ChemWiki - User contributions [en]

Rep:Mod:juneywiki

2014-03-10T11:41:34Z

Jyg11: /* Spectroscopic Simulation using Quantum Mechanics */

=Conformational Analysis using Molecular Mechanics (Part 1)=
==The Hydrogenation of a Cyclopentadiene Dimer==

The dimerisation of cyclopentadiene is a [4+2] cycloaddition reaction. We can predict the stereoselectivity of the dimer product using the Woodward-Hoffmann rules, and therefore the stereochemistry of the dimerisation transition state; the reaction proceeds thermally via a Huckel (suprafacial) transition state or photochemically via a Mobius (antarafacial) transition state.

However, there are two possible products of this reaction depending on the orientation of the cyclopentadiene molecule (see Figure 1). The exo- (1) and endo- (2) products arise from the orientation of a second cyclopentadiene molecule facing "away" or "towards" the first. The Alder rule dictates that the endo-product is the major product, due to the favourable orbital overlap between the molecules - an overlap that is absent in the exo- transition state<ref>R. Hoffmann, R.B. Woodward, ''J. Am. Chem. Soc.'', '''1965''', 87, 4388</ref>.

[[File:The Hydrogenation of Cyclopentadiene Dimer - Compounds 1-4.PNG|centre|frame|Figure 1: the exo- (1) and endo- (2) products of the Diels-Alder [4+2] cycloaddition reaction. The two hydrogenation products of the endo dimer (3) and (4) are also shown.]]

Conformational analysis using molecular mechanics has been conducted on:
* the cyclopentadiene exo dimer (1)
* the cyclopentadiene endo dimer (2)
* the hydrogenation products of the endo dimer - norborene (3) and cyclopentene (4)

using the MM2/MMFF94 force field. The results are presented below.

{| {{class="wikitable" border=1}}
| align="center" style="background:#f0f0f0;"|'''Energy Contributions'''
| align="center" style="background:#f0f0f0;"|'''[[File:1.1 Exo Product.PNG|x150px]]'''
| align="center" style="background:#f0f0f0;"|'''[[File:1.1 Endo Product.PNG|x150px]]'''
| align="center" style="background:#f0f0f0;"|'''[[File:1.1 Norborene.PNG|x150px]]'''
| align="center" style="background:#f0f0f0;"|'''[[File:1.1 Cyclopentene.PNG|x150px]]'''
|-
| ||'''<jmolFile text="Exo-product (1)">1.1 Exo Product.cml</jmolFile>'''||'''<jmolFile text="Endo-product (2)">1.1 Endo Product.cml</jmolFile>'''||'''<jmolFile text="Norborene (3)">1.1 Norborene.cml</jmolFile>'''||'''<jmolFile text="Cyclopentene (4)">1.1 Cyclopentene.cml</jmolFile>'''
|-
| Bond Stretching||3.54268||3.46746||3.30836||2.82294
|-
| Angle Bending||30.77252||33.19101||30.86423||24.68546
|-
| Stretch Bending||-2.04121||-2.08217||-1.92652||-1.65712
|-
| Torsional||-2.72821||-2.94964||0.05942||-0.3782
|-
| Out-of-plane Bending||0.01489||0.02196||0.01536||0.00028
|-
| Van der Waals||12.79923||12.35754||13.281||10.6371
|-
| Electrostatic||13.01361||14.18453||5.12099||5.14702
|-
| Total||55.37351||58.19069||50.72284||41.25748
|-
|}

From this computational analysis we find that the endo dimer is higher in energy than the exo dimer by 2.8 kcal/mol. However, we also know that the endo-product is favoured. This therefore suggests that reactivity is governed by kinetic rather than thermodynamic factors.

We also calculate that the favoured hydrogenation product is (4) rather than (3), which is in accordance with the literature<ref>D. Skála, ''Petroleum and Coal'', '''2003''', 45, 105-108</ref>. The results suggest that the reaction is under thermodynamic control, as (4) is lover in energy than (3) by roughly 9.4 kcal/mol. We see the main contributions towards the difference in energy are due to angle bending and van der Waals, suggesting that the cyclopentene product is the less sterically hindered of the two.

==The Taxol Intermediates==
===Atropisomerism in an Intermediate related to the Synthesis of Taxol===

Taxol is an important drug typically used in the treatment of ovarian, breast and lung cancers amongst others<ref>M.W. Saville; J. Lietzau; J.M. Pluda; W.H. Wilson; R.W. Humphrey; E. Feigel; S.M. Steinberg; S. Broder, et al. ''The Lancet'' , '''1995''', 346, 8966</ref>. The intermediate in this study is a key intermediate identified by Paquette<ref>L. Paquette, S. Elmore, ''Tetrahedron Letters'', 1991, '''32''', 319-322</ref>, and is a good demonstration of atropisomerism.

[[File:1.2 Carbonyl Down and Up Chair.v2.PNG|centre|frame|Figure 2: the taxol intermediate with two possible orientations of ketone.]]

Atropisomerism arises from hindered rotations, which results in two or more conformations that correspond to different isomers. In this molecule, the barrier to rotation is from the C-C bond between the 6- and 10-membered rings, which means that the carbonyl must occupy either the same or opposite face as the isopropyl bridge. Since the conformation of the smaller ring determines that of the larger ring<ref>W. Maier, P. Schleyer, ''J. Am. Chem. Soc.'', 1981, '''103''', 1891-1900</ref>, this results in eight conformers - 4 conformational minima are known for a 6-membered ring, and there are two orientations of ketone.

The ketones were drawn and minimised in Avogadro using the MMFF9s force field, and the results given below.

{| {{class="wikitable" border=1}}
| align="center" style="background:#f0f0f0;"|'''Energy Contributions'''
| align="center" style="background:#f0f0f0;"|'''[[File:1.2 Carbonyl Down.PNG|x150px]]'''
| align="center" style="background:#f0f0f0;"|'''[[File:1.2 Carbonyl Up Chair.v2.PNG|x150px]]'''
|-
| || '''<jmolFile text="Carbonyl Down">1.2 Carbonyl Down.cml</jmolFile>'''||'''<jmolFile text="Carbonyl Up">1.2 Carbonyl Up Chair.v2.cml</jmolFile>'''
|-
| Bond Stretching||7.14282||7.52866
|-
| Angle Bending||22.42601||21.53112
|-
| Stretch Bending||-0.24228||0.012
|-
| Torsional||-1.91312||-0.51744
|-
| Out-of-plane Bending||0.66967||0.93772
|-
| Van der Waals||32.12172||33.49379
|-
| Electrostatic||0.82973||0.27425
|-
| Total||61.03455||63.2601
|-
|}

Only one chair per ketone was computed, however the other energies may be found by changing the conformation of the ring. Chairs are expected to be lower energy than twist-boats, which in turn are lower than the proposed transition state boat and half-chair structures.

Comparison of the two atropisomers allows us to determine which is formed by the oxy-Cope reaction under equilibrating conditions, the one that is most thermodynamically stable will be preferentially formed. (9) is more stable than (10), but only by 2.2 kcal/mol, which would suggest that a mixture forms under equilibrating conditions with (9) being the major component in the mixture.

===Hyperstability===
Bredt's rules states that double bonds at ring junctions are unstable, which leads to enhanced reactivity. However, molecule (10) is only fully hydrogenated after extended periods of time<ref>W. Maier, P. Schleyer, ''J. Am. Chem. Soc.'', 1981, '''103''', 1891-1900</ref>. Therefore we need to investigate the relative energies of the alkene and alkane.

{| {{class="wikitable" border=1}}
| align="center" style="background:#f0f0f0;"|'''Bond Stretching'''
| align="center" style="background:#f0f0f0;"|'''7.14282'''
| align="center" style="background:#f0f0f0;"|'''7.21955'''
|-
| Angle Bending||22.42601||24.73421
|-
| Stretch Bending||-0.24228||0.01292
|-
| Torsional||-1.91312||6.23478
|-
| Out-of-plane Bending||0.66967||0.81524
|-
| Van der Waals||32.12172||31.89353
|-
| Electrostatic||0.82973||0.00163
|-
| Total||61.03455||70.91186
|}

The energy of the alkane was computed using the MMMFF9s force field and Conjugate Gradients method, and it is seen to be less stable than alkene (10) by nearly 10 kcal/mol. However we expect that the alkane would be more stable than the bridghead alkene. This discrepancy can be mainly attributed to the difference in the torsional contribution, whichsuggesets that the conformation adopts a partially eclipsed structure.

Another factor to consider is olefinic strain, which can be calculated by subtracting the total strain of the alkane from the total strain of the alkene. In this case, the olefinic strain is negative, indicating that the enthalpy of hydrogenation is favourable and supporting the relative instability of the alkane to the alkene.

===Spectroscopic Simulation using Quantum Mechanics===

Avogadro was first used to optimise the energies of ketones (17) and (18) using the MMFF9s force field.

[[File:1.3 Ketones 17 and 18.PNG|centre|frame|Ketones 17 and 18, showing the different orientation of the carbonyl group]]

{| {{class="wikitable" border=1}}
| align="center" style="background:#f0f0f0;"|'''Energy Contributions'''
| align="center" style="background:#f0f0f0;"|'''[[File:1.3 Ketone 17 CO Up (Chair).PNG|centre|x200px]]'''
| align="center" style="background:#f0f0f0;"|'''[[File:1.3 Ketone 17 CO Up (Twist Boat).PNG|centre|x200px]]'''
| align="center" style="background:#f0f0f0;"|'''[[File:1.3 Ketone 18 CO Down (Chair).PNG|centre|x200px]]'''
| align="center" style="background:#f0f0f0;"|'''[[File:1.3 Ketone 18 CO Down (Twist Boat).PNG|centre|x200px]]'''
|-
| ||'''<jmolFile text="Carbonyl Up (Chair)">1.3 Ketone 17 CO Up (Chair).cml</jmolFile>'''||'''<jmolFile text="Carbonyl Up (Twist Boat)">1.3 Ketone 17 CO Up (Twist Boat).cml</jmolFile>'''||'''<jmolFile text="Carbonyl Down (Chair)">1.3 Ketone 18 CO Down (Chair).cml</jmolFile>'''||
'''<jmolFile text="Carbonyl Down (Twist Boat)">1.3 Ketone 18 CO Down (Twist Boat).cml</jmolFile>'''
|-
| Bond Stretching||16.57396||15.22508||15.07066||14.39859
|-
| Angle Bending||30.13766||29.15943||30.8648||28.1791
|-
| Stretch Bending||0.237||0.39803||0.60292||0.44557
|-
| Torsional||12.18456||14.35533||9.7361||13.98699
|-
| Out-of-plane Bending||0.99425||1.07303||0.90623||1.04101
|-
| Van der Waals||52.77833||52.65604||49.39199||50.54797
|-
| Electrostatic||-7.66268||-7.40526||-6.10377||-6.37105
|-
| Total||105.24308||105.46168||100.46893||102.22818
|}

The predicted NMR spectra for ketones 17 and 18 are shown below. The reference is TMS and the solvent is benzene.

[[File:1.3 Ketone 17 CO Up (Chair) H NMR Benzene.PNG|left|frame|x350px|The predicted 1H NMR spectrum of Ketone 17]][[File:1.3 Ketone 17 CO Up (Chair) C NMR Benzene.PNG|right|frame|x350px|The predicted 13C NMR spectrum of Ketone 17]]

[[File:1.3 Ketone 18 CO Down (Chair) H NMR Benzene.PNG|left|frame|x350px|The predicted 1H NMR spectrum of Ketone 18]] [[File:1.3 Ketone 18 CO Down (Chair) C NMR Benzene.PNG|right|frame|x350px|The predicted 13C NMR spectrum of Ketone 18]]

=Analysis of the properties of the Synthesised Alkene Epoxides (Part 2)=
==The Shi Asymmetric Catalyst==
===Crystal Structure===
==The Jacobsen Asymmetric Catalyst==
===Crystal Structure===
==The Products - Alkene Epoxides==
===Calculated NMR Properties===
==Absolute Configurations==
Optical Rotation paragraph

Chiroptical Properties paragraph

==Using the (calculated) properties of transition state for the reaction (β-methyl styrene only==
===Shi catalyst===
===Jacobsen catalyst===
===Other Alkenes===
==Investigating the non-covalent interactions in the active-site of the reaction transition state==
==Investigating the Electronic topology (QTAIM) in the active-site of the reaction transition state==
==Suggesting new candidates for investigations==
=References=
<references></references>

File:1.3 Ketone 18 CO Down (Twist Boat).cml

2014-03-10T11:38:33Z

Jyg11: uploaded a new version of "File:1.3 Ketone 18 CO Down (Twist Boat).cml"

File:1.3 Ketone 18 CO Down (Chair).cml

2014-03-10T11:38:33Z

Jyg11: uploaded a new version of "File:1.3 Ketone 18 CO Down (Chair).cml"

File:1.3 Ketone 17 CO Up (Twist Boat).cml

2014-03-10T11:38:32Z

Jyg11: uploaded a new version of "File:1.3 Ketone 17 CO Up (Twist Boat).cml"

File:1.3 Ketone 17 CO Up (Chair).cml

2014-03-10T11:38:32Z

Jyg11: uploaded a new version of "File:1.3 Ketone 17 CO Up (Chair).cml"

Rep:Mod:juneywiki

2014-03-10T11:37:14Z

Jyg11: /* Spectroscopic Simulation using Quantum Mechanics */

=Conformational Analysis using Molecular Mechanics (Part 1)=
==The Hydrogenation of a Cyclopentadiene Dimer==

The dimerisation of cyclopentadiene is a [4+2] cycloaddition reaction. We can predict the stereoselectivity of the dimer product using the Woodward-Hoffmann rules, and therefore the stereochemistry of the dimerisation transition state; the reaction proceeds thermally via a Huckel (suprafacial) transition state or photochemically via a Mobius (antarafacial) transition state.

However, there are two possible products of this reaction depending on the orientation of the cyclopentadiene molecule (see Figure 1). The exo- (1) and endo- (2) products arise from the orientation of a second cyclopentadiene molecule facing "away" or "towards" the first. The Alder rule dictates that the endo-product is the major product, due to the favourable orbital overlap between the molecules - an overlap that is absent in the exo- transition state<ref>R. Hoffmann, R.B. Woodward, ''J. Am. Chem. Soc.'', '''1965''', 87, 4388</ref>.

[[File:The Hydrogenation of Cyclopentadiene Dimer - Compounds 1-4.PNG|centre|frame|Figure 1: the exo- (1) and endo- (2) products of the Diels-Alder [4+2] cycloaddition reaction. The two hydrogenation products of the endo dimer (3) and (4) are also shown.]]

Conformational analysis using molecular mechanics has been conducted on:
* the cyclopentadiene exo dimer (1)
* the cyclopentadiene endo dimer (2)
* the hydrogenation products of the endo dimer - norborene (3) and cyclopentene (4)

using the MM2/MMFF94 force field. The results are presented below.

{| {{class="wikitable" border=1}}
| align="center" style="background:#f0f0f0;"|'''Energy Contributions'''
| align="center" style="background:#f0f0f0;"|'''[[File:1.1 Exo Product.PNG|x150px]]'''
| align="center" style="background:#f0f0f0;"|'''[[File:1.1 Endo Product.PNG|x150px]]'''
| align="center" style="background:#f0f0f0;"|'''[[File:1.1 Norborene.PNG|x150px]]'''
| align="center" style="background:#f0f0f0;"|'''[[File:1.1 Cyclopentene.PNG|x150px]]'''
|-
| ||'''<jmolFile text="Exo-product (1)">1.1 Exo Product.cml</jmolFile>'''||'''<jmolFile text="Endo-product (2)">1.1 Endo Product.cml</jmolFile>'''||'''<jmolFile text="Norborene (3)">1.1 Norborene.cml</jmolFile>'''||'''<jmolFile text="Cyclopentene (4)">1.1 Cyclopentene.cml</jmolFile>'''
|-
| Bond Stretching||3.54268||3.46746||3.30836||2.82294
|-
| Angle Bending||30.77252||33.19101||30.86423||24.68546
|-
| Stretch Bending||-2.04121||-2.08217||-1.92652||-1.65712
|-
| Torsional||-2.72821||-2.94964||0.05942||-0.3782
|-
| Out-of-plane Bending||0.01489||0.02196||0.01536||0.00028
|-
| Van der Waals||12.79923||12.35754||13.281||10.6371
|-
| Electrostatic||13.01361||14.18453||5.12099||5.14702
|-
| Total||55.37351||58.19069||50.72284||41.25748
|-
|}

From this computational analysis we find that the endo dimer is higher in energy than the exo dimer by 2.8 kcal/mol. However, we also know that the endo-product is favoured. This therefore suggests that reactivity is governed by kinetic rather than thermodynamic factors.

We also calculate that the favoured hydrogenation product is (4) rather than (3), which is in accordance with the literature<ref>D. Skála, ''Petroleum and Coal'', '''2003''', 45, 105-108</ref>. The results suggest that the reaction is under thermodynamic control, as (4) is lover in energy than (3) by roughly 9.4 kcal/mol. We see the main contributions towards the difference in energy are due to angle bending and van der Waals, suggesting that the cyclopentene product is the less sterically hindered of the two.

==The Taxol Intermediates==
===Atropisomerism in an Intermediate related to the Synthesis of Taxol===

Taxol is an important drug typically used in the treatment of ovarian, breast and lung cancers amongst others<ref>M.W. Saville; J. Lietzau; J.M. Pluda; W.H. Wilson; R.W. Humphrey; E. Feigel; S.M. Steinberg; S. Broder, et al. ''The Lancet'' , '''1995''', 346, 8966</ref>. The intermediate in this study is a key intermediate identified by Paquette<ref>L. Paquette, S. Elmore, ''Tetrahedron Letters'', 1991, '''32''', 319-322</ref>, and is a good demonstration of atropisomerism.

[[File:1.2 Carbonyl Down and Up Chair.v2.PNG|centre|frame|Figure 2: the taxol intermediate with two possible orientations of ketone.]]

Atropisomerism arises from hindered rotations, which results in two or more conformations that correspond to different isomers. In this molecule, the barrier to rotation is from the C-C bond between the 6- and 10-membered rings, which means that the carbonyl must occupy either the same or opposite face as the isopropyl bridge. Since the conformation of the smaller ring determines that of the larger ring<ref>W. Maier, P. Schleyer, ''J. Am. Chem. Soc.'', 1981, '''103''', 1891-1900</ref>, this results in eight conformers - 4 conformational minima are known for a 6-membered ring, and there are two orientations of ketone.

The ketones were drawn and minimised in Avogadro using the MMFF9s force field, and the results given below.

{| {{class="wikitable" border=1}}
| align="center" style="background:#f0f0f0;"|'''Energy Contributions'''
| align="center" style="background:#f0f0f0;"|'''[[File:1.2 Carbonyl Down.PNG|x150px]]'''
| align="center" style="background:#f0f0f0;"|'''[[File:1.2 Carbonyl Up Chair.v2.PNG|x150px]]'''
|-
| || '''<jmolFile text="Carbonyl Down">1.2 Carbonyl Down.cml</jmolFile>'''||'''<jmolFile text="Carbonyl Up">1.2 Carbonyl Up Chair.v2.cml</jmolFile>'''
|-
| Bond Stretching||7.14282||7.52866
|-
| Angle Bending||22.42601||21.53112
|-
| Stretch Bending||-0.24228||0.012
|-
| Torsional||-1.91312||-0.51744
|-
| Out-of-plane Bending||0.66967||0.93772
|-
| Van der Waals||32.12172||33.49379
|-
| Electrostatic||0.82973||0.27425
|-
| Total||61.03455||63.2601
|-
|}

Only one chair per ketone was computed, however the other energies may be found by changing the conformation of the ring. Chairs are expected to be lower energy than twist-boats, which in turn are lower than the proposed transition state boat and half-chair structures.

Comparison of the two atropisomers allows us to determine which is formed by the oxy-Cope reaction under equilibrating conditions, the one that is most thermodynamically stable will be preferentially formed. (9) is more stable than (10), but only by 2.2 kcal/mol, which would suggest that a mixture forms under equilibrating conditions with (9) being the major component in the mixture.

===Hyperstability===
Bredt's rules states that double bonds at ring junctions are unstable, which leads to enhanced reactivity. However, molecule (10) is only fully hydrogenated after extended periods of time<ref>W. Maier, P. Schleyer, ''J. Am. Chem. Soc.'', 1981, '''103''', 1891-1900</ref>. Therefore we need to investigate the relative energies of the alkene and alkane.

{| {{class="wikitable" border=1}}
| align="center" style="background:#f0f0f0;"|'''Bond Stretching'''
| align="center" style="background:#f0f0f0;"|'''7.14282'''
| align="center" style="background:#f0f0f0;"|'''7.21955'''
|-
| Angle Bending||22.42601||24.73421
|-
| Stretch Bending||-0.24228||0.01292
|-
| Torsional||-1.91312||6.23478
|-
| Out-of-plane Bending||0.66967||0.81524
|-
| Van der Waals||32.12172||31.89353
|-
| Electrostatic||0.82973||0.00163
|-
| Total||61.03455||70.91186
|}

The energy of the alkane was computed using the MMMFF9s force field and Conjugate Gradients method, and it is seen to be less stable than alkene (10) by nearly 10 kcal/mol. However we expect that the alkane would be more stable than the bridghead alkene. This discrepancy can be mainly attributed to the difference in the torsional contribution, whichsuggesets that the conformation adopts a partially eclipsed structure.

Another factor to consider is olefinic strain, which can be calculated by subtracting the total strain of the alkane from the total strain of the alkene. In this case, the olefinic strain is negative, indicating that the enthalpy of hydrogenation is favourable and supporting the relative instability of the alkane to the alkene.

===Spectroscopic Simulation using Quantum Mechanics===

Avogadro was first used to optimise the energies of ketones (17) and (18) using the MMFF9s force field.

[[File:1.3 Ketones 17 and 18.PNG|centre|frame|Ketones 17 and 18, showing the different orientation of the carbonyl group]]

{| {{class="wikitable" border=1}}
| align="center" style="background:#f0f0f0;"|'''Energy Contributions'''
| align="center" style="background:#f0f0f0;"|'''[[File:1.3 Ketone 17 CO Up (Chair).PNG|centre|x200px]]'''
| align="center" style="background:#f0f0f0;"|'''[[File:1.3 Ketone 17 CO Up (Twist Boat).PNG|centre|x200px]]'''
| align="center" style="background:#f0f0f0;"|'''[[File:1.3 Ketone 18 CO Down (Chair).PNG|centre|x200px]]'''
| align="center" style="background:#f0f0f0;"|'''[[File:1.3 Ketone 18 CO Down (Twist Boat).PNG|centre|x200px]]'''
|-
| ||'''<jmolFile text="Carbonyl Up (Chair)">1.3 Ketone 17 Carbonyl Up (Chair).cml</jmolFile>'''||'''<jmolFile text="Carbonyl Up (Twist Boat)">1.3 Ketone 17 Carbonyl Up (Twist Boat).cml</jmolFile>'''||'''<jmolFile text="Carbonyl Down (Chair)">1.3 Ketone 18 Carbonyl Down (Chair).cml</jmolFile>'''||
'''<jmolFile text="Carbonyl Down (Twist Boat)">1.3 Ketone 18 Carbonyl Down (Twist Boat).cml</jmolFile>'''
|-
| Bond Stretching||16.57396||15.22508||15.07066||14.39859
|-
| Angle Bending||30.13766||29.15943||30.8648||28.1791
|-
| Stretch Bending||0.237||0.39803||0.60292||0.44557
|-
| Torsional||12.18456||14.35533||9.7361||13.98699
|-
| Out-of-plane Bending||0.99425||1.07303||0.90623||1.04101
|-
| Van der Waals||52.77833||52.65604||49.39199||50.54797
|-
| Electrostatic||-7.66268||-7.40526||-6.10377||-6.37105
|-
| Total||105.24308||105.46168||100.46893||102.22818
|}

The predicted NMR spectra for ketones 17 and 18 are shown below. The reference is TMS and the solvent is benzene.

[[File:1.3 Ketone 17 CO Up (Chair) H NMR Benzene.PNG|left|frame|x350px|The predicted 1H NMR spectrum of Ketone 17]][[File:1.3 Ketone 17 CO Up (Chair) C NMR Benzene.PNG|right|frame|x350px|The predicted 13C NMR spectrum of Ketone 17]]

[[File:1.3 Ketone 18 CO Down (Chair) H NMR Benzene.PNG|left|frame|x350px|The predicted 1H NMR spectrum of Ketone 18]] [[File:1.3 Ketone 18 CO Down (Chair) C NMR Benzene.PNG|right|frame|x350px|The predicted 13C NMR spectrum of Ketone 18]]

=Analysis of the properties of the Synthesised Alkene Epoxides (Part 2)=
==The Shi Asymmetric Catalyst==
===Crystal Structure===
==The Jacobsen Asymmetric Catalyst==
===Crystal Structure===
==The Products - Alkene Epoxides==
===Calculated NMR Properties===
==Absolute Configurations==
Optical Rotation paragraph

Chiroptical Properties paragraph

==Using the (calculated) properties of transition state for the reaction (β-methyl styrene only==
===Shi catalyst===
===Jacobsen catalyst===
===Other Alkenes===
==Investigating the non-covalent interactions in the active-site of the reaction transition state==
==Investigating the Electronic topology (QTAIM) in the active-site of the reaction transition state==
==Suggesting new candidates for investigations==
=References=
<references></references>

Rep:Mod:juneywiki

2014-03-10T11:33:33Z

Rep:Mod:juneywiki

2014-03-10T11:18:37Z

2014-03-10T09:51:46Z

Jyg11: /* Spectroscopic Simulation using Quantum Mechanics */

=Conformational Analysis using Molecular Mechanics (Part 1)=
==The Hydrogenation of a Cyclopentadiene Dimer==

The dimerisation of cyclopentadiene is a [4+2] cycloaddition reaction. We can predict the stereoselectivity of the dimer product using the Woodward-Hoffmann rules, and therefore the stereochemistry of the dimerisation transition state; the reaction proceeds thermally via a Huckel (suprafacial) transition state or photochemically via a Mobius (antarafacial) transition state.

However, there are two possible products of this reaction depending on the orientation of the cyclopentadiene molecule (see Figure 1). The exo- (1) and endo- (2) products arise from the orientation of a second cyclopentadiene molecule facing "away" or "towards" the first. The Alder rule dictates that the endo-product is the major product, due to the favourable orbital overlap between the molecules - an overlap that is absent in the exo- transition state<ref>R. Hoffmann, R.B. Woodward, ''J. Am. Chem. Soc.'', '''1965''', 87, 4388</ref>.

[[File:The Hydrogenation of Cyclopentadiene Dimer - Compounds 1-4.PNG|centre|frame|Figure 1: the exo- (1) and endo- (2) products of the Diels-Alder [4+2] cycloaddition reaction. The two hydrogenation products of the endo dimer (3) and (4) are also shown.]]

Conformational analysis using molecular mechanics has been conducted on:
* the cyclopentadiene exo dimer (1)
* the cyclopentadiene endo dimer (2)
* the hydrogenation products of the endo dimer - norborene (3) and cyclopentene (4)

using the MM2/MMFF94 force field. The results are presented below.

{| {{class="wikitable" border=1}}
| align="center" style="background:#f0f0f0;"|'''Energy Contributions'''
| align="center" style="background:#f0f0f0;"|'''[[File:1.1 Exo Product.PNG|x150px]]'''
| align="center" style="background:#f0f0f0;"|'''[[File:1.1 Endo Product.PNG|x150px]]'''
| align="center" style="background:#f0f0f0;"|'''[[File:1.1 Norborene.PNG|x150px]]'''
| align="center" style="background:#f0f0f0;"|'''[[File:1.1 Cyclopentene.PNG|x150px]]'''
|-
| ||'''<jmolFile text="Exo-product (1)">1.1 Exo Product.cml</jmolFile>'''||'''<jmolFile text="Endo-product (2)">1.1 Endo Product.cml</jmolFile>'''||'''<jmolFile text="Norborene (3)">1.1 Norborene.cml</jmolFile>'''||'''<jmolFile text="Cyclopentene (4)">1.1 Cyclopentene.cml</jmolFile>'''
|-
| Bond Stretching||3.54268||3.46746||3.30836||2.82294
|-
| Angle Bending||30.77252||33.19101||30.86423||24.68546
|-
| Stretch Bending||-2.04121||-2.08217||-1.92652||-1.65712
|-
| Torsional||-2.72821||-2.94964||0.05942||-0.3782
|-
| Out-of-plane Bending||0.01489||0.02196||0.01536||0.00028
|-
| Van der Waals||12.79923||12.35754||13.281||10.6371
|-
| Electrostatic||13.01361||14.18453||5.12099||5.14702
|-
| Total||55.37351||58.19069||50.72284||41.25748
|-
|}

From this computational analysis we find that the endo dimer is higher in energy than the exo dimer by 2.8 kcal/mol. However, we also know that the endo-product is favoured. This therefore suggests that reactivity is governed by kinetic rather than thermodynamic factors.

We also calculate that the favoured hydrogenation product is (4) rather than (3), which is in accordance with the literature<ref>D. Skála, ''Petroleum and Coal'', '''2003''', 45, 105-108</ref>. The results suggest that the reaction is under thermodynamic control, as (4) is lover in energy than (3) by roughly 9.4 kcal/mol. We see the main contributions towards the difference in energy are due to angle bending and van der Waals, suggesting that the cyclopentene product is the less sterically hindered of the two.

==The Taxol Intermediates==
===Atropisomerism in an Intermediate related to the Synthesis of Taxol===

Taxol is an important drug typically used in the treatment of ovarian, breast and lung cancers amongst others<ref>M.W. Saville; J. Lietzau; J.M. Pluda; W.H. Wilson; R.W. Humphrey; E. Feigel; S.M. Steinberg; S. Broder, et al. ''The Lancet'' , '''1995''', 346, 8966</ref>. The intermediate in this study is a key intermediate identified by Paquette<ref>L. Paquette, S. Elmore, ''Tetrahedron Letters'', 1991, '''32''', 319-322</ref>, and is a good demonstration of atropisomerism.

[[File:1.2 Carbonyl Down and Up Chair.v2.PNG|centre|frame|Figure 2: the taxol intermediate with two possible orientations of ketone.]]

Atropisomerism arises from hindered rotations, which results in two or more conformations that correspond to different isomers. In this molecule, the barrier to rotation is from the C-C bond between the 6- and 10-membered rings, which means that the carbonyl must occupy either the same or opposite face as the isopropyl bridge. Since the conformation of the smaller ring determines that of the larger ring<ref>W. Maier, P. Schleyer, ''J. Am. Chem. Soc.'', 1981, '''103''', 1891-1900</ref>, this results in eight conformers - 4 conformational minima are known for a 6-membered ring, and there are two orientations of ketone.

The ketones were drawn and minimised in Avogadro using the MMFF9s force field, and the results given below.

{| {{class="wikitable" border=1}}
| align="center" style="background:#f0f0f0;"|'''Energy Contributions'''
| align="center" style="background:#f0f0f0;"|'''[[File:1.2 Carbonyl Down.PNG|x150px]]'''
| align="center" style="background:#f0f0f0;"|'''[[File:1.2 Carbonyl Up Chair.v2.PNG|x150px]]'''
|-
| || '''<jmolFile text="Carbonyl Down">1.2 Carbonyl Down.cml</jmolFile>'''||'''<jmolFile text="Carbonyl Up">1.2 Carbonyl Up Chair.v2.cml</jmolFile>'''
|-
| Bond Stretching||7.14282||7.52866
|-
| Angle Bending||22.42601||21.53112
|-
| Stretch Bending||-0.24228||0.012
|-
| Torsional||-1.91312||-0.51744
|-
| Out-of-plane Bending||0.66967||0.93772
|-
| Van der Waals||32.12172||33.49379
|-
| Electrostatic||0.82973||0.27425
|-
| Total||61.03455||63.2601
|-
|}

Only one chair per ketone was computed, however the other energies may be found by changing the conformation of the ring. Chairs are expected to be lower energy than twist-boats, which in turn are lower than the proposed transition state boat and half-chair structures.

Comparison of the two atropisomers allows us to determine which is formed by the oxy-Cope reaction under equilibrating conditions, the one that is most thermodynamically stable will be preferentially formed. (9) is more stable than (10), but only by 2.2 kcal/mol, which would suggest that a mixture forms under equilibrating conditions with (9) being the major component in the mixture.

===Hyperstability===
Bredt's rules states that double bonds at ring junctions are unstable, which leads to enhanced reactivity. However, molecule (10) is only fully hydrogenated after extended periods of time<ref>W. Maier, P. Schleyer, ''J. Am. Chem. Soc.'', 1981, '''103''', 1891-1900</ref>. Therefore we need to investigate the relative energies of the alkene and alkane.

{| {{class="wikitable" border=1}}
| align="center" style="background:#f0f0f0;"|'''Bond Stretching'''
| align="center" style="background:#f0f0f0;"|'''7.14282'''
| align="center" style="background:#f0f0f0;"|'''7.21955'''
|-
| Angle Bending||22.42601||24.73421
|-
| Stretch Bending||-0.24228||0.01292
|-
| Torsional||-1.91312||6.23478
|-
| Out-of-plane Bending||0.66967||0.81524
|-
| Van der Waals||32.12172||31.89353
|-
| Electrostatic||0.82973||0.00163
|-
| Total||61.03455||70.91186
|}

The energy of the alkane was computed using the MMMFF9s force field and Conjugate Gradients method, and it is seen to be less stable than alkene (10) by nearly 10 kcal/mol. However we expect that the alkane would be more stable than the bridghead alkene. This discrepancy can be mainly attributed to the difference in the torsional contribution, whichsuggesets that the conformation adopts a partially eclipsed structure.

Another factor to consider is olefinic strain, which can be calculated by subtracting the total strain of the alkane from the total strain of the alkene. In this case, the olefinic strain is negative, indicating that the enthalpy of hydrogenation is favourable and supporting the relative instability of the alkane to the alkene.

===Spectroscopic Simulation using Quantum Mechanics===

Avogadro was first used to optimise the energies of ketones (17) and (18) using the MMFF9s force field.

{| {{class="wikitable" border=1}}
| align="center" style="background:#f0f0f0;"|'''Energy Contributions'''
| align="center" style="background:#f0f0f0;"|'''[[File:name.type]]'''
| align="center" style="background:#f0f0f0;"|'''[[File:name.type]]'''
| align="center" style="background:#f0f0f0;"|'''[[File:name.type]]'''
| align="center" style="background:#f0f0f0;"|'''[[File:name.type]]'''
|-
| ||Carbonyl Up (Chair)||Carbonyl Up (Twist Boat)||Carbonyl Down (Chair)||Carbonyl Down (Twist Boat)
|-
| Bond Stretching||16.57396||15.22508||15.07066||14.39859
|-
| Angle Bending||30.13766||29.15943||30.8648||28.1791
|-
| Stretch Bending||0.237||0.39803||0.60292||0.44557
|-
| Torsional||12.18456||14.35533||9.7361||13.98699
|-
| Out-of-plane Bending||0.99425||1.07303||0.90623||1.04101
|-
| Van der Waals||52.77833||52.65604||49.39199||50.54797
|-
| Electrostatic||-7.66268||-7.40526||-6.10377||-6.37105
|-
| Total||105.24308||105.46168||100.46893||102.22818
|}

The predicted NMR spectra are shown below. The nucleus is 1H and the reference is TMS.

[[File:name.type]][[File:name.type]]

=Analysis of the properties of the Synthesised Alkene Epoxides (Part 2)=
==The Shi Asymmetric Catalyst==
===Crystal Structure===
==The Jacobsen Asymmetric Catalyst==
===Crystal Structure===
==The Products - Alkene Epoxides==
===Calculated NMR Properties===
==Absolute Configurations==
Optical Rotation paragraph

Chiroptical Properties paragraph

==Using the (calculated) properties of transition state for the reaction (β-methyl styrene only==
===Shi catalyst===
===Jacobsen catalyst===
===Other Alkenes===
==Investigating the non-covalent interactions in the active-site of the reaction transition state==
==Investigating the Electronic topology (QTAIM) in the active-site of the reaction transition state==
==Suggesting new candidates for investigations==
=References=
<references></references>

Rep:Mod:juneywiki

2014-03-10T08:00:39Z

Jyg11: /* Spectroscopic Simulation using Quantum Mechanics */

=Conformational Analysis using Molecular Mechanics (Part 1)=
==The Hydrogenation of a Cyclopentadiene Dimer==

The dimerisation of cyclopentadiene is a [4+2] cycloaddition reaction. We can predict the stereoselectivity of the dimer product using the Woodward-Hoffmann rules, and therefore the stereochemistry of the dimerisation transition state; the reaction proceeds thermally via a Huckel (suprafacial) transition state or photochemically via a Mobius (antarafacial) transition state.

However, there are two possible products of this reaction depending on the orientation of the cyclopentadiene molecule (see Figure 1). The exo- (1) and endo- (2) products arise from the orientation of a second cyclopentadiene molecule facing "away" or "towards" the first. The Alder rule dictates that the endo-product is the major product, due to the favourable orbital overlap between the molecules - an overlap that is absent in the exo- transition state<ref>R. Hoffmann, R.B. Woodward, ''J. Am. Chem. Soc.'', '''1965''', 87, 4388</ref>.

[[File:The Hydrogenation of Cyclopentadiene Dimer - Compounds 1-4.PNG|centre|frame|Figure 1: the exo- (1) and endo- (2) products of the Diels-Alder [4+2] cycloaddition reaction. The two hydrogenation products of the endo dimer (3) and (4) are also shown.]]

Conformational analysis using molecular mechanics has been conducted on:
* the cyclopentadiene exo dimer (1)
* the cyclopentadiene endo dimer (2)
* the hydrogenation products of the endo dimer - norborene (3) and cyclopentene (4)

using the MM2/MMFF94 force field. The results are presented below.

{| {{class="wikitable" border=1}}
| align="center" style="background:#f0f0f0;"|'''Energy Contributions'''
| align="center" style="background:#f0f0f0;"|'''[[File:1.1 Exo Product.PNG|x150px]]'''
| align="center" style="background:#f0f0f0;"|'''[[File:1.1 Endo Product.PNG|x150px]]'''
| align="center" style="background:#f0f0f0;"|'''[[File:1.1 Norborene.PNG|x150px]]'''
| align="center" style="background:#f0f0f0;"|'''[[File:1.1 Cyclopentene.PNG|x150px]]'''
|-
| ||'''<jmolFile text="Exo-product (1)">1.1 Exo Product.cml</jmolFile>'''||'''<jmolFile text="Endo-product (2)">1.1 Endo Product.cml</jmolFile>'''||'''<jmolFile text="Norborene (3)">1.1 Norborene.cml</jmolFile>'''||'''<jmolFile text="Cyclopentene (4)">1.1 Cyclopentene.cml</jmolFile>'''
|-
| Bond Stretching||3.54268||3.46746||3.30836||2.82294
|-
| Angle Bending||30.77252||33.19101||30.86423||24.68546
|-
| Stretch Bending||-2.04121||-2.08217||-1.92652||-1.65712
|-
| Torsional||-2.72821||-2.94964||0.05942||-0.3782
|-
| Out-of-plane Bending||0.01489||0.02196||0.01536||0.00028
|-
| Van der Waals||12.79923||12.35754||13.281||10.6371
|-
| Electrostatic||13.01361||14.18453||5.12099||5.14702
|-
| Total||55.37351||58.19069||50.72284||41.25748
|-
|}

From this computational analysis we find that the endo dimer is higher in energy than the exo dimer by 2.8 kcal/mol. However, we also know that the endo-product is favoured. This therefore suggests that reactivity is governed by kinetic rather than thermodynamic factors.

We also calculate that the favoured hydrogenation product is (4) rather than (3), which is in accordance with the literature<ref>D. Skála, ''Petroleum and Coal'', '''2003''', 45, 105-108</ref>. The results suggest that the reaction is under thermodynamic control, as (4) is lover in energy than (3) by roughly 9.4 kcal/mol. We see the main contributions towards the difference in energy are due to angle bending and van der Waals, suggesting that the cyclopentene product is the less sterically hindered of the two.

==The Taxol Intermediates==
===Atropisomerism in an Intermediate related to the Synthesis of Taxol===

Taxol is an important drug typically used in the treatment of ovarian, breast and lung cancers amongst others<ref>M.W. Saville; J. Lietzau; J.M. Pluda; W.H. Wilson; R.W. Humphrey; E. Feigel; S.M. Steinberg; S. Broder, et al. ''The Lancet'' , '''1995''', 346, 8966</ref>. The intermediate in this study is a key intermediate identified by Paquette<ref>L. Paquette, S. Elmore, ''Tetrahedron Letters'', 1991, '''32''', 319-322</ref>, and is a good demonstration of atropisomerism.

[[File:1.2 Carbonyl Down and Up Chair.v2.PNG|centre|frame|Figure 2: the taxol intermediate with two possible orientations of ketone.]]

Atropisomerism arises from hindered rotations, which results in two or more conformations that correspond to different isomers. In this molecule, the barrier to rotation is from the C-C bond between the 6- and 10-membered rings, which means that the carbonyl must occupy either the same or opposite face as the isopropyl bridge. Since the conformation of the smaller ring determines that of the larger ring<ref>W. Maier, P. Schleyer, ''J. Am. Chem. Soc.'', 1981, '''103''', 1891-1900</ref>, this results in eight conformers - 4 conformational minima are known for a 6-membered ring, and there are two orientations of ketone.

The ketones were drawn and minimised in Avogadro using the MMFF9s force field, and the results given below.

{| {{class="wikitable" border=1}}
| align="center" style="background:#f0f0f0;"|'''Energy Contributions'''
| align="center" style="background:#f0f0f0;"|'''[[File:1.2 Carbonyl Down.PNG|x150px]]'''
| align="center" style="background:#f0f0f0;"|'''[[File:1.2 Carbonyl Up Chair.v2.PNG|x150px]]'''
|-
| || '''<jmolFile text="Carbonyl Down">1.2 Carbonyl Down.cml</jmolFile>'''||'''<jmolFile text="Carbonyl Up">1.2 Carbonyl Up Chair.v2.cml</jmolFile>'''
|-
| Bond Stretching||7.14282||7.52866
|-
| Angle Bending||22.42601||21.53112
|-
| Stretch Bending||-0.24228||0.012
|-
| Torsional||-1.91312||-0.51744
|-
| Out-of-plane Bending||0.66967||0.93772
|-
| Van der Waals||32.12172||33.49379
|-
| Electrostatic||0.82973||0.27425
|-
| Total||61.03455||63.2601
|-
|}

Only one chair per ketone was computed, however the other energies may be found by changing the conformation of the ring. Chairs are expected to be lower energy than twist-boats, which in turn are lower than the proposed transition state boat and half-chair structures.

Comparison of the two atropisomers allows us to determine which is formed by the oxy-Cope reaction under equilibrating conditions, the one that is most thermodynamically stable will be preferentially formed. (9) is more stable than (10), but only by 2.2 kcal/mol, which would suggest that a mixture forms under equilibrating conditions with (9) being the major component in the mixture.

===Hyperstability===
Bredt's rules states that double bonds at ring junctions are unstable, which leads to enhanced reactivity. However, molecule (10) is only fully hydrogenated after extended periods of time<ref>W. Maier, P. Schleyer, ''J. Am. Chem. Soc.'', 1981, '''103''', 1891-1900</ref>. Therefore we need to investigate the relative energies of the alkene and alkane.

{| {{class="wikitable" border=1}}
| align="center" style="background:#f0f0f0;"|'''Bond Stretching'''
| align="center" style="background:#f0f0f0;"|'''7.14282'''
| align="center" style="background:#f0f0f0;"|'''7.21955'''
|-
| Angle Bending||22.42601||24.73421
|-
| Stretch Bending||-0.24228||0.01292
|-
| Torsional||-1.91312||6.23478
|-
| Out-of-plane Bending||0.66967||0.81524
|-
| Van der Waals||32.12172||31.89353
|-
| Electrostatic||0.82973||0.00163
|-
| Total||61.03455||70.91186
|}

The energy of the alkane was computed using the MMMFF9s force field and Conjugate Gradients method, and it is seen to be less stable than alkene (10) by nearly 10 kcal/mol. However we expect that the alkane would be more stable than the bridghead alkene. This discrepancy can be mainly attributed to the difference in the torsional contribution, whichsuggesets that the conformation adopts a partially eclipsed structure.

Another factor to consider is olefinic strain, which can be calculated by subtracting the total strain of the alkane from the total strain of the alkene. In this case, the olefinic strain is negative, indicating that the enthalpy of hydrogenation is favourable and supporting the relative instability of the alkane to the alkene.

===Spectroscopic Simulation using Quantum Mechanics===

Avogadro was first used to optimise the energies of ketones (17) and (18) using the MMFF9s force field.

{| {{class="wikitable" border=1}}
| align="center" style="background:#f0f0f0;"|'''Energy Contributions'''
| align="center" style="background:#f0f0f0;"|'''[[File:name.type]]'''
| align="center" style="background:#f0f0f0;"|'''[[File:name.type]]'''
| align="center" style="background:#f0f0f0;"|'''[[File:name.type]]'''
| align="center" style="background:#f0f0f0;"|'''[[File:name.type]]'''
|-
| ||Carbonyl Up (Chair)||Carbonyl Up (Twist Boat)||Carbonyl Down (Chair)||Carbonyl Down (Twist Boat)
|-
| Bond Stretching||16.57396||15.22508||15.07066||14.39859
|-
| Angle Bending||30.13766||29.15943||30.8648||28.1791
|-
| Stretch Bending||0.237||0.39803||0.60292||0.44557
|-
| Torsional||12.18456||14.35533||9.7361||13.98699
|-
| Out-of-plane Bending||0.99425||1.07303||0.90623||1.04101
|-
| Van der Waals||52.77833||52.65604||49.39199||50.54797
|-
| Electrostatic||-7.66268||-7.40526||-6.10377||-6.37105
|-
| Total||105.24308||105.46168||100.46893||102.22818
|}

=Analysis of the properties of the Synthesised Alkene Epoxides (Part 2)=
==The Shi Asymmetric Catalyst==
===Crystal Structure===
==The Jacobsen Asymmetric Catalyst==
===Crystal Structure===
==The Products - Alkene Epoxides==
===Calculated NMR Properties===
==Absolute Configurations==
Optical Rotation paragraph

Chiroptical Properties paragraph

==Using the (calculated) properties of transition state for the reaction (β-methyl styrene only==
===Shi catalyst===
===Jacobsen catalyst===
===Other Alkenes===
==Investigating the non-covalent interactions in the active-site of the reaction transition state==
==Investigating the Electronic topology (QTAIM) in the active-site of the reaction transition state==
==Suggesting new candidates for investigations==
=References=
<references></references>

File:1.3 Ketone 18 CO Down (Twist Boat).cml

2014-03-10T07:52:34Z

Jyg11:

File:1.3 Ketone 18 CO Down (Chair).cml

2014-03-10T07:52:33Z

Jyg11:

File:1.3 Ketone 17 CO Up (Twist Boat).cml

2014-03-10T07:52:33Z

Jyg11: