Rep:Mod:mod1ii108

2010-10-21T20:31:29Z

Jt108:

=Module 1: The basic techniques of molecular mechanics and semi-empirical molecular orbital methods for structural and spectroscopic evaluations =

==Modelling using Molecular Dynamics==
===The Hydrogenation of Cyclopentadiene Dimer===
Cyclopentadiene undergoes a [4π+2π] Diels-Alder reaction in order to produce a cyclopentadiene dimer. Diels-Alder reactions can produce two different products: the endo (molecule 2) and the exo product (molecule 1). The energies of the two products were analysed through the use of Molecular Dynamics and the results revealed that the endo product had an energy of 34.0153 kcal/mol while the energy of the exo product was found to be 31.8782 kcal/mol. This means that the exo product is the less strained of the two. However, it is the endo product that is formed during the reaction, which suggests that the reaction is in fact kinetically controlled.

[[Image:molecules 1 and 2.jpg|thumb|Diels-Alder reaction]]
{| border=1 align=left
|+ Hydrogenation products' energies
|-
! Energy (kcal/mol)
! Molecule 3
! Molecule 4
|-
| Stretch
| 1.2659 || 1.0963
|-
| Bend
| 19.8063 || 14.5075
|-
| Stretch-Bend
| -0.8276 || -0.5493
|-
| Torsion
| 10.8698 || 12.4972
|-
| Non-1,4 VDW
| -1.2207 || -1.0507
|-
| 1,4 VDW
| 5.6394 || 4.5124
|-
| Dipole/Dipole
| 0.1621 || 0.1407
|-
| Total
| 35.6953 || 31.1540
|}

This can be explained by analysing the frontier orbitals of the two cyclopentadienes as they react. One can see that not only is the symmetry correct in order to form the bond, but there are also additional bonding interactions at the back of the diene. The endo product is therefore favoured. <ref>Clayden et al., Organic Chemistry, 1997, p916</ref>
[[Image:orbitals endo.jpg|thumb]]

[[Image:molecules 3 and 4.jpg|right|thumb|Products from hydrogenation]]

This cyclopentadiene dimer can then be hydrogenated to give a dihydro derivative, needing a long reaction time to get to the tetrahydro molecule. Molecule 3 was found to have an energy of 35.6953 kcal/mol while molecule 4’s energy was significantly lower at 31.1540 kcal/mol. Molecule 4 would therefore be the predicted thermodynamic product of the reaction.

One can rationalise this by analysing the relative contributions from the different energy terms. The main difference between the two derivatives is caused by the bend energy (difference of more than 4 kcal/mol). The hydrogenation of the double bond adjacent to the strained bridge improves the bend energy more than the hydrogenation of the other double bond. This is because the double bond on the norborene unit causes a higher strain in the ring, due to the methylene bridging unit, than the double bond on the cyclopentene. The double bond on the norborene can therefore be hydrogenated more easily, leading to molecule 4 as the first product. This can be further proved by analysing the angles present at the sp2 carbons in both molecules. In the more favourable molecule 4, the angles between the two sp2 carbons and a neighbouring atom are of approximately 112°, while for molecule 3 the angles are 107°, clearly further away from the ideal 120°.

PENIS PENIS PENIS PENIS

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===Stereochemistry of Nucleophilic additions to a pyridinium ring (NAD+ analogue) ===
This section analyses the stereochemistry of nucleophilic additions to a pyridinium ring, unit present in nicotinamide adenine dinucleotide (NAD+).

[[Image:memgi mechanism.jpg|left|thumb|Mechanism of reaction]]
[[Image:molecule 5 ii108.jpg|left|thumb|Molecule 5 showing dihedral angle]]

{| border=1 align=right
|+ Optimisation energies
|-
! Dihedral angle (°)
! Energy of molecule (kcal/mol)
|-
| 11 || 43.1233
|-
| 123 || 168.1987
|-
| 13 || 44.5619
|}

In the first reaction, a derivative of prolinol is reacted with methyl magnesium iodide in order to alkylate the pyridine ring at the 4-position. The mechanism can be seen below. This reaction is highly regio- and stereoselective, due to the high coordination between the Grignard reactions and the carbonyl oxygen, as proposed by Schultz and Flood <ref>A. G. Shultz, L. Flood and J. P. Springer, ''J. Org. Chemistry'', '''1986''', ''51'', 838. {{DOI|10.1021/jo00356a016}}</ref>. This coordination then allows the conjugate delivery of the methyl group from the magnesium to the pyridinium ring. Through the use of Molecular Modelling, the optimum angle between the carbonyl group and the aromatic ring was calculated. This angle was 11°, which means that the MeMgI attacks from the top, therefore the alkylation occurs from the top as well, explaining the stereochemistry of the product. The geometry of the reagent was studied by optimising the energies and geometries of the reagents from different starting points. A table with several of these optimisations can be seen below. It shows that the lowest energy was achieved by having a dihedral angle of 11° and shows how certain conformations can be provided by the program which have an unrealistic energy values.

This model could have been improved by using a more precise technique that took into account things such as stereoelectronic effects and the effect that for example the magnesium would exert on the reacting molecule. A method which used a more quantic approach, taking into account molecular orbitals, would provide a more accurate result. In this example, Mg cannot be used in the calculations as ChemBio3D does not have the parameters needed to perform calculations with it.

[[Image:nhph2 mechanism.jpg|right|thumb|Mechanism of reaction]]

The second reagent is reacted with aniline (PhNH2) to produce N-methylquinolinium (molecule 8). This reaction is also very regio- and stereoselective. The geometry was optimised, to find that the carbonyl is actually 20° below the plane of the ring. Therefore, attack of the aniline on the face below is sterically and electronically unfavourable, making sure that the attack is from the top, explaining the stereochemistry of the product shown. Attack from the bottom is sterically hindered due to the big phenyl group and electronically unfavourable because of the aniline nitrogen and the carbonyl oxygen lone pairs repulsion. The carbonyl therefore plays an important role in the high selectivity of the reaction<ref># S. Leleu, C.; Papamicael, F. Marsais, G. Dupas, V.; Levacher, Vincent. ''Tetrahedron: Asymmetry'', '''2004''', ''15'', 3919-3928. {{DOI|10.1016/j.tetasy.2004.11.004}}</ref>. Attempts at changing the molecule in order to find a different conformer were not succesful, as minimisation of geometry always gave the same result, with an energy of approximately 62.7 kcal/mol.

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===Stereochemistry and Reactivity of an Intermediate in the Synthesis of Taxol===
Atropisomers are stereoisomers that are formed through the hindered rotation about a single bond. In these cases, the conformers can be isolated because the steric strain barrier is very high. An example of this can be seen in an intermediate in the synthesis of taxol, as proposed by Paquette et al.<ref># S. W. Elmore and L. Paquette, ''Tetrahedron Letters'', '''1991''', 319; {{DOI|10.1016/S0040-4039(00)92617-0 10.1016/S0040-4039(00)92617-0}}</ref> The carbonyl of the compound is either up or down, but when left to stand, the compound isomerises to the most stable isomer. In this section, the structures of both isomers were minimised and studied, in order to find the most optimum configuration.

[[Image:taxol atropisomers.jpg|thumb|Atropisomerism from 9 to 10]]

Several conclusions can be drawn from the table of energies shown below. The most stable structure is the optimised isomer 10, with the carbonyl pointing downwards. This can be explained by looking at the conformation of the rings in the molecules. In both cases, the five membered ring has the favourable twisted envelope. However, in the less stable isomer 9, the six membered ring exists in the higher energy twist boat conformation, rather than adopting the chair one. This is the case in the second isomer.

These isomers were found to react abnormally slowly and this is due to the fact that they are hyperstable alkenes. This sometimes occurs in bridgehead groups in medium sized ring systems.<ref># W. F. Maier and P. v R. Schleyer, ''J. Am. Chem. Soc.'', '''1981''', 103; {{DOI|10.1021/ja00398a003}}</ref> This happens when the olefin has a negative olefin strain energy, lower than that of the parent hydrocarbon. Due to this low energy, these molecule's heat of hydrogenation are lower than normal and are therefore very slow to react, as they are very thermodynamically favoured.<ref>A. B. McEwen and P. v R. Schleyer, ''J. Am. Chem. Soc.'', '''1986''', 108; {{DOI|10.1021/ja00274a016}}</ref>

‎<jmol>
<jmolAppletButton>
<uploadedFileContents>Molecule10_ii108.cml</uploadedFileContents>
<text>molecule 10</text>
</jmolAppletButton>
</jmol>

==Modelling Using Semi-empirical Molecular Orbital Theory==
===Regioselective Addition of Dichlorocarbene===

==References==
<references/>

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