
| '''40.82'''
|- align="center"
| 4
| 42.0354
| 1
| '''38.73'''
| Comments
|- align="center"
| 9
| 37.5865
| 1
| '''36.78'''
| rowspan="9" style="text-align:left;"| ''' '''
|- align="center"
| 6
| 35.3106
| 1
| '''35.47'''
|- align="center"
| 15
| 31.0459
| 1
| '''30.84'''
|- align="center"
| 7
| 28.8476
| 1
| '''30.00'''
|- align="center"
| 12
| 28.6623
| 1
| '''25.56'''
|- align="center"
| 17
| 25.7393
| 1
| '''25.35'''
|- align="center"
| 11
| 25.2603
| 1
| '''22.21'''
|- align="center"
| 18
| 23.3944
| 1
| '''21.39'''
|- align="center"
| 5
| 21.0478
| 1
| '''19.83'''
|-
|}
 

== '''Part 4 : Analysis of the Properties of the Synthesized Alkene Epoxides''' ==
=== '''The two catalytics systems''' ===

Assymmetric epoxidation of prochiral alkenes may lead to product with different stereochemical outcome as illustrated as below. To solve this problem, different types of asymmetric epoxidation catalyst have been synthesized. In this study, we shall be focusing on Shi asymmetric fructose catalyst as well as Jacobsen asymmetric catalyst.

[[File:Asymmetric catalyst.png|400px|center]]

==== ''' The Shi Asymmetric Fructose Catalyst''' ====

Molecule 21 is the stable precursor of molecule 22, the active catalyst. Molecule 21 can be converted to molecule 22 by using either persulfuric acid or potassium peroxymonosulphate.

[[File:Molecule 21 to 23.png|400px|center]]

The transition state of the Shi epoxidation was a subject of debate for a few moments. However, recent studies have led to the conclusion that the spiro transition state is more favored than the planar transition state. The spiro transition state is the transition that has its dioxirane perpendicularly bisecting the alkene double bond. This is thought to be more favourable due to interactions between the lone pairs of the oxygen with the LUMO of the alkene.

[[File:Spiro and planar ts.png|500px|center]]

==== ''' The Jacobsen Asymmetric Catalyst''' ====

Molecule 23 is the stable precursor of molecule 24, the active catalyst. Molecule 23 can be converted to molecule 24 by using sodium perchlorate.

[[File:Salen, 23 and 24.png|400px|center]]

Jacobsen catalyst is biphasic. The first phase involves the transfer of oxygen to molecule 23. Sodium perchlorate oxidizes Mn(III) to Mn(V).

In the second step, Jacobsen catalyst acts via a radical mechanism. It is thought to be so because epoxidation of trans-alkene by Jacobsen catalyst yield cis-alkene as well. A radical mechanism will lead to the lost of stereochemical information of the molecule.

=== ''' Crystal structure of the two catalyst''' ===
==== '''Molecule 21''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 21'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 21 strucutre.png|600px|center]]'''
|-
| style="text-align:center;" width="150" | ''' Bond '''
| style="text-align:center;" width="150"| ''' Bond Lenghts (Angstrom)'''
| style="text-align:center;" | ''' Evaluation'''
|-
| style="text-align:center;"| ''' O1-C1 '''
| style="text-align:center;"| ''' 1.400'''
| rowspan="10" style="text-align:left;"| [[File:Molecule 21 2.png|300px|center]]

The normal bond length of an C-O bond is 1.430 angstrom.

The most interesting aspect here is O4 and O2. The lone pair of O4 is antiperplanar to the sigma* orbital of the carbonyl group while the lone pair of O2 is anti periplanar to the carbonyl pi* orbital. Donation of electron can occur because of the correct symmetry. Due to the mixing of the orbitals, the C2-O2 and C4-O4 has been conferred with a certain degree of double bond character.

However, due to the lone pair on oxygen being now donated to the carbonyl antibonding orbitals, the O2 and O4 is slightly “electron deficient” and electron density will be pulled away from O2 and O4. That would explain why the bond length increase for O2-C7 and O4-C10. Increase in bond length is an indicator of the weakening of the bond.
|-
| style="text-align:center;"|'''O1-C7'''
| style="text-align:center;"|'''1.413'''
|-
| style="text-align:center;"|'''O2-C7'''
| style="text-align:center;"|'''1.441'''
|-
| style="text-align:center;"|'''O2-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O4-C4'''
| style="text-align:center;"|'''1.396'''
|-
| style="text-align:center;"|'''O4-C10'''
| style="text-align:center;"|'''1.439'''
|-
| style="text-align:center;"|'''O5-C10'''
| style="text-align:center;"|'''1.409'''
|-
| style="text-align:center;"|'''O5-C5'''
| style="text-align:center;"|'''1.416'''
|-
| style="text-align:center;"|'''O6-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O6-C6'''
| style="text-align:center;"|'''1.420'''
|-
|}
 

==== '''Molecule 23''' ====

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 23'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 23 struc.png|600px|center]]'''
|-
| The most outstanding feature from this molecule is the fact that is adopt a puckered form of the square base pyramidal form. This is no surprise that the molecule is almost planar due to the electron delocalization around each side of the salen ligand.

The tery-butyl hydrogen are oriented closely to one another. Non-covalent interaction studies indicated that repulsion would occur for H---H bond length that are less than 2.1 angstrom while favourable interaction may be dominant with bond length above 2.4 angstrom. It was discovered that all 4 hydrogens have bond length more than 2.4 angstrom hence there should not be any significant repulsion between them. Instead, certain amount of attractive force will ensue and that contributes to the overall stability of the molecule

|-
|}
 

=== ''' The calculated NMR properties of the product''' ===

=== ''' Assigning the absolute configuration of the product''' ===

=== ''' Analysis of the Transition State for Reactions''' ===
==== '''Predicting Enantiomeric Excess based on Transition State energies''' ====

One of the energy output from Gaussian calculation is the “sum of electronic and thermal free energies”. This is Gibbs Free Energy at 298.15K and 1 atm.

Using this term and invoking a variant of the Curtin-Hammett Principle, it is possible to calculate a predicted enantiomeric excess of one enantiomer over the other.

[[File:Ee and transition state energy.png|800px|center]]

Using the derivations from above and equation (4), we analyze the enantiomeric excess of beta-methyl styrene and the results are tabulated as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1343.022970'''
| width="100" | '''-1343.017942'''
| width="150" | '''-0.005028'''
| width="150" | '''4.88E-03'''
| width="150" | '''99.03'''
|- align="center"
| width="100" | '''-1343.019233'''
| width="100" | '''-1343.015603'''
| width="150" | '''-0.003630'''
| width="150" | '''2.14E-02'''
| width="150" | '''95.80'''
|- align="center"
| width="100" | '''-1343.029272'''
| width="100" | '''-1343.023766'''
| width="150" | '''-0.005506'''
| width="150" | '''2.94E-03'''
| width="150" | '''99.41'''
|- align="center"
| width="100" | '''-1343.032443'''
| width="100" | '''-1343.024742'''
| width="150" | '''-0.007701'''
| width="150" | '''2.88E-04'''
| width="150" | '''99.94'''
|-
|}

 

The above hartree units are converted to J/mol for calculation of K where 1 hartress = 4.3597E-18

Studying all the free energies of the (R,R) series and compare them with the (S,S) series, it comes as no surprise that (R,R) product is favoured over (S,S) product as (R,R) is more stable. Indeed, this corresponds with the literature value reporting 92% ee of (R,R) products over that of (S,S).

==== '''Analysis of the Transition State of Epoxidation''' ====
==== '''Shi Fructose Catalyst''' ====
For this section, I will be analyzing the the transition state of 1) styrene and 2) trans-stilbene with the Shi fructose catalyst.

===== '''(R) and (S)-styrene transition state''' =====
The transition state for the formation of (R)-styrene oxide and (S)-styrene oxide are given as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R)-styrene oxide'''
| width="150" | '''(S)-styrene oxide'''
|- align="center"
| width="150" | ''' Structure of Catalyst '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide R.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide S ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| [[File:Steric shi fructose R.png|450px|center]]
| [[File:Steric shi fructose S.png|450px|center]]
|-
|}

 

In the transition state for (R)-styrene, it was discovered that the Re face is reacting with the oxygen of the dioxirane. The phenyl ring is oriented endo with respect to the fructose catalyst. However, the (S)-styrene is reacting at the Si face and the phenyl ring is oriented exo relative to the catalyst.

The approach taken by (R)-styrene and (S)-styrene are restricted to only one due to steric interactions. Therefore, the epoxidation of both styrenes by the Shi catalyst will be stereospecific and retains all the stereochemical information of the reactant. However, whether or not (R)-styrene oxide or (S)-styrene oxide is form is dependent on the relative energies of the transition state. The more stable the transition state, the more likely the product of the transition state will be formed.

So in order to examine this, an example of transition state of both styrenes with Shi catalyst are obtained and analyzed.
 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1303.736813'''
| width="100" | '''-1303.727673'''
| width="150" | '''-0.00914'''
| width="150" | '''6.28E-05'''
| width="150" | '''99.99'''

|-
|}

 

From the above, we can see the predicted high enantiopurity of the reaction favoring the (R) product because of the lower energy of the transition states. To understand the reason, we have to turn to non-covalent interaction (NCI) analysis.

[[File:NCI shi fructose styrene.png|700px|center]]

To complement the NCI analysis, a QTAIM (Quantum Theory of Atoms in Molecules) analysis is conducted as well.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''(R)-styrene transition state'''
| width="200" | '''(S)-styrene transition state'''
|- align="center"
| width="100" | '''[[File:QTAIM R.png|400px|center]]'''
| width="100" | '''[[File:QTAIM S.png|400px|center]]'''
|- align="center"
| colspan="2" width="100" | '''Comments'''
|-
| colspan="2" width="100" | '''Unsurprisingly, QTAIM analysis has also shown that (R)-styrene/Shi catalyst has more interactions with one another. While (R)-styrene has 2 strong interactions, (S)-styrene has only one with the catalyst. Besides, the phenyl ring of (R)-styrene also confers additional positive interaction with the catalyst. QTAIM analysis has also show several interactions between the C=C geminal hydrogen of (R)-styrene intreacting with the oxygen atoms on the dioxacyclopentane ring'''
|-
|}

 

===== '''(R,R) and (S,S)-Stilbene transition state''' =====

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R,R)-Stilbene oxide'''
| width="150" | '''(S,S)-Stilbene oxide'''
|- align="center"
| width="150" | ''' Structure of Transition State '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Stilbene RR ts.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>SS stilbene oxide ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| colspan="2" | [[File:Shi fructose stilbene.png|700px|center]]

|-
|}

 

However, unlike styrene, trans-stilbene seems to approach perpendicularly to the dioxirane. This is proposed to be due to the steric interactions (marked in purple). Based on first inspection, it seems that (S,S)-Stilbene oxide has more steric interactions than (R,R)-Stilbene oxide. Although unsubstantial, it seems like my guess was correct. The (R,R)-stilbene/Shi catalyst transition state is lower in energy.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1534.687808'''
| width="100" | '''-1534.683440'''
| width="150" | '''0.004368'''
| width="150" | '''9.08E-3'''
| width="150" | '''98.20'''

|-
|}

 

NCI Analysis is also done for trans-stilbene

[[File:NCI stilbene.png|700px|center]]

==== '''Jacobsen Catalyst''' ====

For this section, cis-beta methyl styrene transition state will be analyzed.

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-3383.259559'''
| width="100" | '''-3383.251060'''
| width="150" | '''-0.008499'''
| width="150" | '''1.24E-04'''
| width="150" | '''99.98'''
|- align="center"
| width="100" | '''-3383.253442'''
| width="100" | '''-3383.250270'''
| width="150" | '''-0.003172'''
| width="150" | '''3.48E-02'''
| width="150" | '''93.27'''
|-
|}

 

As is obvious from here, the (S,R) transition state is more stable than the (R,S) transition state. Both transition states are exo with respect to the catalyst.

It is not immediately apparent just by looking at the molecule to determine which spatial groups have interactions with one another. Therefore, an NCI analysis is conducted again.

[[File:NCI Jacobsen.png|700px|center]]

File:Molecule 23 struc.png

2013-11-21T19:33:28Z

Xc2611:

File:Table.png

2013-11-21T19:28:58Z

Xc2611:

Rep:Mod:Computationalreport1C

2013-11-21T19:14:39Z

Xc2611: /* Crystal structure of the two catalyst */

= '''Synthesis and Computational Lab: 1C''' =
== '''Part 1: Introduction to Molecular Mechanics''' ==
=== '''Introduction to MMFF94 and MMFF94s''' ===

With the improvement of computational data and computer processing power, the usage of molecular mechanics/dynamics forcefield has become very integrated in predicting properties of chemical molecules. A molecular mechanics/dynamics forcefield should be able to predict characteristics such as molecular geometries, conformational/stereoisomeric energies, vibrational frequencies etc. to a reasonable accuracy as compared to experimental-derived values.

Building on work from Kollman et al. s’ AMBER forcefield and Allinger et al. s’ MM1, MM2, MM3 and MM4, Merck Research Laboratories have managed to optimized and improved the previous computational algorithms and produced MMFF94 (Merck Molecular Force Field 94). One of the most prominent advantages of MMFF94 over other preceeding work is its enhanced prediction accuracy. The reason lies in the fact that MMFF94’s core parameterization utilizes an unprecedently large amount of computational data obtained from ab initio calculations1.

Subsequently after the development of MMFF94, a new “static” variant of the MMFF was introduced i.e. the MMFF94s. Unlike MMFF94 that was developed for the use of molecular dynamics simulations (which can be expensive), MMFF94s was developed with the purpose of energy minimization studies in mind. Although both systems provide identical results for most systems, they differ for amides and unsaturated amines which contain resonance-delocalized trigonal nitrogen atoms2.

In this computational exercise, MMFF94s is used predominantly as oppose to the alternative Universal Force Field (UFF). Although versatile across the entire periodic table, UFF is derived from simple rules and atomic parameters such as fixed hybridization that increases the likelihood of erroneous structural and energetic predictions3.

=== '''Forms of MMFF94s''' ===

Steric energy of a molecule is the energy arise due to its geometry or conformation. Energy minimization of steric energy process ensures that the molecule is in its lowest energy conformation.

MMFF94s assumes that the total steric energy of a molecule can be found by the sum of a few specific interactions in a molecule.

ES = EBS + EAB + E SB + ET + EOOP + EVdW + EEE

'''where the bonded interactions are:'''

ES = Total Steric energy

EBS = Total Bond Stretching energy

EAB = Total Angle Bending energy

ESB = Total Stretch Bending energy

ET = Total Torsional Energy

EOOP = Total Out-Of-Plane Bending energy, and

'''where the non-bonded interactions are:'''

EVdW = Total Van der Waals Energy

EEE = Total Electrostatic Energy

{| border="1" cellspacing="1" cellpadding="10"
|-
| width="300" align="center" | '''Types of Energies'''
! width="600" align="center" | '''Explanation'''
|-
| colspan="2" style="text-align: center;" | '''Bonded Interactions'''
|-
| width="300" align="center" | '''Total Bond Stretching Energy'''
! width="600" align="left" | The total bond stretching energy is related to the vibration energy of the molecules in comparison to the equilibrium bond length. Whenever a bond deviates from the equilibrium bond length, the energy value increases.

MMFF94s uses a quartic function that has the force constant term (relate to bond strength). The quartic function term is superior to the cubic function term (used in MM2) in the sense that it avoid the “cubic stretch catastrophe” where progressive elongation of molecule bond length leads to negative infinity.
|-
| width="300" align="center" | '''Total Angle Bending Energy'''
! width="600" align="left" | Similar to Total Bond Stretching Energy, the total angle bending energy is also related to the vibration energy of the molecules about the equilibrium bond length. However, unlike EBS that measures the bond strength, EAB is associated with the stiffness of the molecules based on the Hookiean potential. Whenever bond angles deviate from the norm during vibration, this energy term increases as well.
|-
| width="300" align="center" | '''Total Stretch-Bending Energy'''
! width="600" align="left" | This energy term takes into account of the energy due to increase in bond length when bond angle between two atoms changes.
|-
| width="300" align="center" | '''Total Torsional Energy'''
! width="600" align="left" | Total torsional energy is the energy required for intermolecular rotation about the bonds. In molecule mechanics, however, this term is often used as a correction that must be added or subtracted to the total energy of the molecule to fit a quantum mechanical calculation about the dihedral angles of bonds.
|-
| width="300" align="center" | '''Total Out-Of-Plane Bending Energy'''
! width="600" align="left" | This energy term refers to the energy needed to deform the dihedral angle (zero degrees) of a planar group of atoms such as carbonyl or amide functional groups.
|-
| colspan="2" style="text-align: center;" | '''Non-Bonded Interactions'''
|-
| width="300" align="center" | '''Total Van der Waals Energy'''
! width="600" align="left" | The total Van der Waals energy term examines the intramolecular interactions such as repulsion or attraction between non-bonded atoms in the molecule. This term is crucial in determining the preferred conformation of the molecule.

MMFF94s employs the novel “Buffered-14-7”. The name is derived from a buffering constant and the 14th and 7th power dependencies of the repulsive and attractive energy in the equation.
|-
| width="300" align="center" | '''Total Electrostatic Energy'''
! width="600" align="left" | The total electrostatic energy functions take into account of the Coulombic potential and partial charge/dipole/atomic point charges interactions within the molecule.
|-

|}

 

== '''Part 2 : Conformational Analysis Using Molecular Mechanics''' ==
=== '''The Hydrogenation of Cyclopentadiene Dimer''' ===

==== '''Endo and exo adduct from the Dimerization of Cyclopentadiene''' ====
Cyclopentadiene will undergo dimerization by Diels-alder reaction to form either an endo or exo adduct.

[[File:XcwDimerization of CP.png|500px|center]]

==== '''Stereoselectivity of Dimerization of Cyclopentadiene''' ====
Although the exo adduct is thermodynamically more stable than the endo adduct, the endo adduct is form preferentially. Using the QST2 method, the transition state of the Diels Alder dimerization was found. It was discovered that due to the secondary orbital interactions in the endo transition state, the endo dimer is formed preferentially (the kinetic product). Hence, it is proven that the Diels Alder dimerization between two cyclopentadiene are kinetically controlled.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Transition State of Dimerization of Cyclopentadiene'''
| '''Imaginary Stretch Frequency (-881.25) of the Endo Transition State (click to animate)'''
| '''Secondary Orbital Interaction (Red overlapping orbitals)'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<uploadedFileContents>EndotsDCPD2.mol
</uploadedFileContents>
</jmolApplet></jmol>
| [[File:Xcwendotsimaginary.gif|300px|center]]
| [[File:XcwSecondary orbital interaction1.jpg|300px|center]]
|-
|}

 

==== '''Asynchronous Bond Formation of Dimerization of Cyclopentadiene''' ====

The initial study of the molecular orbitals of the transition states seemed a bit peculiar. Instead of getting a LUMO with symmetrical orbitals, the calculations showed a HOMO that is asymetric at the carbons where the new sigma bonds will be formed. Running an IRC further, it soon became clear that the asymmetry of the HOMO leads to an asychronous bond formation before leading to the product.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''IRC plot following the Endo Transition State '''
| '''IRC following the Endo Transition State (click to animate)'''
| '''Asymmetry of orbitals at the carbons where the new sigma bonds will be formed'''
|- align="center"
| [[File:XcwendotscyclopentadieneIRC.png|300px|center]]
| [[File:XcwendotsIRC.gif|300px|center]]
| [[File:XcwAsynchronous mo.jpg|300px|center]]
|-
|}

 

==== '''Comparison of Energies between the Endo and Exo adduct of Dicyclopentadiene''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Adduct of Dicyclopentadiene dimerization'''
| '''Exo Adduct of Dicyclopentadiene dimerization'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=19,atomno=1,atomno=2; color green;measure 19 1;measure 19 2;</script>
<uploadedFileContents>XcwEndodimer3.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>Exodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=7,atomno=17; color green;measure 17 7;</script>
<uploadedFileContents>XcwExodimer1.mol</uploadedFileContents>
</jmolApplet></jmol>
|-
|}

 

Using MMFF94s ab initio calculations, the energies for the exo dimer and the endo dimer are derived.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Exodimer'''
| '''55.374'''
| 3.543
| 30.772
| -2.041
| -2.728
| 0.015
| 12.800
| 13.014
|-
| '''Endodimer'''
| '''58.191'''
| 3.468
| 33.187
| -2.082
| -2.950
| 0.023
| 12.360
| 14.186
|-
|}

 

The MMFF94s steric energy (after minimization) for the exo dimer is lower than that of the endo dimer. This is reflected by the large difference for the EEE between the endo dimer and the exo dimer due to unfavourable steric repulsion between the two “arched down” cyclopentene rings.

==== '''Hydrogenation of Dicyclopentadiene''' ====

Hydrogenation of the endo dicyclopentadiene (DCPD) would lead to two potential products: dihydro product 1 and dihydro product 2.

[[File:XcwFormation of Dihydro products.png|500px|center]]

Using MMFF94s, the energy of the two dihydro products are calculated.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Dihydro Product 1'''
| '''50.123'''
| 3.308
| 30.864
| -1.927
| 0.060
| 0.015(2)
| 13.281
| 5.121
|-
| '''Dihydro Product 2'''
| '''41.257'''
| 2.823
| 24.685
| -1.657
| -0.379
| 0.000(2)
| 10.639
| 5.147
|-
| '''Tetrahydro Product'''
| '''39.042'''
| 2.730
| 25.151
| -1.676
| 1.287
| 0.000
| 11.551
| 0.000
|}

 

From the MMFF94s calculation, it can be seen that dihydro product 2 has a lower steric energy than dihydro product 1. Therefore, dihydro product 2 is the thermodynamic product for the hydrogenation of dicylopentadiene. And indeed, this was what was observed by Skala et al.. He observed that the first hydrogenation occur at the norborene part of the molecule (rate of hydrogenation several times faster than that in the cyclopentene ring)6. The first heat of hydrogenation at the norborene is 138.8 kJ/mol while the second hydrogenation at the cyclopentene right is 109.5 kJ/mol6.

From the above results, it is also obvious that tetrahydro product is much more stable than either dihydro product. And yet, studies have shown that the tetrahydro product will only form after prolonged hydrogenation under high temperature. However, subjecting DCPD to high temperature leads to low yield due to cracking of DCPD.

Since thermodynamically it is predicted to form favourably, the fact that it does not could only mean that the hydrogenation of DCPD to tetrahydrodicyclopentadiene (TH-DCPD) is kinetically controlled. Most possibly, the transition state of the hydrogenation of DCPD is highly unstable hence it is unlikely to form.

=== '''Atropisomerism in an Intermediate related to the Synthesis of Taxol''' ===

Atropisomerism is a type of stereoisomerism that is form as a result of hindered rotation about a single bond.

[[File:XcwAtropisomerism example.png|500px|center]]

In the case of the 6,6’-dinitro-2,2’-diphenic acid, rotation about the bonds joining the two substituted phenyl rings would have to overcome large steric interaction between the bulky substituents. The barrier of rotation is high enough for the two conformers to be isolated individually.

In the synthesis of taxol, one of the key intermediates exhibit atropisomerism.

==== '''Atropisomerism in Taxol Synthesis''' ====

For the key intermediate, rotation about the carbon-carbon bonds would lead to two types of atropisomers, each with either the carbonyl group poining upwards or downwards in relative to the bridge.

[[File:XcwIntermediate 9 and Intermediate 10.png|500px|center]]

Once again by using MMFF94s ab initio calculations, the steric energies for the two intermediates are illustrated as below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 9'''
| '''70.571'''
| 7.743
| 28.356
| -0.062
| 0.004
| 0.949
| 33.293
| 0.288
|-
| '''Intermediate 10'''
| '''60.553'''
| 7.599
| 18.838
| -0.139
| 0.199
| 0.844
| 33.269
| -0.056
|-

|}

 

Analyzing the data above, the largest energy difference between Intermediate 9 and Intermediate 10 stems from the EAB which is related to the strain of the ring. Intermediate 9 has an excess of 9.518 kcal/mol EAB as compared to Intermediate 10. This comes as a surprise as intermediate 9 is predicted to be more stable alkene.

The rationale behind the prediction of the stability of intermediate 9 stems from the fact that the through-space distance of the upward-pointing carbonyl oxygen with the carbon-carbon is further than the through space distance between the downward-pointing carbonyl oxygen with the -CH2-CH2- fragment at the norbornene part in intermediate 10.

==== '''Hyperstable Olefins''' ====

Intermediate 9 and Intermediate 10 does not react readily with other reagents during functionalization. This is due to the hyperstability effect found in hyperstable olefins.

Hyperstable olefins are alkenes that contain less strain in the ring (i.e. negative olefin strain values) compared to the parent hydrocarbon. To study this further, further MMFF94s calculation was done to compare Intermediate 10 with the parent hydrocarbon.

[[File:XcwIntermediate10andPH.png|500px|center]]

The energies that we calculated are tabulated as shown below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 10'''
| '''44.878 '''
| 5.211
| 15.488
| -0.267
| -1.655
| 0.998
| 25.014
| 0.088
|-
| '''Parent Hydrocarbon'''
| '''50.564'''
| 4.692
| 21.979
| 0.109
| -0.958
| 0.247
| 24.495
| 0.000
|-

|}

 

Scrutinizing the results, the largest energy difference between intermediate 10 and the parent hydrocarbon stems from the Total Angle Bending Energy, EAB. Since the Total Angle bending energy is related to the angle strain in the molecules, it is apparent that the parent hydrocarbon has more ring strain as compared to the bridgehead olefin.

== '''Part 3 : Spectroscopic Simulation Using Quantum Mechanics''' ==
=== '''Spectroscopy of an Intermediate Related to the Synthesis of Taxol''' ===

Molecule 17 and 18 are derivatives of intermediate 9 and 10. In this exercise, MMFF94s is used to predict the 1H and 13C NMR of molecule 17 and molecule 18.

[[File:XcwIntermediate17&18.png|500px|center]]

==== '''NMR Spectra of Molecule 17''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 17.mol
</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwHNMRMolecule 17 Chair Overall NMR.png|500px|center]]
| [[File:XcwHNMRMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.1825
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| The first three results were fairly straight forward to be deduced and correlate wit experimental data.

The hydrogen atom that is geminally attached to the carbon of the double bonds is the most deshielded due to the ring current anisotropic effect of the ring current

The second most deshielded hydrogen atom is the hydrogen atom on the methyl group on the bridge. The hydrogen atom is pointing directly to the oxygen atom of the carbonyl functional group.

The peaks with an integration height of 4 is assigned to the hydrogen atoms in the 1,3-dithiolane ring fragment.

Subsequent analysis of the 1H NMR became very complicated very quickly for two reasons:

1. Gaussian calculations showed some atoms with an integration height of 3. Comparing their file atom number and checking their chemical environment, it is not possible to find any correlation between them.

2. Some of the peaks in the literature remains unresolved and are given as multiplets or grouped together.

|- align="center"
| 52
| 3.1775
| 1
| '''2.99'''
|- align="center"
| 53,52,50,51
| 3.0867
| 4
| '''3.40-3.10'''
|- align="center"
| 42,43,39
| 2.7445
| 3
| ''' '''
|- align="center"
| 49
| 2.6187
| 1
| ''' '''
|- align="center"
| 34
| 2.4371
| 1
| ''' '''
|- align="center"
| 35
| 2.3782
| 1
| ''' '''
|- align="center"
| 40,37,26
| 2.2730
| 3
| ''' '''
|- align="center"
| 30
| 2.1566
| 1
| ''' '''
|- align="center"
| 36
| 2.1033
| 1
| ''' '''
|- align="center"
| 32,28
| 2.0259
| 2
| ''' '''
|- align="center"
| 25
| 1.8535
| 2
| ''' '''
|- align="center"
| 38,46,27
| 1.5898
| 3
| '''1.25'''
|- align="center"
| 29
| 1.4557
| 1
| ''' '''
|- align="center"
| 31
| 1.0123
| 1
| ''' '''
|- align="center"
| 44,48,45
| 0.9087
| 3
| '''1.10'''
|- align="center"
| 47
| 0.8354
| 1
| ''' '''
|- align="center"
| 33
| 0.5790
| 1
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 17 Chair Overall NMR2.png|500px|center]]
| [[File:XcwMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 216.2725
| 1
| '''218.79'''
| rowspan="10" style="text-align:center;"| [[File:XcwMolecule 17 image for CNMR.jpg|600px|center]]
|- align="center"
| 13
| 144.8626
| 1
| '''144.63'''
|- align="center"
| 14
| 124.7193
| 1
| '''125.33'''
|- align="center"
| 3
| 91.3340
| 1
| '''72.88'''
|- align="center"
| 2
| 60.9568
| 1
| '''56.19'''
|- align="center"
| 1
| 57.0811
| 1
| '''52.52'''
|- align="center"
| 10
| 52.4663
| 1
| '''48.50'''
|- align="center"
| 16
| 51.4857
| 1
| '''46.80'''
|- align="center"
| 9
| 46.9196
| 1
| '''45.76'''
|- align="center"
| 23
| 43.8647
| 1
| '''39.80'''
|- align="center"
| 22
| 41.9450
| 1
| '''38.81'''
| Comments
|- align="center"
| 4
| 41.8724
| 1
| '''35.85'''
| rowspan="9" style="text-align:left;"| The carbon bonded to the oxygen atom is the most deshielded, as is shown in the predicted values and the experimental values. There is a deviation between the values. Quite possibly, this is due to the fact that in reality, the carbonyl functional group is pointing slightly towards the equatorial position rather than a lateral position relative to the ring (as is in the input for Gaussian calculation)

Most of the 1CNMR values that was predicted by Gaussian are all within an acceptable range of deviation. However, there is carbon 3 that has significant deviation between the predicted value and experimental value.

Carbon 3 is the carbon bonded to the two sulphurs in the 1,3-dithiolane ring fragment. Such a huge deviation would possibly mean that the conformer that was given as input to Gaussian differs from the literature.

The above NMR spectra was corrected with a level of theory B3LYP/6-31G(d,p) using TMS as reference and in chloroform.

|- align="center"
| 15
| 35.4348
| 1
| '''32.66'''
|- align="center"
| 11
| 31.1964
| 1
| '''28.79'''
|- align="center"
| 6
| 28.9432
| 1
| '''28.29'''
|- align="center"
| 7
| 28.3640
| 1
| '''26.88'''
|- align="center"
| 12
| 27.3767
| 1
| '''25.66'''
|- align="center"
| 17
| 26.3311
| 1
| '''23.86'''
|- align="center"
| 15
| 24.5483
| 1
| '''20.96'''
|- align="center"
| 18
| 19.7788
| 1
| '''18.71'''
|-
|}
 

==== '''NMR Spectra of Molecule 18''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 18 Boat for Image2.mol</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"-
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 18 Chair Overall NMR.png|500px|center]]
| [[File:Molecule 18 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.2832
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| ''' '''
|- align="center"
| 50
| 3.3175
| 1
| rowspan="4" style="text-align:centre;"| '''3.00-2.70'''
|- align="center"
| 52
| 3.2153
| 1
|- align="center"
| 51,53
| 3.1161
| 2
|- align="center"
| 34,43
| 2.8606
| 2
|- align="center"
| 38
| 2.4549
| 1
| ''' '''
|- align="center"
| 42
| 2.3968
| 1
| ''' '''
|- align="center"
| 25,29,26
| 2.2796
| 3
| ''' '''
|- align="center"
| 39
| 2.0844
| 1
| ''' '''
|- align="center"
| 40,36
| 1.9699
| 2
| ''' '''
|- align="center"
| 37,24
| 1.8519
| 2
| ''' '''
|- align="center"
| 31,27
| 1.6780
| 2
| ''' '''
|- align="center"
| 28
| 1.6175
| 1
| ''' '''
|- align="center"
| 46,49
| 1.4979
| 2
| ''' '''
|- align="center"
| 35
| 1.4150
| 1
| ''' '''
|- align="center"
| 32
| 1.3531
| 1
| ''' '''
|- align="center"
| 48
| 1.1606
| 1
| ''' '''
|- align="center"
| 33,30,47
| 1.0653
| 3
| '''1.03'''
|- align="center"
| 44,45
| 0.9643
| 2
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwMolecule 18 Boat Overall NMR.png|500px|center]]
| [[File:XcwMolecule 18 Boat zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 211.8325
| 1
| '''211.49'''
| rowspan="10" style="text-align:center;"| [[File:Molecule 18 Boat for 13 CNMR.jpg|600px|center]]
|- align="center"
| 13
| 148.6673
| 1
| '''148.72'''
|- align="center"
| 14
| 118.8373
| 1
| '''120.90'''
|- align="center"
| 3
| 89.0869
| 1
| '''74.61'''
|- align="center"
| 2
| 67.8886
| 1
| '''60.53'''
|- align="center"
| 1
| 56.1133
| 1
| '''51.30'''
|- align="center"
| 10
| 55.5998
| 1
| '''50.94'''
|- align="center"
| 16
| 50.1124
| 1
| '''45.53'''
|- align="center"
| 22
| 48.2030
| 1
| '''43.28'''
|- align="center"
| 23
| 44.2222
| 1
| '''40.82'''
|- align="center"
| 4
| 42.0354
| 1
| '''38.73'''
| Comments
|- align="center"
| 9
| 37.5865
| 1
| '''36.78'''
| rowspan="9" style="text-align:left;"| ''' '''
|- align="center"
| 6
| 35.3106
| 1
| '''35.47'''
|- align="center"
| 15
| 31.0459
| 1
| '''30.84'''
|- align="center"
| 7
| 28.8476
| 1
| '''30.00'''
|- align="center"
| 12
| 28.6623
| 1
| '''25.56'''
|- align="center"
| 17
| 25.7393
| 1
| '''25.35'''
|- align="center"
| 11
| 25.2603
| 1
| '''22.21'''
|- align="center"
| 18
| 23.3944
| 1
| '''21.39'''
|- align="center"
| 5
| 21.0478
| 1
| '''19.83'''
|-
|}
 

== '''Part 4 : Analysis of the Properties of the Synthesized Alkene Epoxides''' ==
=== '''The two catalytics systems''' ===

Assymmetric epoxidation of prochiral alkenes may lead to product with different stereochemical outcome as illustrated as below. To solve this problem, different types of asymmetric epoxidation catalyst have been synthesized. In this study, we shall be focusing on Shi asymmetric fructose catalyst as well as Jacobsen asymmetric catalyst.

[[File:Asymmetric catalyst.png|400px|center]]

==== ''' The Shi Asymmetric Fructose Catalyst''' ====

Molecule 21 is the stable precursor of molecule 22, the active catalyst. Molecule 21 can be converted to molecule 22 by using either persulfuric acid or potassium peroxymonosulphate.

[[File:Molecule 21 to 23.png|400px|center]]

The transition state of the Shi epoxidation was a subject of debate for a few moments. However, recent studies have led to the conclusion that the spiro transition state is more favored than the planar transition state. The spiro transition state is the transition that has its dioxirane perpendicularly bisecting the alkene double bond. This is thought to be more favourable due to interactions between the lone pairs of the oxygen with the LUMO of the alkene.

[[File:Spiro and planar ts.png|500px|center]]

==== ''' The Jacobsen Asymmetric Catalyst''' ====

Molecule 23 is the stable precursor of molecule 24, the active catalyst. Molecule 23 can be converted to molecule 24 by using sodium perchlorate.

[[File:Salen, 23 and 24.png|400px|center]]

Jacobsen catalyst is biphasic. The first phase involves the transfer of oxygen to molecule 23. Sodium perchlorate oxidizes Mn(III) to Mn(V).

In the second step, Jacobsen catalyst acts via a radical mechanism. It is thought to be so because epoxidation of trans-alkene by Jacobsen catalyst yield cis-alkene as well. A radical mechanism will lead to the lost of stereochemical information of the molecule.

=== ''' Crystal structure of the two catalyst''' ===
==== '''Molecule 21''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 21'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 21 strucutre.png|600px|center]]'''
|-
| style="text-align:center;" width="150" | ''' Bond '''
| style="text-align:center;" width="150"| ''' Bond Lenghts (Angstrom)'''
| style="text-align:center;" | ''' Evaluation'''
|-
| style="text-align:center;"| ''' O1-C1 '''
| style="text-align:center;"| ''' 1.400'''
| rowspan="10" style="text-align:left;"| [[File:Molecule 21 2.png|300px|center]]

The normal bond length of an C-O bond is 1.430 angstrom.

The most interesting aspect here is O4 and O2. The lone pair of O4 is antiperplanar to the sigma* orbital of the carbonyl group while the lone pair of O2 is anti periplanar to the carbonyl pi* orbital. Donation of electron can occur because of the correct symmetry. Due to the mixing of the orbitals, the C2-O2 and C4-O4 has been conferred with a certain degree of double bond character.

However, due to the lone pair on oxygen being now donated to the carbonyl antibonding orbitals, the O2 and O4 is slightly “electron deficient” and electron density will be pulled away from O2 and O4. That would explain why the bond length increase for O2-C7 and O4-C10. Increase in bond length is an indicator of the weakening of the bond.
|-
| style="text-align:center;"|'''O1-C7'''
| style="text-align:center;"|'''1.413'''
|-
| style="text-align:center;"|'''O2-C7'''
| style="text-align:center;"|'''1.441'''
|-
| style="text-align:center;"|'''O2-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O4-C4'''
| style="text-align:center;"|'''1.396'''
|-
| style="text-align:center;"|'''O4-C10'''
| style="text-align:center;"|'''1.439'''
|-
| style="text-align:center;"|'''O5-C10'''
| style="text-align:center;"|'''1.409'''
|-
| style="text-align:center;"|'''O5-C5'''
| style="text-align:center;"|'''1.416'''
|-
| style="text-align:center;"|'''O6-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O6-C6'''
| style="text-align:center;"|'''1.420'''
|-
|}
 

==== '''Molecule 23''' ====

=== ''' The calculated NMR properties of the product''' ===

=== ''' Assigning the absolute configuration of the product''' ===

=== ''' Analysis of the Transition State for Reactions''' ===
==== '''Predicting Enantiomeric Excess based on Transition State energies''' ====

One of the energy output from Gaussian calculation is the “sum of electronic and thermal free energies”. This is Gibbs Free Energy at 298.15K and 1 atm.

Using this term and invoking a variant of the Curtin-Hammett Principle, it is possible to calculate a predicted enantiomeric excess of one enantiomer over the other.

[[File:Ee and transition state energy.png|800px|center]]

Using the derivations from above and equation (4), we analyze the enantiomeric excess of beta-methyl styrene and the results are tabulated as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1343.022970'''
| width="100" | '''-1343.017942'''
| width="150" | '''-0.005028'''
| width="150" | '''4.88E-03'''
| width="150" | '''99.03'''
|- align="center"
| width="100" | '''-1343.019233'''
| width="100" | '''-1343.015603'''
| width="150" | '''-0.003630'''
| width="150" | '''2.14E-02'''
| width="150" | '''95.80'''
|- align="center"
| width="100" | '''-1343.029272'''
| width="100" | '''-1343.023766'''
| width="150" | '''-0.005506'''
| width="150" | '''2.94E-03'''
| width="150" | '''99.41'''
|- align="center"
| width="100" | '''-1343.032443'''
| width="100" | '''-1343.024742'''
| width="150" | '''-0.007701'''
| width="150" | '''2.88E-04'''
| width="150" | '''99.94'''
|-
|}

 

The above hartree units are converted to J/mol for calculation of K where 1 hartress = 4.3597E-18

Studying all the free energies of the (R,R) series and compare them with the (S,S) series, it comes as no surprise that (R,R) product is favoured over (S,S) product as (R,R) is more stable. Indeed, this corresponds with the literature value reporting 92% ee of (R,R) products over that of (S,S).

==== '''Analysis of the Transition State of Epoxidation''' ====
==== '''Shi Fructose Catalyst''' ====
For this section, I will be analyzing the the transition state of 1) styrene and 2) trans-stilbene with the Shi fructose catalyst.

===== '''(R) and (S)-styrene transition state''' =====
The transition state for the formation of (R)-styrene oxide and (S)-styrene oxide are given as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R)-styrene oxide'''
| width="150" | '''(S)-styrene oxide'''
|- align="center"
| width="150" | ''' Structure of Catalyst '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide R.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide S ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| [[File:Steric shi fructose R.png|450px|center]]
| [[File:Steric shi fructose S.png|450px|center]]
|-
|}

 

In the transition state for (R)-styrene, it was discovered that the Re face is reacting with the oxygen of the dioxirane. The phenyl ring is oriented endo with respect to the fructose catalyst. However, the (S)-styrene is reacting at the Si face and the phenyl ring is oriented exo relative to the catalyst.

The approach taken by (R)-styrene and (S)-styrene are restricted to only one due to steric interactions. Therefore, the epoxidation of both styrenes by the Shi catalyst will be stereospecific and retains all the stereochemical information of the reactant. However, whether or not (R)-styrene oxide or (S)-styrene oxide is form is dependent on the relative energies of the transition state. The more stable the transition state, the more likely the product of the transition state will be formed.

So in order to examine this, an example of transition state of both styrenes with Shi catalyst are obtained and analyzed.
 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1303.736813'''
| width="100" | '''-1303.727673'''
| width="150" | '''-0.00914'''
| width="150" | '''6.28E-05'''
| width="150" | '''99.99'''

|-
|}

 

From the above, we can see the predicted high enantiopurity of the reaction favoring the (R) product because of the lower energy of the transition states. To understand the reason, we have to turn to non-covalent interaction (NCI) analysis.

[[File:NCI shi fructose styrene.png|700px|center]]

To complement the NCI analysis, a QTAIM (Quantum Theory of Atoms in Molecules) analysis is conducted as well.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''(R)-styrene transition state'''
| width="200" | '''(S)-styrene transition state'''
|- align="center"
| width="100" | '''[[File:QTAIM R.png|400px|center]]'''
| width="100" | '''[[File:QTAIM S.png|400px|center]]'''
|- align="center"
| colspan="2" width="100" | '''Comments'''
|-
| colspan="2" width="100" | '''Unsurprisingly, QTAIM analysis has also shown that (R)-styrene/Shi catalyst has more interactions with one another. While (R)-styrene has 2 strong interactions, (S)-styrene has only one with the catalyst. Besides, the phenyl ring of (R)-styrene also confers additional positive interaction with the catalyst. QTAIM analysis has also show several interactions between the C=C geminal hydrogen of (R)-styrene intreacting with the oxygen atoms on the dioxacyclopentane ring'''
|-
|}

 

===== '''(R,R) and (S,S)-Stilbene transition state''' =====

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R,R)-Stilbene oxide'''
| width="150" | '''(S,S)-Stilbene oxide'''
|- align="center"
| width="150" | ''' Structure of Transition State '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Stilbene RR ts.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>SS stilbene oxide ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| colspan="2" | [[File:Shi fructose stilbene.png|700px|center]]

|-
|}

 

However, unlike styrene, trans-stilbene seems to approach perpendicularly to the dioxirane. This is proposed to be due to the steric interactions (marked in purple). Based on first inspection, it seems that (S,S)-Stilbene oxide has more steric interactions than (R,R)-Stilbene oxide. Although unsubstantial, it seems like my guess was correct. The (R,R)-stilbene/Shi catalyst transition state is lower in energy.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1534.687808'''
| width="100" | '''-1534.683440'''
| width="150" | '''0.004368'''
| width="150" | '''9.08E-3'''
| width="150" | '''98.20'''

|-
|}

 

NCI Analysis is also done for trans-stilbene

[[File:NCI stilbene.png|700px|center]]

==== '''Jacobsen Catalyst''' ====

For this section, cis-beta methyl styrene transition state will be analyzed.

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-3383.259559'''
| width="100" | '''-3383.251060'''
| width="150" | '''-0.008499'''
| width="150" | '''1.24E-04'''
| width="150" | '''99.98'''
|- align="center"
| width="100" | '''-3383.253442'''
| width="100" | '''-3383.250270'''
| width="150" | '''-0.003172'''
| width="150" | '''3.48E-02'''
| width="150" | '''93.27'''
|-
|}

 

As is obvious from here, the (S,R) transition state is more stable than the (R,S) transition state. Both transition states are exo with respect to the catalyst.

It is not immediately apparent just by looking at the molecule to determine which spatial groups have interactions with one another. Therefore, an NCI analysis is conducted again.

[[File:NCI Jacobsen.png|700px|center]]

Rep:Mod:Computationalreport1C

2013-11-21T19:13:31Z

Xc2611: /* Crystal structure of the two catalyst */

= '''Synthesis and Computational Lab: 1C''' =
== '''Part 1: Introduction to Molecular Mechanics''' ==
=== '''Introduction to MMFF94 and MMFF94s''' ===

With the improvement of computational data and computer processing power, the usage of molecular mechanics/dynamics forcefield has become very integrated in predicting properties of chemical molecules. A molecular mechanics/dynamics forcefield should be able to predict characteristics such as molecular geometries, conformational/stereoisomeric energies, vibrational frequencies etc. to a reasonable accuracy as compared to experimental-derived values.

Building on work from Kollman et al. s’ AMBER forcefield and Allinger et al. s’ MM1, MM2, MM3 and MM4, Merck Research Laboratories have managed to optimized and improved the previous computational algorithms and produced MMFF94 (Merck Molecular Force Field 94). One of the most prominent advantages of MMFF94 over other preceeding work is its enhanced prediction accuracy. The reason lies in the fact that MMFF94’s core parameterization utilizes an unprecedently large amount of computational data obtained from ab initio calculations1.

Subsequently after the development of MMFF94, a new “static” variant of the MMFF was introduced i.e. the MMFF94s. Unlike MMFF94 that was developed for the use of molecular dynamics simulations (which can be expensive), MMFF94s was developed with the purpose of energy minimization studies in mind. Although both systems provide identical results for most systems, they differ for amides and unsaturated amines which contain resonance-delocalized trigonal nitrogen atoms2.

In this computational exercise, MMFF94s is used predominantly as oppose to the alternative Universal Force Field (UFF). Although versatile across the entire periodic table, UFF is derived from simple rules and atomic parameters such as fixed hybridization that increases the likelihood of erroneous structural and energetic predictions3.

=== '''Forms of MMFF94s''' ===

Steric energy of a molecule is the energy arise due to its geometry or conformation. Energy minimization of steric energy process ensures that the molecule is in its lowest energy conformation.

MMFF94s assumes that the total steric energy of a molecule can be found by the sum of a few specific interactions in a molecule.

ES = EBS + EAB + E SB + ET + EOOP + EVdW + EEE

'''where the bonded interactions are:'''

ES = Total Steric energy

EBS = Total Bond Stretching energy

EAB = Total Angle Bending energy

ESB = Total Stretch Bending energy

ET = Total Torsional Energy

EOOP = Total Out-Of-Plane Bending energy, and

'''where the non-bonded interactions are:'''

EVdW = Total Van der Waals Energy

EEE = Total Electrostatic Energy

{| border="1" cellspacing="1" cellpadding="10"
|-
| width="300" align="center" | '''Types of Energies'''
! width="600" align="center" | '''Explanation'''
|-
| colspan="2" style="text-align: center;" | '''Bonded Interactions'''
|-
| width="300" align="center" | '''Total Bond Stretching Energy'''
! width="600" align="left" | The total bond stretching energy is related to the vibration energy of the molecules in comparison to the equilibrium bond length. Whenever a bond deviates from the equilibrium bond length, the energy value increases.

MMFF94s uses a quartic function that has the force constant term (relate to bond strength). The quartic function term is superior to the cubic function term (used in MM2) in the sense that it avoid the “cubic stretch catastrophe” where progressive elongation of molecule bond length leads to negative infinity.
|-
| width="300" align="center" | '''Total Angle Bending Energy'''
! width="600" align="left" | Similar to Total Bond Stretching Energy, the total angle bending energy is also related to the vibration energy of the molecules about the equilibrium bond length. However, unlike EBS that measures the bond strength, EAB is associated with the stiffness of the molecules based on the Hookiean potential. Whenever bond angles deviate from the norm during vibration, this energy term increases as well.
|-
| width="300" align="center" | '''Total Stretch-Bending Energy'''
! width="600" align="left" | This energy term takes into account of the energy due to increase in bond length when bond angle between two atoms changes.
|-
| width="300" align="center" | '''Total Torsional Energy'''
! width="600" align="left" | Total torsional energy is the energy required for intermolecular rotation about the bonds. In molecule mechanics, however, this term is often used as a correction that must be added or subtracted to the total energy of the molecule to fit a quantum mechanical calculation about the dihedral angles of bonds.
|-
| width="300" align="center" | '''Total Out-Of-Plane Bending Energy'''
! width="600" align="left" | This energy term refers to the energy needed to deform the dihedral angle (zero degrees) of a planar group of atoms such as carbonyl or amide functional groups.
|-
| colspan="2" style="text-align: center;" | '''Non-Bonded Interactions'''
|-
| width="300" align="center" | '''Total Van der Waals Energy'''
! width="600" align="left" | The total Van der Waals energy term examines the intramolecular interactions such as repulsion or attraction between non-bonded atoms in the molecule. This term is crucial in determining the preferred conformation of the molecule.

MMFF94s employs the novel “Buffered-14-7”. The name is derived from a buffering constant and the 14th and 7th power dependencies of the repulsive and attractive energy in the equation.
|-
| width="300" align="center" | '''Total Electrostatic Energy'''
! width="600" align="left" | The total electrostatic energy functions take into account of the Coulombic potential and partial charge/dipole/atomic point charges interactions within the molecule.
|-

|}

 

== '''Part 2 : Conformational Analysis Using Molecular Mechanics''' ==
=== '''The Hydrogenation of Cyclopentadiene Dimer''' ===

==== '''Endo and exo adduct from the Dimerization of Cyclopentadiene''' ====
Cyclopentadiene will undergo dimerization by Diels-alder reaction to form either an endo or exo adduct.

[[File:XcwDimerization of CP.png|500px|center]]

==== '''Stereoselectivity of Dimerization of Cyclopentadiene''' ====
Although the exo adduct is thermodynamically more stable than the endo adduct, the endo adduct is form preferentially. Using the QST2 method, the transition state of the Diels Alder dimerization was found. It was discovered that due to the secondary orbital interactions in the endo transition state, the endo dimer is formed preferentially (the kinetic product). Hence, it is proven that the Diels Alder dimerization between two cyclopentadiene are kinetically controlled.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Transition State of Dimerization of Cyclopentadiene'''
| '''Imaginary Stretch Frequency (-881.25) of the Endo Transition State (click to animate)'''
| '''Secondary Orbital Interaction (Red overlapping orbitals)'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<uploadedFileContents>EndotsDCPD2.mol
</uploadedFileContents>
</jmolApplet></jmol>
| [[File:Xcwendotsimaginary.gif|300px|center]]
| [[File:XcwSecondary orbital interaction1.jpg|300px|center]]
|-
|}

 

==== '''Asynchronous Bond Formation of Dimerization of Cyclopentadiene''' ====

The initial study of the molecular orbitals of the transition states seemed a bit peculiar. Instead of getting a LUMO with symmetrical orbitals, the calculations showed a HOMO that is asymetric at the carbons where the new sigma bonds will be formed. Running an IRC further, it soon became clear that the asymmetry of the HOMO leads to an asychronous bond formation before leading to the product.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''IRC plot following the Endo Transition State '''
| '''IRC following the Endo Transition State (click to animate)'''
| '''Asymmetry of orbitals at the carbons where the new sigma bonds will be formed'''
|- align="center"
| [[File:XcwendotscyclopentadieneIRC.png|300px|center]]
| [[File:XcwendotsIRC.gif|300px|center]]
| [[File:XcwAsynchronous mo.jpg|300px|center]]
|-
|}

 

==== '''Comparison of Energies between the Endo and Exo adduct of Dicyclopentadiene''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Adduct of Dicyclopentadiene dimerization'''
| '''Exo Adduct of Dicyclopentadiene dimerization'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=19,atomno=1,atomno=2; color green;measure 19 1;measure 19 2;</script>
<uploadedFileContents>XcwEndodimer3.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>Exodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=7,atomno=17; color green;measure 17 7;</script>
<uploadedFileContents>XcwExodimer1.mol</uploadedFileContents>
</jmolApplet></jmol>
|-
|}

 

Using MMFF94s ab initio calculations, the energies for the exo dimer and the endo dimer are derived.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Exodimer'''
| '''55.374'''
| 3.543
| 30.772
| -2.041
| -2.728
| 0.015
| 12.800
| 13.014
|-
| '''Endodimer'''
| '''58.191'''
| 3.468
| 33.187
| -2.082
| -2.950
| 0.023
| 12.360
| 14.186
|-
|}

 

The MMFF94s steric energy (after minimization) for the exo dimer is lower than that of the endo dimer. This is reflected by the large difference for the EEE between the endo dimer and the exo dimer due to unfavourable steric repulsion between the two “arched down” cyclopentene rings.

==== '''Hydrogenation of Dicyclopentadiene''' ====

Hydrogenation of the endo dicyclopentadiene (DCPD) would lead to two potential products: dihydro product 1 and dihydro product 2.

[[File:XcwFormation of Dihydro products.png|500px|center]]

Using MMFF94s, the energy of the two dihydro products are calculated.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Dihydro Product 1'''
| '''50.123'''
| 3.308
| 30.864
| -1.927
| 0.060
| 0.015(2)
| 13.281
| 5.121
|-
| '''Dihydro Product 2'''
| '''41.257'''
| 2.823
| 24.685
| -1.657
| -0.379
| 0.000(2)
| 10.639
| 5.147
|-
| '''Tetrahydro Product'''
| '''39.042'''
| 2.730
| 25.151
| -1.676
| 1.287
| 0.000
| 11.551
| 0.000
|}

 

From the MMFF94s calculation, it can be seen that dihydro product 2 has a lower steric energy than dihydro product 1. Therefore, dihydro product 2 is the thermodynamic product for the hydrogenation of dicylopentadiene. And indeed, this was what was observed by Skala et al.. He observed that the first hydrogenation occur at the norborene part of the molecule (rate of hydrogenation several times faster than that in the cyclopentene ring)6. The first heat of hydrogenation at the norborene is 138.8 kJ/mol while the second hydrogenation at the cyclopentene right is 109.5 kJ/mol6.

From the above results, it is also obvious that tetrahydro product is much more stable than either dihydro product. And yet, studies have shown that the tetrahydro product will only form after prolonged hydrogenation under high temperature. However, subjecting DCPD to high temperature leads to low yield due to cracking of DCPD.

Since thermodynamically it is predicted to form favourably, the fact that it does not could only mean that the hydrogenation of DCPD to tetrahydrodicyclopentadiene (TH-DCPD) is kinetically controlled. Most possibly, the transition state of the hydrogenation of DCPD is highly unstable hence it is unlikely to form.

=== '''Atropisomerism in an Intermediate related to the Synthesis of Taxol''' ===

Atropisomerism is a type of stereoisomerism that is form as a result of hindered rotation about a single bond.

[[File:XcwAtropisomerism example.png|500px|center]]

In the case of the 6,6’-dinitro-2,2’-diphenic acid, rotation about the bonds joining the two substituted phenyl rings would have to overcome large steric interaction between the bulky substituents. The barrier of rotation is high enough for the two conformers to be isolated individually.

In the synthesis of taxol, one of the key intermediates exhibit atropisomerism.

==== '''Atropisomerism in Taxol Synthesis''' ====

For the key intermediate, rotation about the carbon-carbon bonds would lead to two types of atropisomers, each with either the carbonyl group poining upwards or downwards in relative to the bridge.

[[File:XcwIntermediate 9 and Intermediate 10.png|500px|center]]

Once again by using MMFF94s ab initio calculations, the steric energies for the two intermediates are illustrated as below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 9'''
| '''70.571'''
| 7.743
| 28.356
| -0.062
| 0.004
| 0.949
| 33.293
| 0.288
|-
| '''Intermediate 10'''
| '''60.553'''
| 7.599
| 18.838
| -0.139
| 0.199
| 0.844
| 33.269
| -0.056
|-

|}

 

Analyzing the data above, the largest energy difference between Intermediate 9 and Intermediate 10 stems from the EAB which is related to the strain of the ring. Intermediate 9 has an excess of 9.518 kcal/mol EAB as compared to Intermediate 10. This comes as a surprise as intermediate 9 is predicted to be more stable alkene.

The rationale behind the prediction of the stability of intermediate 9 stems from the fact that the through-space distance of the upward-pointing carbonyl oxygen with the carbon-carbon is further than the through space distance between the downward-pointing carbonyl oxygen with the -CH2-CH2- fragment at the norbornene part in intermediate 10.

==== '''Hyperstable Olefins''' ====

Intermediate 9 and Intermediate 10 does not react readily with other reagents during functionalization. This is due to the hyperstability effect found in hyperstable olefins.

Hyperstable olefins are alkenes that contain less strain in the ring (i.e. negative olefin strain values) compared to the parent hydrocarbon. To study this further, further MMFF94s calculation was done to compare Intermediate 10 with the parent hydrocarbon.

[[File:XcwIntermediate10andPH.png|500px|center]]

The energies that we calculated are tabulated as shown below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 10'''
| '''44.878 '''
| 5.211
| 15.488
| -0.267
| -1.655
| 0.998
| 25.014
| 0.088
|-
| '''Parent Hydrocarbon'''
| '''50.564'''
| 4.692
| 21.979
| 0.109
| -0.958
| 0.247
| 24.495
| 0.000
|-

|}

 

Scrutinizing the results, the largest energy difference between intermediate 10 and the parent hydrocarbon stems from the Total Angle Bending Energy, EAB. Since the Total Angle bending energy is related to the angle strain in the molecules, it is apparent that the parent hydrocarbon has more ring strain as compared to the bridgehead olefin.

== '''Part 3 : Spectroscopic Simulation Using Quantum Mechanics''' ==
=== '''Spectroscopy of an Intermediate Related to the Synthesis of Taxol''' ===

Molecule 17 and 18 are derivatives of intermediate 9 and 10. In this exercise, MMFF94s is used to predict the 1H and 13C NMR of molecule 17 and molecule 18.

[[File:XcwIntermediate17&18.png|500px|center]]

==== '''NMR Spectra of Molecule 17''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 17.mol
</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwHNMRMolecule 17 Chair Overall NMR.png|500px|center]]
| [[File:XcwHNMRMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.1825
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| The first three results were fairly straight forward to be deduced and correlate wit experimental data.

The hydrogen atom that is geminally attached to the carbon of the double bonds is the most deshielded due to the ring current anisotropic effect of the ring current

The second most deshielded hydrogen atom is the hydrogen atom on the methyl group on the bridge. The hydrogen atom is pointing directly to the oxygen atom of the carbonyl functional group.

The peaks with an integration height of 4 is assigned to the hydrogen atoms in the 1,3-dithiolane ring fragment.

Subsequent analysis of the 1H NMR became very complicated very quickly for two reasons:

1. Gaussian calculations showed some atoms with an integration height of 3. Comparing their file atom number and checking their chemical environment, it is not possible to find any correlation between them.

2. Some of the peaks in the literature remains unresolved and are given as multiplets or grouped together.

|- align="center"
| 52
| 3.1775
| 1
| '''2.99'''
|- align="center"
| 53,52,50,51
| 3.0867
| 4
| '''3.40-3.10'''
|- align="center"
| 42,43,39
| 2.7445
| 3
| ''' '''
|- align="center"
| 49
| 2.6187
| 1
| ''' '''
|- align="center"
| 34
| 2.4371
| 1
| ''' '''
|- align="center"
| 35
| 2.3782
| 1
| ''' '''
|- align="center"
| 40,37,26
| 2.2730
| 3
| ''' '''
|- align="center"
| 30
| 2.1566
| 1
| ''' '''
|- align="center"
| 36
| 2.1033
| 1
| ''' '''
|- align="center"
| 32,28
| 2.0259
| 2
| ''' '''
|- align="center"
| 25
| 1.8535
| 2
| ''' '''
|- align="center"
| 38,46,27
| 1.5898
| 3
| '''1.25'''
|- align="center"
| 29
| 1.4557
| 1
| ''' '''
|- align="center"
| 31
| 1.0123
| 1
| ''' '''
|- align="center"
| 44,48,45
| 0.9087
| 3
| '''1.10'''
|- align="center"
| 47
| 0.8354
| 1
| ''' '''
|- align="center"
| 33
| 0.5790
| 1
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 17 Chair Overall NMR2.png|500px|center]]
| [[File:XcwMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 216.2725
| 1
| '''218.79'''
| rowspan="10" style="text-align:center;"| [[File:XcwMolecule 17 image for CNMR.jpg|600px|center]]
|- align="center"
| 13
| 144.8626
| 1
| '''144.63'''
|- align="center"
| 14
| 124.7193
| 1
| '''125.33'''
|- align="center"
| 3
| 91.3340
| 1
| '''72.88'''
|- align="center"
| 2
| 60.9568
| 1
| '''56.19'''
|- align="center"
| 1
| 57.0811
| 1
| '''52.52'''
|- align="center"
| 10
| 52.4663
| 1
| '''48.50'''
|- align="center"
| 16
| 51.4857
| 1
| '''46.80'''
|- align="center"
| 9
| 46.9196
| 1
| '''45.76'''
|- align="center"
| 23
| 43.8647
| 1
| '''39.80'''
|- align="center"
| 22
| 41.9450
| 1
| '''38.81'''
| Comments
|- align="center"
| 4
| 41.8724
| 1
| '''35.85'''
| rowspan="9" style="text-align:left;"| The carbon bonded to the oxygen atom is the most deshielded, as is shown in the predicted values and the experimental values. There is a deviation between the values. Quite possibly, this is due to the fact that in reality, the carbonyl functional group is pointing slightly towards the equatorial position rather than a lateral position relative to the ring (as is in the input for Gaussian calculation)

Most of the 1CNMR values that was predicted by Gaussian are all within an acceptable range of deviation. However, there is carbon 3 that has significant deviation between the predicted value and experimental value.

Carbon 3 is the carbon bonded to the two sulphurs in the 1,3-dithiolane ring fragment. Such a huge deviation would possibly mean that the conformer that was given as input to Gaussian differs from the literature.

The above NMR spectra was corrected with a level of theory B3LYP/6-31G(d,p) using TMS as reference and in chloroform.

|- align="center"
| 15
| 35.4348
| 1
| '''32.66'''
|- align="center"
| 11
| 31.1964
| 1
| '''28.79'''
|- align="center"
| 6
| 28.9432
| 1
| '''28.29'''
|- align="center"
| 7
| 28.3640
| 1
| '''26.88'''
|- align="center"
| 12
| 27.3767
| 1
| '''25.66'''
|- align="center"
| 17
| 26.3311
| 1
| '''23.86'''
|- align="center"
| 15
| 24.5483
| 1
| '''20.96'''
|- align="center"
| 18
| 19.7788
| 1
| '''18.71'''
|-
|}
 

==== '''NMR Spectra of Molecule 18''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 18 Boat for Image2.mol</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"-
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 18 Chair Overall NMR.png|500px|center]]
| [[File:Molecule 18 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.2832
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| ''' '''
|- align="center"
| 50
| 3.3175
| 1
| rowspan="4" style="text-align:centre;"| '''3.00-2.70'''
|- align="center"
| 52
| 3.2153
| 1
|- align="center"
| 51,53
| 3.1161
| 2
|- align="center"
| 34,43
| 2.8606
| 2
|- align="center"
| 38
| 2.4549
| 1
| ''' '''
|- align="center"
| 42
| 2.3968
| 1
| ''' '''
|- align="center"
| 25,29,26
| 2.2796
| 3
| ''' '''
|- align="center"
| 39
| 2.0844
| 1
| ''' '''
|- align="center"
| 40,36
| 1.9699
| 2
| ''' '''
|- align="center"
| 37,24
| 1.8519
| 2
| ''' '''
|- align="center"
| 31,27
| 1.6780
| 2
| ''' '''
|- align="center"
| 28
| 1.6175
| 1
| ''' '''
|- align="center"
| 46,49
| 1.4979
| 2
| ''' '''
|- align="center"
| 35
| 1.4150
| 1
| ''' '''
|- align="center"
| 32
| 1.3531
| 1
| ''' '''
|- align="center"
| 48
| 1.1606
| 1
| ''' '''
|- align="center"
| 33,30,47
| 1.0653
| 3
| '''1.03'''
|- align="center"
| 44,45
| 0.9643
| 2
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwMolecule 18 Boat Overall NMR.png|500px|center]]
| [[File:XcwMolecule 18 Boat zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 211.8325
| 1
| '''211.49'''
| rowspan="10" style="text-align:center;"| [[File:Molecule 18 Boat for 13 CNMR.jpg|600px|center]]
|- align="center"
| 13
| 148.6673
| 1
| '''148.72'''
|- align="center"
| 14
| 118.8373
| 1
| '''120.90'''
|- align="center"
| 3
| 89.0869
| 1
| '''74.61'''
|- align="center"
| 2
| 67.8886
| 1
| '''60.53'''
|- align="center"
| 1
| 56.1133
| 1
| '''51.30'''
|- align="center"
| 10
| 55.5998
| 1
| '''50.94'''
|- align="center"
| 16
| 50.1124
| 1
| '''45.53'''
|- align="center"
| 22
| 48.2030
| 1
| '''43.28'''
|- align="center"
| 23
| 44.2222
| 1
| '''40.82'''
|- align="center"
| 4
| 42.0354
| 1
| '''38.73'''
| Comments
|- align="center"
| 9
| 37.5865
| 1
| '''36.78'''
| rowspan="9" style="text-align:left;"| ''' '''
|- align="center"
| 6
| 35.3106
| 1
| '''35.47'''
|- align="center"
| 15
| 31.0459
| 1
| '''30.84'''
|- align="center"
| 7
| 28.8476
| 1
| '''30.00'''
|- align="center"
| 12
| 28.6623
| 1
| '''25.56'''
|- align="center"
| 17
| 25.7393
| 1
| '''25.35'''
|- align="center"
| 11
| 25.2603
| 1
| '''22.21'''
|- align="center"
| 18
| 23.3944
| 1
| '''21.39'''
|- align="center"
| 5
| 21.0478
| 1
| '''19.83'''
|-
|}
 

== '''Part 4 : Analysis of the Properties of the Synthesized Alkene Epoxides''' ==
=== '''The two catalytics systems''' ===

Assymmetric epoxidation of prochiral alkenes may lead to product with different stereochemical outcome as illustrated as below. To solve this problem, different types of asymmetric epoxidation catalyst have been synthesized. In this study, we shall be focusing on Shi asymmetric fructose catalyst as well as Jacobsen asymmetric catalyst.

[[File:Asymmetric catalyst.png|400px|center]]

==== ''' The Shi Asymmetric Fructose Catalyst''' ====

Molecule 21 is the stable precursor of molecule 22, the active catalyst. Molecule 21 can be converted to molecule 22 by using either persulfuric acid or potassium peroxymonosulphate.

[[File:Molecule 21 to 23.png|400px|center]]

The transition state of the Shi epoxidation was a subject of debate for a few moments. However, recent studies have led to the conclusion that the spiro transition state is more favored than the planar transition state. The spiro transition state is the transition that has its dioxirane perpendicularly bisecting the alkene double bond. This is thought to be more favourable due to interactions between the lone pairs of the oxygen with the LUMO of the alkene.

[[File:Spiro and planar ts.png|500px|center]]

==== ''' The Jacobsen Asymmetric Catalyst''' ====

Molecule 23 is the stable precursor of molecule 24, the active catalyst. Molecule 23 can be converted to molecule 24 by using sodium perchlorate.

[[File:Salen, 23 and 24.png|400px|center]]

Jacobsen catalyst is biphasic. The first phase involves the transfer of oxygen to molecule 23. Sodium perchlorate oxidizes Mn(III) to Mn(V).

In the second step, Jacobsen catalyst acts via a radical mechanism. It is thought to be so because epoxidation of trans-alkene by Jacobsen catalyst yield cis-alkene as well. A radical mechanism will lead to the lost of stereochemical information of the molecule.

=== ''' Crystal structure of the two catalyst''' ===

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 21'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 21 strucutre.png|600px|center]]'''
|-
| style="text-align:center;" width="150" | ''' Bond '''
| style="text-align:center;" width="150"| ''' Bond Lenghts (Angstrom)'''
| style="text-align:center;" | ''' Evaluation'''
|-
| style="text-align:center;"| ''' O1-C1 '''
| style="text-align:center;"| ''' 1.400'''
| rowspan="10" style="text-align:left;"| [[File:Molecule 21 2.png|300px|center]]

The normal bond length of an C-O bond is 1.430 angstrom.

The most interesting aspect here is O4 and O2. The lone pair of O4 is antiperplanar to the sigma* orbital of the carbonyl group while the lone pair of O2 is anti periplanar to the carbonyl pi* orbital. Donation of electron can occur because of the correct symmetry. Due to the mixing of the orbitals, the C2-O2 and C4-O4 has been conferred with a certain degree of double bond character.

However, due to the lone pair on oxygen being now donated to the carbonyl antibonding orbitals, the O2 and O4 is slightly “electron deficient” and electron density will be pulled away from O2 and O4. That would explain why the bond length increase for O2-C7 and O4-C10. Increase in bond length is an indicator of the weakening of the bond.
|-
| style="text-align:center;"|'''O1-C7'''
| style="text-align:center;"|'''1.413'''
|-
| style="text-align:center;"|'''O2-C7'''
| style="text-align:center;"|'''1.441'''
|-
| style="text-align:center;"|'''O2-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O4-C4'''
| style="text-align:center;"|'''1.396'''
|-
| style="text-align:center;"|'''O4-C10'''
| style="text-align:center;"|'''1.439'''
|-
| style="text-align:center;"|'''O5-C10'''
| style="text-align:center;"|'''1.409'''
|-
| style="text-align:center;"|'''O5-C5'''
| style="text-align:center;"|'''1.416'''
|-
| style="text-align:center;"|'''O6-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O6-C6'''
| style="text-align:center;"|'''1.420'''
|-
|}
 

=== ''' The calculated NMR properties of the product''' ===

=== ''' Assigning the absolute configuration of the product''' ===

=== ''' Analysis of the Transition State for Reactions''' ===
==== '''Predicting Enantiomeric Excess based on Transition State energies''' ====

One of the energy output from Gaussian calculation is the “sum of electronic and thermal free energies”. This is Gibbs Free Energy at 298.15K and 1 atm.

Using this term and invoking a variant of the Curtin-Hammett Principle, it is possible to calculate a predicted enantiomeric excess of one enantiomer over the other.

[[File:Ee and transition state energy.png|800px|center]]

Using the derivations from above and equation (4), we analyze the enantiomeric excess of beta-methyl styrene and the results are tabulated as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1343.022970'''
| width="100" | '''-1343.017942'''
| width="150" | '''-0.005028'''
| width="150" | '''4.88E-03'''
| width="150" | '''99.03'''
|- align="center"
| width="100" | '''-1343.019233'''
| width="100" | '''-1343.015603'''
| width="150" | '''-0.003630'''
| width="150" | '''2.14E-02'''
| width="150" | '''95.80'''
|- align="center"
| width="100" | '''-1343.029272'''
| width="100" | '''-1343.023766'''
| width="150" | '''-0.005506'''
| width="150" | '''2.94E-03'''
| width="150" | '''99.41'''
|- align="center"
| width="100" | '''-1343.032443'''
| width="100" | '''-1343.024742'''
| width="150" | '''-0.007701'''
| width="150" | '''2.88E-04'''
| width="150" | '''99.94'''
|-
|}

 

The above hartree units are converted to J/mol for calculation of K where 1 hartress = 4.3597E-18

Studying all the free energies of the (R,R) series and compare them with the (S,S) series, it comes as no surprise that (R,R) product is favoured over (S,S) product as (R,R) is more stable. Indeed, this corresponds with the literature value reporting 92% ee of (R,R) products over that of (S,S).

==== '''Analysis of the Transition State of Epoxidation''' ====
==== '''Shi Fructose Catalyst''' ====
For this section, I will be analyzing the the transition state of 1) styrene and 2) trans-stilbene with the Shi fructose catalyst.

===== '''(R) and (S)-styrene transition state''' =====
The transition state for the formation of (R)-styrene oxide and (S)-styrene oxide are given as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R)-styrene oxide'''
| width="150" | '''(S)-styrene oxide'''
|- align="center"
| width="150" | ''' Structure of Catalyst '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide R.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide S ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| [[File:Steric shi fructose R.png|450px|center]]
| [[File:Steric shi fructose S.png|450px|center]]
|-
|}

 

In the transition state for (R)-styrene, it was discovered that the Re face is reacting with the oxygen of the dioxirane. The phenyl ring is oriented endo with respect to the fructose catalyst. However, the (S)-styrene is reacting at the Si face and the phenyl ring is oriented exo relative to the catalyst.

The approach taken by (R)-styrene and (S)-styrene are restricted to only one due to steric interactions. Therefore, the epoxidation of both styrenes by the Shi catalyst will be stereospecific and retains all the stereochemical information of the reactant. However, whether or not (R)-styrene oxide or (S)-styrene oxide is form is dependent on the relative energies of the transition state. The more stable the transition state, the more likely the product of the transition state will be formed.

So in order to examine this, an example of transition state of both styrenes with Shi catalyst are obtained and analyzed.
 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1303.736813'''
| width="100" | '''-1303.727673'''
| width="150" | '''-0.00914'''
| width="150" | '''6.28E-05'''
| width="150" | '''99.99'''

|-
|}

 

From the above, we can see the predicted high enantiopurity of the reaction favoring the (R) product because of the lower energy of the transition states. To understand the reason, we have to turn to non-covalent interaction (NCI) analysis.

[[File:NCI shi fructose styrene.png|700px|center]]

To complement the NCI analysis, a QTAIM (Quantum Theory of Atoms in Molecules) analysis is conducted as well.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''(R)-styrene transition state'''
| width="200" | '''(S)-styrene transition state'''
|- align="center"
| width="100" | '''[[File:QTAIM R.png|400px|center]]'''
| width="100" | '''[[File:QTAIM S.png|400px|center]]'''
|- align="center"
| colspan="2" width="100" | '''Comments'''
|-
| colspan="2" width="100" | '''Unsurprisingly, QTAIM analysis has also shown that (R)-styrene/Shi catalyst has more interactions with one another. While (R)-styrene has 2 strong interactions, (S)-styrene has only one with the catalyst. Besides, the phenyl ring of (R)-styrene also confers additional positive interaction with the catalyst. QTAIM analysis has also show several interactions between the C=C geminal hydrogen of (R)-styrene intreacting with the oxygen atoms on the dioxacyclopentane ring'''
|-
|}

 

===== '''(R,R) and (S,S)-Stilbene transition state''' =====

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R,R)-Stilbene oxide'''
| width="150" | '''(S,S)-Stilbene oxide'''
|- align="center"
| width="150" | ''' Structure of Transition State '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Stilbene RR ts.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>SS stilbene oxide ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| colspan="2" | [[File:Shi fructose stilbene.png|700px|center]]

|-
|}

 

However, unlike styrene, trans-stilbene seems to approach perpendicularly to the dioxirane. This is proposed to be due to the steric interactions (marked in purple). Based on first inspection, it seems that (S,S)-Stilbene oxide has more steric interactions than (R,R)-Stilbene oxide. Although unsubstantial, it seems like my guess was correct. The (R,R)-stilbene/Shi catalyst transition state is lower in energy.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1534.687808'''
| width="100" | '''-1534.683440'''
| width="150" | '''0.004368'''
| width="150" | '''9.08E-3'''
| width="150" | '''98.20'''

|-
|}

 

NCI Analysis is also done for trans-stilbene

[[File:NCI stilbene.png|700px|center]]

==== '''Jacobsen Catalyst''' ====

For this section, cis-beta methyl styrene transition state will be analyzed.

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-3383.259559'''
| width="100" | '''-3383.251060'''
| width="150" | '''-0.008499'''
| width="150" | '''1.24E-04'''
| width="150" | '''99.98'''
|- align="center"
| width="100" | '''-3383.253442'''
| width="100" | '''-3383.250270'''
| width="150" | '''-0.003172'''
| width="150" | '''3.48E-02'''
| width="150" | '''93.27'''
|-
|}

 

As is obvious from here, the (S,R) transition state is more stable than the (R,S) transition state. Both transition states are exo with respect to the catalyst.

It is not immediately apparent just by looking at the molecule to determine which spatial groups have interactions with one another. Therefore, an NCI analysis is conducted again.

[[File:NCI Jacobsen.png|700px|center]]

Rep:Mod:Computationalreport1C

2013-11-21T19:13:08Z

Xc2611: /* Crystal structure of the two catalyst */

= '''Synthesis and Computational Lab: 1C''' =
== '''Part 1: Introduction to Molecular Mechanics''' ==
=== '''Introduction to MMFF94 and MMFF94s''' ===

With the improvement of computational data and computer processing power, the usage of molecular mechanics/dynamics forcefield has become very integrated in predicting properties of chemical molecules. A molecular mechanics/dynamics forcefield should be able to predict characteristics such as molecular geometries, conformational/stereoisomeric energies, vibrational frequencies etc. to a reasonable accuracy as compared to experimental-derived values.

Building on work from Kollman et al. s’ AMBER forcefield and Allinger et al. s’ MM1, MM2, MM3 and MM4, Merck Research Laboratories have managed to optimized and improved the previous computational algorithms and produced MMFF94 (Merck Molecular Force Field 94). One of the most prominent advantages of MMFF94 over other preceeding work is its enhanced prediction accuracy. The reason lies in the fact that MMFF94’s core parameterization utilizes an unprecedently large amount of computational data obtained from ab initio calculations1.

Subsequently after the development of MMFF94, a new “static” variant of the MMFF was introduced i.e. the MMFF94s. Unlike MMFF94 that was developed for the use of molecular dynamics simulations (which can be expensive), MMFF94s was developed with the purpose of energy minimization studies in mind. Although both systems provide identical results for most systems, they differ for amides and unsaturated amines which contain resonance-delocalized trigonal nitrogen atoms2.

In this computational exercise, MMFF94s is used predominantly as oppose to the alternative Universal Force Field (UFF). Although versatile across the entire periodic table, UFF is derived from simple rules and atomic parameters such as fixed hybridization that increases the likelihood of erroneous structural and energetic predictions3.

=== '''Forms of MMFF94s''' ===

Steric energy of a molecule is the energy arise due to its geometry or conformation. Energy minimization of steric energy process ensures that the molecule is in its lowest energy conformation.

MMFF94s assumes that the total steric energy of a molecule can be found by the sum of a few specific interactions in a molecule.

ES = EBS + EAB + E SB + ET + EOOP + EVdW + EEE

'''where the bonded interactions are:'''

ES = Total Steric energy

EBS = Total Bond Stretching energy

EAB = Total Angle Bending energy

ESB = Total Stretch Bending energy

ET = Total Torsional Energy

EOOP = Total Out-Of-Plane Bending energy, and

'''where the non-bonded interactions are:'''

EVdW = Total Van der Waals Energy

EEE = Total Electrostatic Energy

{| border="1" cellspacing="1" cellpadding="10"
|-
| width="300" align="center" | '''Types of Energies'''
! width="600" align="center" | '''Explanation'''
|-
| colspan="2" style="text-align: center;" | '''Bonded Interactions'''
|-
| width="300" align="center" | '''Total Bond Stretching Energy'''
! width="600" align="left" | The total bond stretching energy is related to the vibration energy of the molecules in comparison to the equilibrium bond length. Whenever a bond deviates from the equilibrium bond length, the energy value increases.

MMFF94s uses a quartic function that has the force constant term (relate to bond strength). The quartic function term is superior to the cubic function term (used in MM2) in the sense that it avoid the “cubic stretch catastrophe” where progressive elongation of molecule bond length leads to negative infinity.
|-
| width="300" align="center" | '''Total Angle Bending Energy'''
! width="600" align="left" | Similar to Total Bond Stretching Energy, the total angle bending energy is also related to the vibration energy of the molecules about the equilibrium bond length. However, unlike EBS that measures the bond strength, EAB is associated with the stiffness of the molecules based on the Hookiean potential. Whenever bond angles deviate from the norm during vibration, this energy term increases as well.
|-
| width="300" align="center" | '''Total Stretch-Bending Energy'''
! width="600" align="left" | This energy term takes into account of the energy due to increase in bond length when bond angle between two atoms changes.
|-
| width="300" align="center" | '''Total Torsional Energy'''
! width="600" align="left" | Total torsional energy is the energy required for intermolecular rotation about the bonds. In molecule mechanics, however, this term is often used as a correction that must be added or subtracted to the total energy of the molecule to fit a quantum mechanical calculation about the dihedral angles of bonds.
|-
| width="300" align="center" | '''Total Out-Of-Plane Bending Energy'''
! width="600" align="left" | This energy term refers to the energy needed to deform the dihedral angle (zero degrees) of a planar group of atoms such as carbonyl or amide functional groups.
|-
| colspan="2" style="text-align: center;" | '''Non-Bonded Interactions'''
|-
| width="300" align="center" | '''Total Van der Waals Energy'''
! width="600" align="left" | The total Van der Waals energy term examines the intramolecular interactions such as repulsion or attraction between non-bonded atoms in the molecule. This term is crucial in determining the preferred conformation of the molecule.

MMFF94s employs the novel “Buffered-14-7”. The name is derived from a buffering constant and the 14th and 7th power dependencies of the repulsive and attractive energy in the equation.
|-
| width="300" align="center" | '''Total Electrostatic Energy'''
! width="600" align="left" | The total electrostatic energy functions take into account of the Coulombic potential and partial charge/dipole/atomic point charges interactions within the molecule.
|-

|}

 

== '''Part 2 : Conformational Analysis Using Molecular Mechanics''' ==
=== '''The Hydrogenation of Cyclopentadiene Dimer''' ===

==== '''Endo and exo adduct from the Dimerization of Cyclopentadiene''' ====
Cyclopentadiene will undergo dimerization by Diels-alder reaction to form either an endo or exo adduct.

[[File:XcwDimerization of CP.png|500px|center]]

==== '''Stereoselectivity of Dimerization of Cyclopentadiene''' ====
Although the exo adduct is thermodynamically more stable than the endo adduct, the endo adduct is form preferentially. Using the QST2 method, the transition state of the Diels Alder dimerization was found. It was discovered that due to the secondary orbital interactions in the endo transition state, the endo dimer is formed preferentially (the kinetic product). Hence, it is proven that the Diels Alder dimerization between two cyclopentadiene are kinetically controlled.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Transition State of Dimerization of Cyclopentadiene'''
| '''Imaginary Stretch Frequency (-881.25) of the Endo Transition State (click to animate)'''
| '''Secondary Orbital Interaction (Red overlapping orbitals)'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<uploadedFileContents>EndotsDCPD2.mol
</uploadedFileContents>
</jmolApplet></jmol>
| [[File:Xcwendotsimaginary.gif|300px|center]]
| [[File:XcwSecondary orbital interaction1.jpg|300px|center]]
|-
|}

 

==== '''Asynchronous Bond Formation of Dimerization of Cyclopentadiene''' ====

The initial study of the molecular orbitals of the transition states seemed a bit peculiar. Instead of getting a LUMO with symmetrical orbitals, the calculations showed a HOMO that is asymetric at the carbons where the new sigma bonds will be formed. Running an IRC further, it soon became clear that the asymmetry of the HOMO leads to an asychronous bond formation before leading to the product.

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''IRC plot following the Endo Transition State '''
| '''IRC following the Endo Transition State (click to animate)'''
| '''Asymmetry of orbitals at the carbons where the new sigma bonds will be formed'''
|- align="center"
| [[File:XcwendotscyclopentadieneIRC.png|300px|center]]
| [[File:XcwendotsIRC.gif|300px|center]]
| [[File:XcwAsynchronous mo.jpg|300px|center]]
|-
|}

 

==== '''Comparison of Energies between the Endo and Exo adduct of Dicyclopentadiene''' ====
 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''Endo Adduct of Dicyclopentadiene dimerization'''
| '''Exo Adduct of Dicyclopentadiene dimerization'''
|- align="center"
| <jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=19,atomno=1,atomno=2; color green;measure 19 1;measure 19 2;</script>
<uploadedFileContents>XcwEndodimer3.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>Exodimer</title>
<color>white</color>
<size>300</size>
<script>select atomno=7,atomno=17; color green;measure 17 7;</script>
<uploadedFileContents>XcwExodimer1.mol</uploadedFileContents>
</jmolApplet></jmol>
|-
|}

 

Using MMFF94s ab initio calculations, the energies for the exo dimer and the endo dimer are derived.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Exodimer'''
| '''55.374'''
| 3.543
| 30.772
| -2.041
| -2.728
| 0.015
| 12.800
| 13.014
|-
| '''Endodimer'''
| '''58.191'''
| 3.468
| 33.187
| -2.082
| -2.950
| 0.023
| 12.360
| 14.186
|-
|}

 

The MMFF94s steric energy (after minimization) for the exo dimer is lower than that of the endo dimer. This is reflected by the large difference for the EEE between the endo dimer and the exo dimer due to unfavourable steric repulsion between the two “arched down” cyclopentene rings.

==== '''Hydrogenation of Dicyclopentadiene''' ====

Hydrogenation of the endo dicyclopentadiene (DCPD) would lead to two potential products: dihydro product 1 and dihydro product 2.

[[File:XcwFormation of Dihydro products.png|500px|center]]

Using MMFF94s, the energy of the two dihydro products are calculated.

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Dihydro Product 1'''
| '''50.123'''
| 3.308
| 30.864
| -1.927
| 0.060
| 0.015(2)
| 13.281
| 5.121
|-
| '''Dihydro Product 2'''
| '''41.257'''
| 2.823
| 24.685
| -1.657
| -0.379
| 0.000(2)
| 10.639
| 5.147
|-
| '''Tetrahydro Product'''
| '''39.042'''
| 2.730
| 25.151
| -1.676
| 1.287
| 0.000
| 11.551
| 0.000
|}

 

From the MMFF94s calculation, it can be seen that dihydro product 2 has a lower steric energy than dihydro product 1. Therefore, dihydro product 2 is the thermodynamic product for the hydrogenation of dicylopentadiene. And indeed, this was what was observed by Skala et al.. He observed that the first hydrogenation occur at the norborene part of the molecule (rate of hydrogenation several times faster than that in the cyclopentene ring)6. The first heat of hydrogenation at the norborene is 138.8 kJ/mol while the second hydrogenation at the cyclopentene right is 109.5 kJ/mol6.

From the above results, it is also obvious that tetrahydro product is much more stable than either dihydro product. And yet, studies have shown that the tetrahydro product will only form after prolonged hydrogenation under high temperature. However, subjecting DCPD to high temperature leads to low yield due to cracking of DCPD.

Since thermodynamically it is predicted to form favourably, the fact that it does not could only mean that the hydrogenation of DCPD to tetrahydrodicyclopentadiene (TH-DCPD) is kinetically controlled. Most possibly, the transition state of the hydrogenation of DCPD is highly unstable hence it is unlikely to form.

=== '''Atropisomerism in an Intermediate related to the Synthesis of Taxol''' ===

Atropisomerism is a type of stereoisomerism that is form as a result of hindered rotation about a single bond.

[[File:XcwAtropisomerism example.png|500px|center]]

In the case of the 6,6’-dinitro-2,2’-diphenic acid, rotation about the bonds joining the two substituted phenyl rings would have to overcome large steric interaction between the bulky substituents. The barrier of rotation is high enough for the two conformers to be isolated individually.

In the synthesis of taxol, one of the key intermediates exhibit atropisomerism.

==== '''Atropisomerism in Taxol Synthesis''' ====

For the key intermediate, rotation about the carbon-carbon bonds would lead to two types of atropisomers, each with either the carbonyl group poining upwards or downwards in relative to the bridge.

[[File:XcwIntermediate 9 and Intermediate 10.png|500px|center]]

Once again by using MMFF94s ab initio calculations, the steric energies for the two intermediates are illustrated as below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 9'''
| '''70.571'''
| 7.743
| 28.356
| -0.062
| 0.004
| 0.949
| 33.293
| 0.288
|-
| '''Intermediate 10'''
| '''60.553'''
| 7.599
| 18.838
| -0.139
| 0.199
| 0.844
| 33.269
| -0.056
|-

|}

 

Analyzing the data above, the largest energy difference between Intermediate 9 and Intermediate 10 stems from the EAB which is related to the strain of the ring. Intermediate 9 has an excess of 9.518 kcal/mol EAB as compared to Intermediate 10. This comes as a surprise as intermediate 9 is predicted to be more stable alkene.

The rationale behind the prediction of the stability of intermediate 9 stems from the fact that the through-space distance of the upward-pointing carbonyl oxygen with the carbon-carbon is further than the through space distance between the downward-pointing carbonyl oxygen with the -CH2-CH2- fragment at the norbornene part in intermediate 10.

==== '''Hyperstable Olefins''' ====

Intermediate 9 and Intermediate 10 does not react readily with other reagents during functionalization. This is due to the hyperstability effect found in hyperstable olefins.

Hyperstable olefins are alkenes that contain less strain in the ring (i.e. negative olefin strain values) compared to the parent hydrocarbon. To study this further, further MMFF94s calculation was done to compare Intermediate 10 with the parent hydrocarbon.

[[File:XcwIntermediate10andPH.png|500px|center]]

The energies that we calculated are tabulated as shown below:

{| border="1" cellspacing="1" cellpadding="10"
|-
| rowspan="2" style="text-align:center;"|''' '''
| colspan="8" style="text-align:center;"|'''Energies'''
|- align="center"
| '''ES'''
| '''EBS'''
| '''EAB'''
| '''ESB'''
| '''ET'''
| '''EOOP'''
| '''EVdW'''
| '''EEE'''
|-
| '''Intermediate 10'''
| '''44.878 '''
| 5.211
| 15.488
| -0.267
| -1.655
| 0.998
| 25.014
| 0.088
|-
| '''Parent Hydrocarbon'''
| '''50.564'''
| 4.692
| 21.979
| 0.109
| -0.958
| 0.247
| 24.495
| 0.000
|-

|}

 

Scrutinizing the results, the largest energy difference between intermediate 10 and the parent hydrocarbon stems from the Total Angle Bending Energy, EAB. Since the Total Angle bending energy is related to the angle strain in the molecules, it is apparent that the parent hydrocarbon has more ring strain as compared to the bridgehead olefin.

== '''Part 3 : Spectroscopic Simulation Using Quantum Mechanics''' ==
=== '''Spectroscopy of an Intermediate Related to the Synthesis of Taxol''' ===

Molecule 17 and 18 are derivatives of intermediate 9 and 10. In this exercise, MMFF94s is used to predict the 1H and 13C NMR of molecule 17 and molecule 18.

[[File:XcwIntermediate17&18.png|500px|center]]

==== '''NMR Spectra of Molecule 17''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 17.mol
</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwHNMRMolecule 17 Chair Overall NMR.png|500px|center]]
| [[File:XcwHNMRMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.1825
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| The first three results were fairly straight forward to be deduced and correlate wit experimental data.

The hydrogen atom that is geminally attached to the carbon of the double bonds is the most deshielded due to the ring current anisotropic effect of the ring current

The second most deshielded hydrogen atom is the hydrogen atom on the methyl group on the bridge. The hydrogen atom is pointing directly to the oxygen atom of the carbonyl functional group.

The peaks with an integration height of 4 is assigned to the hydrogen atoms in the 1,3-dithiolane ring fragment.

Subsequent analysis of the 1H NMR became very complicated very quickly for two reasons:

1. Gaussian calculations showed some atoms with an integration height of 3. Comparing their file atom number and checking their chemical environment, it is not possible to find any correlation between them.

2. Some of the peaks in the literature remains unresolved and are given as multiplets or grouped together.

|- align="center"
| 52
| 3.1775
| 1
| '''2.99'''
|- align="center"
| 53,52,50,51
| 3.0867
| 4
| '''3.40-3.10'''
|- align="center"
| 42,43,39
| 2.7445
| 3
| ''' '''
|- align="center"
| 49
| 2.6187
| 1
| ''' '''
|- align="center"
| 34
| 2.4371
| 1
| ''' '''
|- align="center"
| 35
| 2.3782
| 1
| ''' '''
|- align="center"
| 40,37,26
| 2.2730
| 3
| ''' '''
|- align="center"
| 30
| 2.1566
| 1
| ''' '''
|- align="center"
| 36
| 2.1033
| 1
| ''' '''
|- align="center"
| 32,28
| 2.0259
| 2
| ''' '''
|- align="center"
| 25
| 1.8535
| 2
| ''' '''
|- align="center"
| 38,46,27
| 1.5898
| 3
| '''1.25'''
|- align="center"
| 29
| 1.4557
| 1
| ''' '''
|- align="center"
| 31
| 1.0123
| 1
| ''' '''
|- align="center"
| 44,48,45
| 0.9087
| 3
| '''1.10'''
|- align="center"
| 47
| 0.8354
| 1
| ''' '''
|- align="center"
| 33
| 0.5790
| 1
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 17''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 17 Chair Overall NMR2.png|500px|center]]
| [[File:XcwMolecule 17 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 216.2725
| 1
| '''218.79'''
| rowspan="10" style="text-align:center;"| [[File:XcwMolecule 17 image for CNMR.jpg|600px|center]]
|- align="center"
| 13
| 144.8626
| 1
| '''144.63'''
|- align="center"
| 14
| 124.7193
| 1
| '''125.33'''
|- align="center"
| 3
| 91.3340
| 1
| '''72.88'''
|- align="center"
| 2
| 60.9568
| 1
| '''56.19'''
|- align="center"
| 1
| 57.0811
| 1
| '''52.52'''
|- align="center"
| 10
| 52.4663
| 1
| '''48.50'''
|- align="center"
| 16
| 51.4857
| 1
| '''46.80'''
|- align="center"
| 9
| 46.9196
| 1
| '''45.76'''
|- align="center"
| 23
| 43.8647
| 1
| '''39.80'''
|- align="center"
| 22
| 41.9450
| 1
| '''38.81'''
| Comments
|- align="center"
| 4
| 41.8724
| 1
| '''35.85'''
| rowspan="9" style="text-align:left;"| The carbon bonded to the oxygen atom is the most deshielded, as is shown in the predicted values and the experimental values. There is a deviation between the values. Quite possibly, this is due to the fact that in reality, the carbonyl functional group is pointing slightly towards the equatorial position rather than a lateral position relative to the ring (as is in the input for Gaussian calculation)

Most of the 1CNMR values that was predicted by Gaussian are all within an acceptable range of deviation. However, there is carbon 3 that has significant deviation between the predicted value and experimental value.

Carbon 3 is the carbon bonded to the two sulphurs in the 1,3-dithiolane ring fragment. Such a huge deviation would possibly mean that the conformer that was given as input to Gaussian differs from the literature.

The above NMR spectra was corrected with a level of theory B3LYP/6-31G(d,p) using TMS as reference and in chloroform.

|- align="center"
| 15
| 35.4348
| 1
| '''32.66'''
|- align="center"
| 11
| 31.1964
| 1
| '''28.79'''
|- align="center"
| 6
| 28.9432
| 1
| '''28.29'''
|- align="center"
| 7
| 28.3640
| 1
| '''26.88'''
|- align="center"
| 12
| 27.3767
| 1
| '''25.66'''
|- align="center"
| 17
| 26.3311
| 1
| '''23.86'''
|- align="center"
| 15
| 24.5483
| 1
| '''20.96'''
|- align="center"
| 18
| 19.7788
| 1
| '''18.71'''
|-
|}
 

==== '''NMR Spectra of Molecule 18''' ====

<jmol><jmolApplet>
<title>Endodimer</title>
<color>white</color>
<size>500</size>
<uploadedFileContents>XcwMolecule 18 Boat for Image2.mol</uploadedFileContents>
</jmolApplet></jmol>

===== '''1H NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"-
| '''1H NMR Spectra of Molecule 17 Full Spectra'''
| '''1H NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:Molecule 18 Chair Overall NMR.png|500px|center]]
| [[File:Molecule 18 Chair zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' H-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature values'''
| style="text-align:center;"|''' Comments'''
|- align="center"
| 41
| 5.2832
| 1
| '''5.21'''
| rowspan="19" style="text-align:left;"| ''' '''
|- align="center"
| 50
| 3.3175
| 1
| rowspan="4" style="text-align:centre;"| '''3.00-2.70'''
|- align="center"
| 52
| 3.2153
| 1
|- align="center"
| 51,53
| 3.1161
| 2
|- align="center"
| 34,43
| 2.8606
| 2
|- align="center"
| 38
| 2.4549
| 1
| ''' '''
|- align="center"
| 42
| 2.3968
| 1
| ''' '''
|- align="center"
| 25,29,26
| 2.2796
| 3
| ''' '''
|- align="center"
| 39
| 2.0844
| 1
| ''' '''
|- align="center"
| 40,36
| 1.9699
| 2
| ''' '''
|- align="center"
| 37,24
| 1.8519
| 2
| ''' '''
|- align="center"
| 31,27
| 1.6780
| 2
| ''' '''
|- align="center"
| 28
| 1.6175
| 1
| ''' '''
|- align="center"
| 46,49
| 1.4979
| 2
| ''' '''
|- align="center"
| 35
| 1.4150
| 1
| ''' '''
|- align="center"
| 32
| 1.3531
| 1
| ''' '''
|- align="center"
| 48
| 1.1606
| 1
| ''' '''
|- align="center"
| 33,30,47
| 1.0653
| 3
| '''1.03'''
|- align="center"
| 44,45
| 0.9643
| 2
| ''' '''
|-
|}

 

===== '''13C NMR Spectra of Molecule 18''' =====

 

{| border="1" cellspacing="1" cellpadding="10"
|- align="center"
| '''13C NMR Spectra of Molecule 17 Full Spectra'''
| '''13C NMR Spectra of Molecule 17 Truncated Spectra'''
|- align="center"
| [[File:XcwMolecule 18 Boat Overall NMR.png|500px|center]]
| [[File:XcwMolecule 18 Boat zoomin NMR.png|500px|center]]
|-
|}

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| style="text-align:center;"|''' C-Atoms '''
| style="text-align:center;"|''' Chemical Shift (ppm)'''
| style="text-align:center;"|''' Integration Height/Degeneracy'''
| style="text-align:center;"|''' Literature Values'''
| style="text-align:center;"|''' Image of carbon skeleton'''
|- align="center"
| 8
| 211.8325
| 1
| '''211.49'''
| rowspan="10" style="text-align:center;"| [[File:Molecule 18 Boat for 13 CNMR.jpg|600px|center]]
|- align="center"
| 13
| 148.6673
| 1
| '''148.72'''
|- align="center"
| 14
| 118.8373
| 1
| '''120.90'''
|- align="center"
| 3
| 89.0869
| 1
| '''74.61'''
|- align="center"
| 2
| 67.8886
| 1
| '''60.53'''
|- align="center"
| 1
| 56.1133
| 1
| '''51.30'''
|- align="center"
| 10
| 55.5998
| 1
| '''50.94'''
|- align="center"
| 16
| 50.1124
| 1
| '''45.53'''
|- align="center"
| 22
| 48.2030
| 1
| '''43.28'''
|- align="center"
| 23
| 44.2222
| 1
| '''40.82'''
|- align="center"
| 4
| 42.0354
| 1
| '''38.73'''
| Comments
|- align="center"
| 9
| 37.5865
| 1
| '''36.78'''
| rowspan="9" style="text-align:left;"| ''' '''
|- align="center"
| 6
| 35.3106
| 1
| '''35.47'''
|- align="center"
| 15
| 31.0459
| 1
| '''30.84'''
|- align="center"
| 7
| 28.8476
| 1
| '''30.00'''
|- align="center"
| 12
| 28.6623
| 1
| '''25.56'''
|- align="center"
| 17
| 25.7393
| 1
| '''25.35'''
|- align="center"
| 11
| 25.2603
| 1
| '''22.21'''
|- align="center"
| 18
| 23.3944
| 1
| '''21.39'''
|- align="center"
| 5
| 21.0478
| 1
| '''19.83'''
|-
|}
 

== '''Part 4 : Analysis of the Properties of the Synthesized Alkene Epoxides''' ==
=== '''The two catalytics systems''' ===

Assymmetric epoxidation of prochiral alkenes may lead to product with different stereochemical outcome as illustrated as below. To solve this problem, different types of asymmetric epoxidation catalyst have been synthesized. In this study, we shall be focusing on Shi asymmetric fructose catalyst as well as Jacobsen asymmetric catalyst.

[[File:Asymmetric catalyst.png|400px|center]]

==== ''' The Shi Asymmetric Fructose Catalyst''' ====

Molecule 21 is the stable precursor of molecule 22, the active catalyst. Molecule 21 can be converted to molecule 22 by using either persulfuric acid or potassium peroxymonosulphate.

[[File:Molecule 21 to 23.png|400px|center]]

The transition state of the Shi epoxidation was a subject of debate for a few moments. However, recent studies have led to the conclusion that the spiro transition state is more favored than the planar transition state. The spiro transition state is the transition that has its dioxirane perpendicularly bisecting the alkene double bond. This is thought to be more favourable due to interactions between the lone pairs of the oxygen with the LUMO of the alkene.

[[File:Spiro and planar ts.png|500px|center]]

==== ''' The Jacobsen Asymmetric Catalyst''' ====

Molecule 23 is the stable precursor of molecule 24, the active catalyst. Molecule 23 can be converted to molecule 24 by using sodium perchlorate.

[[File:Salen, 23 and 24.png|400px|center]]

Jacobsen catalyst is biphasic. The first phase involves the transfer of oxygen to molecule 23. Sodium perchlorate oxidizes Mn(III) to Mn(V).

In the second step, Jacobsen catalyst acts via a radical mechanism. It is thought to be so because epoxidation of trans-alkene by Jacobsen catalyst yield cis-alkene as well. A radical mechanism will lead to the lost of stereochemical information of the molecule.

=== ''' Crystal structure of the two catalyst''' ===

 

{| border="1" cellspacing="1" cellpadding="10"
|-
| colspan="13" style="text-align:center;"| '''Analysis of Crystal Structure of Molecule 21'''
|-
| colspan="13" style="text-align:center;"| '''[[File:Molecule 21 strucutre.png|600px|center]]'''
|-
| style="text-align:center;" width="150" | ''' Bond '''
| style="text-align:center;" width="150"| ''' Bond Lenghts (Angstrom)'''
| style="text-align:center;" | ''' Evaluation'''
|-
| style="text-align:center;"| ''' O1-C1 '''
| style="text-align:center;"| ''' 1.400'''
| rowspan="10" style="text-align:left;"| [[File:Molecule 21 2.png|400px|center]]

The normal bond length of an C-O bond is 1.430 angstrom.

The most interesting aspect here is O4 and O2. The lone pair of O4 is antiperplanar to the sigma* orbital of the carbonyl group while the lone pair of O2 is anti periplanar to the carbonyl pi* orbital. Donation of electron can occur because of the correct symmetry. Due to the mixing of the orbitals, the C2-O2 and C4-O4 has been conferred with a certain degree of double bond character.

However, due to the lone pair on oxygen being now donated to the carbonyl antibonding orbitals, the O2 and O4 is slightly “electron deficient” and electron density will be pulled away from O2 and O4. That would explain why the bond length increase for O2-C7 and O4-C10. Increase in bond length is an indicator of the weakening of the bond.
|-
| style="text-align:center;"|'''O1-C7'''
| style="text-align:center;"|'''1.413'''
|-
| style="text-align:center;"|'''O2-C7'''
| style="text-align:center;"|'''1.441'''
|-
| style="text-align:center;"|'''O2-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O4-C4'''
| style="text-align:center;"|'''1.396'''
|-
| style="text-align:center;"|'''O4-C10'''
| style="text-align:center;"|'''1.439'''
|-
| style="text-align:center;"|'''O5-C10'''
| style="text-align:center;"|'''1.409'''
|-
| style="text-align:center;"|'''O5-C5'''
| style="text-align:center;"|'''1.416'''
|-
| style="text-align:center;"|'''O6-C2'''
| style="text-align:center;"|'''1.403'''
|-
| style="text-align:center;"|'''O6-C6'''
| style="text-align:center;"|'''1.420'''
|-
|}
 

=== ''' The calculated NMR properties of the product''' ===

=== ''' Assigning the absolute configuration of the product''' ===

=== ''' Analysis of the Transition State for Reactions''' ===
==== '''Predicting Enantiomeric Excess based on Transition State energies''' ====

One of the energy output from Gaussian calculation is the “sum of electronic and thermal free energies”. This is Gibbs Free Energy at 298.15K and 1 atm.

Using this term and invoking a variant of the Curtin-Hammett Principle, it is possible to calculate a predicted enantiomeric excess of one enantiomer over the other.

[[File:Ee and transition state energy.png|800px|center]]

Using the derivations from above and equation (4), we analyze the enantiomeric excess of beta-methyl styrene and the results are tabulated as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1343.022970'''
| width="100" | '''-1343.017942'''
| width="150" | '''-0.005028'''
| width="150" | '''4.88E-03'''
| width="150" | '''99.03'''
|- align="center"
| width="100" | '''-1343.019233'''
| width="100" | '''-1343.015603'''
| width="150" | '''-0.003630'''
| width="150" | '''2.14E-02'''
| width="150" | '''95.80'''
|- align="center"
| width="100" | '''-1343.029272'''
| width="100" | '''-1343.023766'''
| width="150" | '''-0.005506'''
| width="150" | '''2.94E-03'''
| width="150" | '''99.41'''
|- align="center"
| width="100" | '''-1343.032443'''
| width="100" | '''-1343.024742'''
| width="150" | '''-0.007701'''
| width="150" | '''2.88E-04'''
| width="150" | '''99.94'''
|-
|}

 

The above hartree units are converted to J/mol for calculation of K where 1 hartress = 4.3597E-18

Studying all the free energies of the (R,R) series and compare them with the (S,S) series, it comes as no surprise that (R,R) product is favoured over (S,S) product as (R,R) is more stable. Indeed, this corresponds with the literature value reporting 92% ee of (R,R) products over that of (S,S).

==== '''Analysis of the Transition State of Epoxidation''' ====
==== '''Shi Fructose Catalyst''' ====
For this section, I will be analyzing the the transition state of 1) styrene and 2) trans-stilbene with the Shi fructose catalyst.

===== '''(R) and (S)-styrene transition state''' =====
The transition state for the formation of (R)-styrene oxide and (S)-styrene oxide are given as below:

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R)-styrene oxide'''
| width="150" | '''(S)-styrene oxide'''
|- align="center"
| width="150" | ''' Structure of Catalyst '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide R.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Styrene oxide S ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| [[File:Steric shi fructose R.png|450px|center]]
| [[File:Steric shi fructose S.png|450px|center]]
|-
|}

 

In the transition state for (R)-styrene, it was discovered that the Re face is reacting with the oxygen of the dioxirane. The phenyl ring is oriented endo with respect to the fructose catalyst. However, the (S)-styrene is reacting at the Si face and the phenyl ring is oriented exo relative to the catalyst.

The approach taken by (R)-styrene and (S)-styrene are restricted to only one due to steric interactions. Therefore, the epoxidation of both styrenes by the Shi catalyst will be stereospecific and retains all the stereochemical information of the reactant. However, whether or not (R)-styrene oxide or (S)-styrene oxide is form is dependent on the relative energies of the transition state. The more stable the transition state, the more likely the product of the transition state will be formed.

So in order to examine this, an example of transition state of both styrenes with Shi catalyst are obtained and analyzed.
 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1303.736813'''
| width="100" | '''-1303.727673'''
| width="150" | '''-0.00914'''
| width="150" | '''6.28E-05'''
| width="150" | '''99.99'''

|-
|}

 

From the above, we can see the predicted high enantiopurity of the reaction favoring the (R) product because of the lower energy of the transition states. To understand the reason, we have to turn to non-covalent interaction (NCI) analysis.

[[File:NCI shi fructose styrene.png|700px|center]]

To complement the NCI analysis, a QTAIM (Quantum Theory of Atoms in Molecules) analysis is conducted as well.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''(R)-styrene transition state'''
| width="200" | '''(S)-styrene transition state'''
|- align="center"
| width="100" | '''[[File:QTAIM R.png|400px|center]]'''
| width="100" | '''[[File:QTAIM S.png|400px|center]]'''
|- align="center"
| colspan="2" width="100" | '''Comments'''
|-
| colspan="2" width="100" | '''Unsurprisingly, QTAIM analysis has also shown that (R)-styrene/Shi catalyst has more interactions with one another. While (R)-styrene has 2 strong interactions, (S)-styrene has only one with the catalyst. Besides, the phenyl ring of (R)-styrene also confers additional positive interaction with the catalyst. QTAIM analysis has also show several interactions between the C=C geminal hydrogen of (R)-styrene intreacting with the oxygen atoms on the dioxacyclopentane ring'''
|-
|}

 

===== '''(R,R) and (S,S)-Stilbene transition state''' =====

 

{| border="1" cellpadding="5"
|- align="center"
| width="150" | ''' '''
| width="150" | '''(R,R)-Stilbene oxide'''
| width="150" | '''(S,S)-Stilbene oxide'''
|- align="center"
| width="150" | ''' Structure of Transition State '''
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>Stilbene RR ts.mol</uploadedFileContents>
</jmolApplet></jmol>
| <jmol><jmolApplet>
<title>test molecule</title>
<color>white</color>
<size>400</size>
<uploadedFileContents>SS stilbene oxide ts.mol</uploadedFileContents>
</jmolApplet></jmol>
|- align="center"
| width="150" | ''' Approach of ligand '''
| colspan="2" | [[File:Shi fructose stilbene.png|700px|center]]

|-
|}

 

However, unlike styrene, trans-stilbene seems to approach perpendicularly to the dioxirane. This is proposed to be due to the steric interactions (marked in purple). Based on first inspection, it seems that (S,S)-Stilbene oxide has more steric interactions than (R,R)-Stilbene oxide. Although unsubstantial, it seems like my guess was correct. The (R,R)-stilbene/Shi catalyst transition state is lower in energy.

 

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-1534.687808'''
| width="100" | '''-1534.683440'''
| width="150" | '''0.004368'''
| width="150" | '''9.08E-3'''
| width="150" | '''98.20'''

|-
|}

 

NCI Analysis is also done for trans-stilbene

[[File:NCI stilbene.png|700px|center]]

==== '''Jacobsen Catalyst''' ====

For this section, cis-beta methyl styrene transition state will be analyzed.

{| border="1" cellpadding="5"
|- align="center"
| width="200" | '''Free Energy of (R,R) transition state'''
| width="200" | '''Free Energy of (S,S) transition state'''
| width="300" | '''Difference in free energies (Hartrees)'''
| width="100" | '''K'''
| width="150" | '''Enantiomeric Excess (%)'''
|- align="center"
| width="100" | '''-3383.259559'''
| width="100" | '''-3383.251060'''
| width="150" | '''-0.008499'''
| width="150" | '''1.24E-04'''
| width="150" | '''99.98'''
|- align="center"
| width="100" | '''-3383.253442'''
| width="100" | '''-3383.250270'''
| width="150" | '''-0.003172'''
| width="150" | '''3.48E-02'''
| width="150" | '''93.27'''
|-
|}

 

As is obvious from here, the (S,R) transition state is more stable than the (R,S) transition state. Both transition states are exo with respect to the catalyst.

It is not immediately apparent just by looking at the molecule to determine which spatial groups have interactions with one another. Therefore, an NCI analysis is conducted again.

[[File:NCI Jacobsen.png|700px|center]]

File:Molecule 21 2.png

2013-11-21T19:12:43Z

Xc2611: