ChemWiki - User contributions [en]

Mod:Hunt Research Group/calendar

2015-04-07T22:03:17Z

Ohb09: /* Calendar */

Back to the main [https://www.ch.ic.ac.uk/wiki/index.php/Mod:Hunt_Research_Group wiki-page]
== Calendar ==

{| class="wikitable"
|-
! 1
! 2
! 3
! 4
|-
| Tricia (Done)
| Bryan Ward (Done)
| Claire Ashworth (Done)
| Precious Ugbomah (Done)
|-
| Vincent Chen (Done)
| Gabriel Lau (Not Done)
| Rebecca Rowe (Done)
| Ken Watson (Done)
|-
| Laila Bana (Done)
| Oliver Benton (Done)
| Christopher Sewell (Done)
| Chen Chen (Not Done)
|-
| Aiswarya Prabha (Done)
|Ziyun Zhang (Done)
|Richard Fogarty (Done)
|
|-
|-)
|}

<table border="1" cellpadding="5" width="1190">
<tr bgcolor="#66CCFF">
<th width="170px">Mon</th>
<th width="170px">Tues</th>
<th width="170px">Wed</th>
<th width="170px">Thur</th>
<th width="170px">Fri</th>
<th width="170px" bgcolor="#CCCCCC">Sat</th>
<th width="170px" bgcolor="#CCCCCC">Sun</th>
</tr>

<tr valign="top">
<td>16th<br></td>
<td>17th<br><br></td>
<td>18th<br></td>
<td>19th<br></td>
<td>20th<br></td>
<td bgcolor="#CCCCCC">21st<br></td>
<td bgcolor="#CCCCCC">22nd<br></td>
</tr>
<tr valign="top">
<td>23rd<br>Richard F Away<br></td>
<td>24th<br>Richard F Away<br></td>
<td>25th<br>Richard F Away<br></td>
<td>26th<br></td>
<td bgcolor="#FFFF00">27th<br>'''END OF TERM'''</td>
<td bgcolor="#CCCCCC">28th<br></td>
<td bgcolor="#CCCCCC">29th<br></td>
</tr>
<tr valign="top">
<td>30th<br></td>
<td>31st<br><br></td>
<td bgcolor="#4357CFF"><span style="color:white">'''1st April'''</span><br></td>
<td bgcolor="#33CC99">2nd<br>'''College closed'''</td>
<td bgcolor="#33CC99">3rd Good Friday<br>'''College closed'''</td>
<td bgcolor="#33CC99">4th<br>'''College closed'''</td>
<td bgcolor="#33CC99">5th<br>'''College closed'''</td>
</tr>
<tr valign="top">
<td bgcolor="#33CC99">6th Easter Monday<br>'''College closed'''</td>
<td bgcolor="#33CC99">7th<br>'''College closed'''<br></td>
<td>8th<br>Precious Away<br>Bryan Away<br>Richard Away<br>Oli Away <br> Becky Away<br>Chris Away</td>
<td>9th<br>Chris Away<br>Becky Away</td>
<td>10th<br>Ken Away<br>Tricia Away<br>Claire Away<br>Chris Away<br>Vincent Away</td>
<td bgcolor="#CCCCCC">11th<br></td>
<td bgcolor="#CCCCCC">12th<br></td>
</tr>
<tr valign="top">
<td >13th<br>Ken Away<br>Chris Away</td>
<td>14th<br><br></td>
<td>15th<br></td>
<td>16th<br></td>
<td>17th<br></td>
<td bgcolor="#CCCCCC">18th<br></td>
<td bgcolor="#CCCCCC">19th<br></td>
</tr>
<tr valign="top">
<td >20th<br></td>
<td>21st<br><br></td>
<td>22nd<br></td>
<td>23rd<br></td>
<td>24th<br></td>
<td bgcolor="#CCCCCC">25th<br></td>
<td bgcolor="#CCCCCC">26th<br></td>
</tr>
<tr valign="top">
<td bgcolor="#FFFF00" >27th<br>'''NEW TERM'''</td>
<td>28th<br><br></td>
<td>29th<br></td>
<td>30th<br></td>
<td bgcolor="#4357CFF"><span style="color:white">'''1st May'''</span><br></td>
<td bgcolor="#CCCCCC">2nd<br></td>
<td bgcolor="#CCCCCC">3rd<br></td>
</tr>
<tr valign="top">
<td bgcolor="#33CC99">4th Bank Holiday<br>'''College closed'''</td>
<td>5th<br><br></td>
<td>6th<br></td>
<td>7th<br></td>
<td>8th<br></td>
<td bgcolor="#CCCCCC">9th<br></td>
<td bgcolor="#CCCCCC">10th<br></td>
</tr>
<tr valign="top">
<td>11th<br></td>
<td>12th<br><br></td>
<td>13th<br></td>
<td>14th<br></td>
<td>15th<br></td>
<td bgcolor="#CCCCCC">16th<br></td>
<td bgcolor="#CCCCCC">17th<br></td>
</tr>
<tr valign="top">
<td>18th<br></td>
<td>19th<br><br></td>
<td>20th<br></td>
<td>21st<br></td>
<td>22nd<br></td>
<td bgcolor="#CCCCCC">23rd<br></td>
<td bgcolor="#CCCCCC">24th<br></td>
</tr>
<tr valign="top">
<td bgcolor="#33CC99">25th Bank Holiday<br>'''College closed'''</td>
<td>26th<br><br></td>
<td>27th<br></td>
<td>28th<br></td>
<td>29th<br></td>
<td bgcolor="#CCCCCC">30th<br></td>
<td bgcolor="#CCCCCC">31st<br></td>
</tr>
</table>

Mod:Hunt Research Group/calendar

2015-03-31T09:26:14Z

Ohb09: /* Calendar */

Back to the main [https://www.ch.ic.ac.uk/wiki/index.php/Mod:Hunt_Research_Group wiki-page]
== Calendar ==

{| class="wikitable"
|-
! 1
! 2
! 3
! 4
|-
| Tricia (Done)
| Bryan Ward (Not Done)
| Claire Ashworth (Done)
| Precious Ugbomah (Not Done)
|-
| Vincent Chen (Not Done)
| Gabriel Lau (Not Done)
| Rebecca Rowe (Not Done)
| Ken Watson (Not Done)
|-
| Laila Bana (Not Done)
| Oliver Benton (Done)
| Christopher Sewell (Not Done)
| Chen Chen (Not Done)
|-
| Aiswarya Prabha (Not Done)
|Ziyun Zhang (Not Done)
|
|
|-
|-)
|}

<table border="1" cellpadding="5" width="1190">
<tr bgcolor="#66CCFF">
<th width="170px">Mon</th>
<th width="170px">Tues</th>
<th width="170px">Wed</th>
<th width="170px">Thur</th>
<th width="170px">Fri</th>
<th width="170px" bgcolor="#CCCCCC">Sat</th>
<th width="170px" bgcolor="#CCCCCC">Sun</th>
</tr>

<tr valign="top">
<td>16th<br></td>
<td>17th<br><br></td>
<td>18th<br></td>
<td>19th<br></td>
<td>20th<br></td>
<td bgcolor="#CCCCCC">21st<br></td>
<td bgcolor="#CCCCCC">22nd<br></td>
</tr>
<tr valign="top">
<td>23rd<br>Richard F Away<br></td>
<td>24th<br>Richard F Away<br></td>
<td>25th<br>Richard F Away<br></td>
<td>26th<br></td>
<td bgcolor="#FFFF00">27th<br>'''END OF TERM'''</td>
<td bgcolor="#CCCCCC">28th<br></td>
<td bgcolor="#CCCCCC">29th<br></td>
</tr>
<tr valign="top">
<td>30th<br></td>
<td>31st<br><br></td>
<td bgcolor="#4357CFF"><span style="color:white">'''1st April'''</span><br></td>
<td bgcolor="#33CC99">2nd<br>'''College closed'''</td>
<td bgcolor="#33CC99">3rd Good Friday<br>'''College closed'''</td>
<td bgcolor="#33CC99">4th<br>'''College closed'''</td>
<td bgcolor="#33CC99">5th<br>'''College closed'''</td>
</tr>
<tr valign="top">
<td bgcolor="#33CC99">6th Easter Monday<br>'''College closed'''</td>
<td bgcolor="#33CC99">7th<br>'''College closed'''<br></td>
<td>8th<br></td>
<td>9th<br></td>
<td>10th<br>Ken Away<br>Tricia Away<br>Claire Away</td>
<td bgcolor="#CCCCCC">11th<br></td>
<td bgcolor="#CCCCCC">12th<br></td>
</tr>
<tr valign="top">
<td >13th<br>Ken Away</td>
<td>14th<br><br></td>
<td>15th<br></td>
<td>16th<br></td>
<td>17th<br></td>
<td bgcolor="#CCCCCC">18th<br></td>
<td bgcolor="#CCCCCC">19th<br></td>
</tr>
<tr valign="top">
<td >20th<br></td>
<td>21st<br><br></td>
<td>22nd<br></td>
<td>23rd<br></td>
<td>24th<br></td>
<td bgcolor="#CCCCCC">25th<br></td>
<td bgcolor="#CCCCCC">26th<br></td>
</tr>
<tr valign="top">
<td bgcolor="#FFFF00" >27th<br>'''NEW TERM'''</td>
<td>28th<br><br></td>
<td>29th<br></td>
<td>30th<br></td>
<td bgcolor="#4357CFF"><span style="color:white">'''1st May'''</span><br></td>
<td bgcolor="#CCCCCC">2nd<br></td>
<td bgcolor="#CCCCCC">3rd<br></td>
</tr>
<tr valign="top">
<td bgcolor="#33CC99">4th Bank Holiday<br>'''College closed'''</td>
<td>5th<br><br></td>
<td>6th<br></td>
<td>7th<br></td>
<td>8th<br></td>
<td bgcolor="#CCCCCC">9th<br></td>
<td bgcolor="#CCCCCC">10th<br></td>
</tr>
<tr valign="top">
<td>11th<br></td>
<td>12th<br><br></td>
<td>13th<br></td>
<td>14th<br></td>
<td>15th<br></td>
<td bgcolor="#CCCCCC">16th<br></td>
<td bgcolor="#CCCCCC">17th<br></td>
</tr>
<tr valign="top">
<td>18th<br></td>
<td>19th<br><br></td>
<td>20th<br></td>
<td>21st<br></td>
<td>22nd<br></td>
<td bgcolor="#CCCCCC">23rd<br></td>
<td bgcolor="#CCCCCC">24th<br></td>
</tr>
<tr valign="top">
<td bgcolor="#33CC99">25th Bank Holiday<br>'''College closed'''</td>
<td>26th<br><br></td>
<td>27th<br></td>
<td>28th<br></td>
<td>29th<br></td>
<td bgcolor="#CCCCCC">30th<br></td>
<td bgcolor="#CCCCCC">31st<br></td>
</tr>
</table>

Mod:Hunt Research Group/calendar

2014-12-22T10:19:56Z

Ohb09: /* Calendar */

Back to the main [https://www.ch.ic.ac.uk/wiki/index.php/Mod:Hunt_Research_Group wiki-page]
== Calendar ==

{| class="wikitable"
|-
! 1
! 2
! 3
! 4
|-
| Tricia (Done)
| Matthew Clough (Not Done)
| Bryan Ward (Done)
| Claire Ashworth (Done)
|-
| Precious Ugbomah (Done)
| Richard Matthews (Done)
| Vincent Chen (Done)
| Gabriel Lau (Done)
|-
| Rebecca Rowe (Done)
| Patricia Ho (Done)
| Ken Watson (Done)
| Laila Bana (Done)
|-
| Oliver Benton (Done)
|Christopher Sewell (Not Done)
|Chen Chen (Done)
|Aiswarya Prabha (Done)
|-
|-)
|}

<table border="1" cellpadding="5" width="1190">
<tr bgcolor="#66CCFF">
<th width="170px">Mon</th>
<th width="170px">Tues</th>
<th width="170px">Wed</th>
<th width="170px">Thur</th>
<th width="170px">Fri</th>
<th width="170px" bgcolor="#CCCCCC">Sat</th>
<th width="170px" bgcolor="#CCCCCC">Sun</th>
</tr>
<tr valign="top">
<td bgcolor="#4357CFF"><span style="color:white">'''1st December'''</span><br><br></td>
<td>2nd<br><br></td>
<td>3rd<br><br></td>
<td>4th<br><br></td>
<td>5th<br><br></td>
<td bgcolor="#CCCCCC">6th<br></td>
<td bgcolor="#CCCCCC">7th<br></td>
</tr>
<tr valign="top">
<td>8th<br>Richard F Away<br></td>
<td>9th<br>Richard F Away<br></td>
<td>10th<br>Richard F Away<br></td>
<td>11th<br>Richard F Away<br></td>
<td>12th<br><br></td>
<td bgcolor="#CCCCCC">13th<br></td>
<td bgcolor="#CCCCCC">14th<br></td>
</tr>
<tr valign="top">
<td>15th<br>Richard M Away<br></td>
<td>16th<br>Richard F Away<br>Richard M Away<br></td>
<td>17th<br>Richard F Away<br>Richard M Away<br></td>
<td>18th<br><br>Richard M Away<br></td>
<td bgcolor="#FFFF00">19th<br>'''END OF TERM'''<br>Bryan Away<br>Precious Away<br>Richard M Away<br></td>
<td bgcolor="#CCCCCC">20th<br></td>
<td bgcolor="#CCCCCC">21st<br></td>
</tr>
<tr valign="top">
<td>22nd<br>Tricia Away<br>Ken Away<br>Bryan Away<br>Claire Away<br>Precious Away<br>Richard M Away<br>Aiswarya Away<br>Gabriel Away<br>Rebecca Away<br>Oli Away<br></td>
<td>23rd<br>Tricia Away<br>Ken Away<br>Bryan Away<br>Claire Away<br>Precious Away<br>Richard M Away<br>Aiswarya Away<br>Gabriel Away<br>Rebecca Away<br>Richard F Away<br>Oli Away</td>
<td bgcolor="#33CC99">24th<br>'''College closed'''</td>
<td bgcolor="#33CC99">25th<br>'''College closed'''</td>
<td bgcolor="#33CC99">26th<br>'''College closed'''</td>
<td bgcolor="#CCCCCC">27th<br></td>
<td bgcolor="#CCCCCC">28th<br></td>
</tr>
<tr valign="top">
<td bgcolor="#33CC99">29th<br>'''College closed'''</td>
<td bgcolor="#33CC99">30th<br>'''College closed'''</td>
<td bgcolor="#33CC99">31st<br>'''College closed'''</td>
<td bgcolor="#4357CFF"><span style="color:white">'''1st January 2015'''</span><br>'''College closed'''</td>
<td bgcolor="#33CC99">2nd<br>'''College closed'''</td>
<td bgcolor="#CCCCCC">3rd<br></td>
<td bgcolor="#CCCCCC">4th<br></td>
<tr valign="top">
<td>5th<br>Precious Away<br>Aiswarya Away<br>Gabriel Away<br>Chen Chen Away<br>Rebecca Away<br></td>
<td>6th<br>Aiswarya Away<br>Gabriel Away<br>Rebecca Away<br></td>
<td>7th<br>Aiswarya Away<br>Gabriel Away<br>Rebecca Away<br></td>
<td>8th<br>Aiswarya Away<br>Gabriel Away<br>Rebecca Away<br>Richard F Away<br></td>
<td>9th<br>Aiswarya Away<br>Gabriel Away<br>Rebecca Away<br>Richard F Away<br></td>
<td bgcolor="#CCCCCC">10th<br></td>
<td bgcolor="#CCCCCC">11th<br></td>
</tr>
<tr valign="top">
<td bgcolor="#FFFF00">12th<br>'''NEW TERM'''<br>Aiswarya Away (P)<br></td>
<td>13th<br>Aiswarya Away (P)<br></td>
<td>14th<br><br></td>
<td>15th<br>Richard F Away<br></td>
<td>16th<br>Richard F Away<br></td>
<td bgcolor="#CCCCCC">17th<br></td>
<td bgcolor="#CCCCCC">18th<br></td>
</tr>
<tr valign="top">
<td>19th<br></td>
<td>20th<br><br></td>
<td>21st<br><br></td>
<td>22nd<br><br></td>
<td>23rd<br><br></td>
<td bgcolor="#CCCCCC">24th<br></td>
<td bgcolor="#CCCCCC">25th<br></td>
</tr>
<tr valign="top">
<td>26th<br></td>
<td>27th<br><br></td>
<td>28th<br><br></td>
<td>29th<br><br></td>
<td>30th<br><br></td>
<td bgcolor="#CCCCCC">31st<br></td>
<td bgcolor="#4357CFF"><span style="color:white">'''1st February 2015'''</span><br></td>
</tr>
</table>

Rep:Mod:benton2

2013-02-08T16:18:12Z

Ohb09: /* Regioselective Addition of Dichlorocarbene to a diene */

=Module 1 - Intro=
In this experiment, MM2 is compared to the more advanced MOPAC minimisation technique. A minimised molecule is then analysed and compared to literature.
Molecular mechanics, used here in its MM2 form is a very good first order approximation. Using data from previous experiments and breaking down the overall energy into different categories, such as van der Waals interaction, dipole-dipole, and bending before summing them to provide an overall energy is a very useful and more importantly quick method to calculate a molecules energy. The energy of molecule can then be iteratively reduced by tweaking the position of the atoms and conformations, providing a low energy structure. However it does have its limitations. Firstly, because of the large approximations used, the method is liable to fall, and remain, in an initial, smaller, potential well at a higher energy than the minimum possible. This can be overcome by carefully arranging the molecule by the user of the program to avoid these early, high energy minima, but requires a lot of rearrangement and prioir knowledge of low energy arrangements. As MM2 uses previously aquired data, it is also not that useful in determining new structures, or functional groups for which it does not have the data for.
MOPAC uses a different approach for minimisation. It uses semi empirical quantum chemistry functions to determine the energy of a molecule. This allows more advanced effects to be included in the calculation and allows for analysis of the neighbouring group effect in sacchardie chemistry and regioselectivity effects, as studied here.
Computational chemistry can also predict spectra, and in the last part of the experiment predicted spectra are compared to literature and the results analysed.

==Week 1==

===Hydrogenation of the Cyclopentadiene Dimer===
The endo dimer is primarily produced when cyclopentadiene dimerises, in a ratio of 99.5% to 0.5% <ref>
Małgorzata E Jamróz, Sławomir Gałka, Jan Cz Dobrowolski,
On dicyclopentadiene isomers,
Journal of Molecular Structure: THEOCHEM,
Volume 634, Issues 1–3, 5 September 2003,
Pages 225-233, ISSN 0166-1280,
<DOI|10.1016/S0166-1280(03)00348-8>
</ref>(at least when thermally initiated; photo initiation produces a racemic mixture of the two isomers<ref>
The Photosensitited Dimerization of Cyclopentadiene
Nicholas J. Turro and George S. Hammond
Journal of the American Chemical Society 1962 84 (14), 2841-2842
<DOI|10.1021/ja00873a050>
</ref>)
{| class="wikitable" border="1"

! rowspan="2" | Molecule
|style="text-align: center;" |Exo
|style="text-align: center;" |Endo
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbexodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Total E (kcal/mol)
|33.9975
|31.8764
|-
|}
[[file:Endoexoohb.bmp|thumb|left|500px]]
The small energy difference calculated by the MM2 forcefield does not highlight why the endo for is favoured over the exo form as it shows the exo form is lower in energy. While the difference between the two energies is relatively trivial, the high enationmeric excess of the products suggest that this is only part of the story, and suggest that this reaction is under kinetic rather than thermodynamic control.<ref> W.C.Herndon, C.R.Grayson, J.M.Manion; "Retro-Diels-Alder reactions. III. Kinetics of the thermal decompositions of exo- and endo-dicyclopentadiene" J. Org. Chem.; 1967, 32 (3); 526-529.DOI:10.1021/jo01278a003</ref> Being under kinetic control would imply the activation energy, and hence transition state, for the endo species is lower than the exo form and so the endo enantiomer is formed faster. This can be rationalised by looking at the orbital interactions in the two transition states.

The endo transition state is stabilised by the secondary favourable overlap whereas in the exo form there is no such overlap to stabilised the molecule meaning that the transition state is a higher energy, and so is less favourable. This cannot be handled by the simple MM2 calculation however.

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" colspan="2" |Different hydrogenation sites
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh3.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh4.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|1.2489
|1.1303
|-
!Bend
|19.1608
|13.10259
|-
!Torsion
|11.0730
|12.4118
|-
!VDW
|5.7962
|4.4398
|-
!Dipole-Dipole
|0.1622
|0.1410
|-
!Total E (kcal/mol)
|34.9643
|29.2475
|-
|}

The site of initial hydrogenation of the endo dimer can also be determined by calculating the energies of the two possible isomers. From these calculations it is clear that the second molecule is favoured more, as it is ~5.5kcalmol<sup>-1</sup> more stable. The bending energy in both of these molecules is the major difference. This manifests itself in the amount that the atoms are ebent away from their ideal positions, which is 109.5 for an sp3 carbon and 120 for an sp2 carbon. Across all of the key bonds, the second isomer has bond angles that are closer to the ideal than the first isomer; in particular the C-C=C bond angles; in the first molecule they are 107.6 and in the second 112.8. This difference of five degrees is enough to significantly stabilise the second isomer, making hydrogenation at that site the more preferable.

===Atropisomerism in an Intermediate related to the synthesis of Taxol===
In the complete synthesis of Taxol, and important cancer fighting drug, proposed by Pacquette <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 10.1016/S0040-4039(00)92617-0</ref> a key intermediate is either "Precursor 9" or "Precursor 10".

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" |Precursor 10
|style="text-align: center;" |Precursor 9
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol9.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol10.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|2.4687
|2.7846
|-
!Bend
|10.5555
|16.5411
|-
!Torsion
|17.4240
|18.2518
|-
!VDW
|13.1930
|13.1096
|-
!Dipole-Dipole
| -1.8818
| -1.7248
|-
!Total E (kcal/mol)
|39.1215
|47.8395
|-
|}
Precursor 9 and 10 are synthesised using a reversible oxy-Cope rearrangement as demonstrated below. As this process is in equilibrium that, with precursor 10 being more stable, it is predicted that this isomer will be the one produced as all of the molecules attempt to reduce the energy. As analysis of the individual energy componenets shows, this arrangement is a lot less strained than Precursor nine, which requires a lot more bending energy.

The molecule was then optimised with an MMFF94. Rather than rely on a large set of experimentally determined parameters like MM2, MMFF94 minimises the potential of each atom iteratively, attempting to minimise the whole molecule. Although the values produced for these two methods cannot be directly compared, they both correctly identify the correct altropisomer as being lower in energy.
{|class="wikitable" border="1"
! colspan="3" | Comparison of MMFF94 and MM2 minimisations
|-
!Molecule
| Precursor 9
| Precursor 10
|-
!MM2 minimised Energy (kJmol<sup><-1</sup>)
|39.1215
|47.8395
|-
!MMFF94 minimised Energy (kcalmol<sup><-1</sup>)
|58.7513
|70.5377
|-
|}

===Regioselective Addition of Dichlorocarbene to a diene===

The addition of a dichlorocarbene to 9-chloromethanonaphthalene occurs in a surprisingly stereospcific manor. Why this happens can be predicted using computational techniques.

Molecule A, 9-chloromethanonaphthalene, was initially optimised using a molecular mechanics (MM2) calculation

{| style="wikitable" border="1"
|<jmol>
<jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
It was then further optimised with a MOPAC calculation, which takes into effect stereoelectronic effects. The two were then compared.

{| class="wikitable" border="1"
!colspan="3" | Comparison of two optimisation calculations
|-
! Overlay of two optimised molecules !! MM2 optimised molecule !! MOPAC Optimised Molecule
|-
|[[file:Ohboverlaydiene.png|300px]]
The MM2 optimised molecule is coloured yellow for clarity
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1mopac.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! rowspan="6" | Distances between
corresponding atoms

on the overlaid molecules (Å)
|style="text-align: center;" | C(34)-C(9)
|0.5247
|-
|style="text-align: center;" | C(26)-C(1)
|0.5246
|-
|style="text-align: center;" | H(47)-H(22)
|0.8526
|-
|style="text-align: center;" | H(38)-H(13)
|0.8524
|-
|style="text-align: center;" | Cl(37)-Cl(12)
|0.0689
|}

As can be seen by the comparison above, when using the stereoelectronic interactions, the cyclohexadiene ring on the side with the Cl atom is moved further away from the Cl using the MOPAC calculation than the MM2. This is because the electronic effects included in this calculation include the repulsion between the electron rich Chlorine atom and the electron rich double bond, whereas the MM2 calculation doesn't include this and so a symmetrical molecule is formed.

====MOs====

The MOs of the previously MOPAC optimised molecule where then calculated using Guassian (B3LYP 6-31G)
{| style="wikitable" border="1"
! Homo-1 !! colspan="2" | Homo
|-
|[[File:Ohbclhomo-1.jpg|250px]]
| <jmol>
<jmolApplet>
<title>Orbital</title><color>white</color><size>250</size>
<script>isosurface color orange purple "images/f/f2/Ohbdienemo48.cub.jvxl" translucent; </script>
<uploadedFileContents>Ohbdienemo48.cub.xyz</uploadedFileContents>
</jmolApplet>
</jmol>
|[[File:Ohbclhomo.jpg|250px]]
|-
!Lumo !! Lumo+1 !! Lumo+2
|-
|[[File:Ohbcllumo.jpg|250px]]
|[[File:Ohbcllumo+1.jpg|250px]]
|[[File:Ohbcllumo+2.jpg|250px]]
|-
|colspan="2" | [[File:Ohbclmep.jpg|500px|rotate="90"]] Electrostatic diagram.
| [[File:Ohbclelevels.png|250px]]
|}

Molecule 2 was initially minimised using an MM2 calculation. The reactions of molecule A with an electrophile can be illustrated by taking a more advanced, quantum mechanical approach to modelling the molecule and its orbitals. This will also allow prediction of which C=C reacts with an electrophile.
Of the two alekenes, the endo is favoured rather than the exo because the cl-c sigma star orbital mixes with the exo alkene. This stabilises both orbitals, as shown by the frequency calculation having a higher value than the endo alkene, but reduces the pi bond character of the exo alkene. This is also shown by the comparative lengths of the alkene bonds - the exo is 1.3355A and the endo is 1.33190A. The cycloaddition of the carbene requires an alkene and so favours the endo alkene as it has a higher p character. The homo is also focused entirely on the endo side of the molecule, with the lumo focused mainly on the exo side. The Homo shows the high pi bond character of the endo alkene. The Homo-1 is mainly focused ont he exo alekene, so shows the pi bond character of the exo alekene. This is lower in energy and so is less likely to react with the carbene molecule.
The electrostatic diagram at the bottom displays how there is more negative charge on the endo alkene, which again is favourable to electrophillic attack.

====Glycosidation====

When the monosaccharide pyranose has an acetal in the 2 position, four different isomers can be formed, all of differing stability. These differing positions of the acetal group and its interactions with the neighbouring group means that it acts as a directing group to nucleophilic attack. With deprotonation to an oxenium cation being the initial step, the acetal group can then stabilise this to varying degrees depending on its position. Due to the Sn1 nature of the glycosidation nucleophilic attack occurring, the access of the nucleophile to the sigma* orbital of the carbon is crucial, and this depends on the Burgi-Dunitz angle of 107<ref> H. B. Bürgi, J. D. Dunitz, J. M. Lehn, G. Wipff (1974). "Stereochemistry of reaction paths at carbonyl centres". Tetrahedron 30 (12): 1563–1572. doi:10.1016/S0040-4020(01)90678-7</ref>.
Two sets of calculations were performed; initially using an MM2 forcefield, and then with using the MOPAC approach. While both approaches showed a similar trend, the benefit of the MOPAC, to make and break bond meant that the structures formed by this minimisation resembled the transition state a lot more closely than those formed by the MM2.
As shown by the table, below, all of the initial cations are at a lower energy than the intermediate forms, however the structures differ slightly depending on whether an MM2 or MOPAC minimisation was performed; the MOPAC structures much more closely resemble the transition states.
The differences in energy can be directly related to the amount of strain present within the molecule and the repulsion between the oxygen atoms. The large amount of strain present in the intermediates, particularly of molecule 2, mean that they have a lot higher energy. A notable differences is that the MM2 struggles to accurately deal with the oxenium cation, whereas the MOPAC produces a more lifelike picture in this area.
The glycosidation mainly produces the trans isomers, ie molecules going through the pathways of molecules 1 & 4. This is predicted well by the computational methods used, with both the initial molecules and the intermediates being lower in energy and having lower anomeric carbon-acetal oxygen distances.

=====Mechanisms=====

[[file:Ohbglymech.gif|800px]]

{|class="wikitable" border="2"
!rowspan="5" |Initial molecule
!colspan="2" | Conformation
|1
|2
|3
|4
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2amm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 11.5430
| 46.2672
| 35.5277
| 29.5144
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -90.51343
| -70.57703
| -72.56010
| -85.04737
|-
!rowspan="5" |Intermediate
!colspan="2" | Conformation
|chemdraw
|chemdraw
|chemdraw
|chemdraw
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2Bmm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 28.4913
| 43.2706
| 41.0918
| 31.8763
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -91.66112
| -66.72331
| -84.44899
| -88.08089

|-
|}

==Comparison of coumpational results to a molecule from literature.==

===Taxol intermediate===

Computational chemistry can be a powerful tool in the analysis and reproduction of spectra. in this exercise, literature values and spectra are compared to computed data and the effectiveness and accuracy of both methods is compared and contrasted.

A different intermediate in the synthesis of taxol was optimised using MM2 to produce the structure (right) with a total energy of 66.7072kcal<sup>-1</sup>
{| class="wikitable border="1"
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
This file was then optimised using Guassian and B3LYP 6-31G(d,p) basis set. The resulting file was then resubmitted to the SCAN cluster for computation of the nmr spectrum using these keywords # mpw1pw91/6-31G(d,p) NMR SCRF=(CPCM,Solvent=chloroform). These results were then compared to those found in the literature<ref>#L. Paquette, N. A. Pegg, D. Toops, G. D. Maynard, R. D. Rogers, ''J. Am. Chem. Soc.,'', '''1990''', ''112'', 277-283. {{DOI|10.1021/ja00157a043}}</ref>.
The results are below. As can be seen by this comparison chart, in general there is very good agreement between the predicted and measured shift values. With the only major discrepancy being at Carbon 16.

This however, can be resolved. The large distance is probably to do with this carbon being bonded to two sulphur atoms. The 6-31G(d,p) basis set is not very good at approximating, and hence optimising sulphur molecules. This is because Sulphur contains f type functions, of which there are 7. However there are 10<ref>SIMPLIFIED INTRODUCTION TO AB INITIO
BASIS SETS. TERMS AND NOTATION.
Jan K. Labanowski, Ohio Supercomputer Center,
1224 Kinnear Rd., Columbus, OH 43212-1163,</ref> possible Guassians, and so an element of contamination from the 4p orbitals is brought in. As the 6-31G(d,p) does not containg any f functions, it is not that good at predicting the behaviour of the sulphur molecule to the level required by the nmr calculation. Despite all of this, the shift values are still similar, and so the assignmnet of this molecule inth e literature can be deemed correct.
{|class="wikitable" border="2"
!Atom number !! Calculated ppm value !! Lit. ppm value
|-
| 1
| 27.5886
| 25.66
|-
| 2
| 31.6721
| 28.79
|-
| 3
| 52.6851
| 48.5
|-
| 4
| 146.8944
| 144.63
|-
| 5
| 51.4817
| 46.8
|-
| 6
| 20.6456
| 18.71
|-
| 7
| 27.0826
| 23.86
|-
| 8
| 125.7193
| 125.33
|-
| 9
| 50.5885
| 45.76
|-
| 10
| 218.6545
| 218.79
|-
| 11
| colspan="2" | Oxygen
|-
| 12
| 54.1882
| 52.52
|-
| 13
| 30.8219
| 28.29
|-
| 14
| 63.85
| 56.19
|-
| 15
| 29.5406
| 26.88
|-
| 16
| 89.99
| 72.88
|-
| 17
| 48.9728
| 39.8
|-
| 18
| 24.6905
| 20.96
|-
| 19
| 41.3115
| 32.66
|-
| 21
| 44.3139
| 35.85
|-
| 22
| 45.5337
| 38.81
|}

===Literature Molecule===

In the synthesis of molecule A (below), using Kobayashi aldol chemistry, two stereoisomers are produced. Initially, the syn isomer is formed, with a diasteromic ratio of 1:14, and via a similar synthetic route, the anti isomer is also produced, with a high dr of 1:>50. The high stereoselectivity of both of these reactions is an important step in the synthesis of enationmerically pure natural products.

{| class="wikitable border="1"
!Molecule A
! Syn
! Anti
|-
![[File:Ohbmol.gif|300px]]
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbsyn.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbanti.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
|}
Initiallyu the models were optimised using an MM2 optimisation within ChemBio 12.0. They were then further optimised using an RB3LYP-6-31G(d,p) method and basis set. After the optimisation, and checking to see that the the two molecules were still distinct, with one syn and one anti form, they were submitted for nmr analysis, to produce a predicted nmr. This was then compared with the reported nmr, with a view to see if the assignments and conclusions made in the literature were correct. There was a good correlations between the predicted and measured nmr peaks, with deviations, as show below, of less than 1ppm for the H nmr and less than 10ppm for the <sup>13</sup>C nmr.
[[File:Ohbccomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each carbon atom]]
[[File:Ohbhcomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each Hydrogen atom]]

This correlation helps confirm that the structures are correct; the different enantiomers are differentiated and assigned correctly. If they were not, and the calculated syn nmr is compared to the measured anti nmr, and vice versa, larger differences are noted. This is highlighted on the graph below. The blue and red graphs are the correctly assigned and matched nmrs, the green and purple nmrs are if they are assigned incorrectly. It can clearly be seen that the green and purple line are consistently higher than their counterparts.
[[file:Ohbcomparisonnmr.png|thumb|900px|none|left|Comparison of correct and incorrect assignment for the two conformers]]
Within the literature all of the hydrogens and carbons are assigned, with the exception of Hydrogen 48. This is because this is a labile proton and so does not show up on measured nmrs due to rapid exchange with the deuterium in the deuterated solvent. However the calculated spectra does not take this into account and so displays the shift value for this hydrogen.

The computed IR spectra are very similar for the two molecules. The OH stretch is increased by 30cm<sup>-1</sup> in the syn form of the molecule and the CH bend region between 1000-1500cm<sup>-1</sup> is also significantly different. This can be rationalised by the different atomic orbital overlaps that are occuring due to the different positioning of the methyl group. The literature does not supply data for the IR spectra of these two compounds, and it is understandable why as it would be impossible to differentiate between the two molecules through the IR, as they are so similar.

[[File:Irnzohb.png|thumb|900px|none|left|Comparison of the two computed IR spectra]]
[[File:Irzoomedohb.png|thumb|900px|none|left|Zoom showing main differences between spectra]]

As can be seen above, the differences, while there, are slight and insufficient to draw conclusions from.

As both molecules are chiral, they both rotate light in opposite directions. However due to the large size of this molecule and although it is relatively conformationally limited due to the double bond and ring, the calculation for the syn and anti variants did not converge after 48 a 48 hour run on the SCAN.

Despite the inconclusive IR I believe the correct assignments have been made in this case due to the close correlation between the predicted and measured <sup>13</sup>C and H nmr; this highlights the importance of computational chemistry, it can easily help corroborate results.

==References==
<references></references>

Rep:Mod:benton2

2013-02-08T16:16:34Z

Ohb09: /* MOs */

=Module 1 - Intro=
In this experiment, MM2 is compared to the more advanced MOPAC minimisation technique. A minimised molecule is then analysed and compared to literature.
Molecular mechanics, used here in its MM2 form is a very good first order approximation. Using data from previous experiments and breaking down the overall energy into different categories, such as van der Waals interaction, dipole-dipole, and bending before summing them to provide an overall energy is a very useful and more importantly quick method to calculate a molecules energy. The energy of molecule can then be iteratively reduced by tweaking the position of the atoms and conformations, providing a low energy structure. However it does have its limitations. Firstly, because of the large approximations used, the method is liable to fall, and remain, in an initial, smaller, potential well at a higher energy than the minimum possible. This can be overcome by carefully arranging the molecule by the user of the program to avoid these early, high energy minima, but requires a lot of rearrangement and prioir knowledge of low energy arrangements. As MM2 uses previously aquired data, it is also not that useful in determining new structures, or functional groups for which it does not have the data for.
MOPAC uses a different approach for minimisation. It uses semi empirical quantum chemistry functions to determine the energy of a molecule. This allows more advanced effects to be included in the calculation and allows for analysis of the neighbouring group effect in sacchardie chemistry and regioselectivity effects, as studied here.
Computational chemistry can also predict spectra, and in the last part of the experiment predicted spectra are compared to literature and the results analysed.

==Week 1==

===Hydrogenation of the Cyclopentadiene Dimer===
The endo dimer is primarily produced when cyclopentadiene dimerises, in a ratio of 99.5% to 0.5% <ref>
Małgorzata E Jamróz, Sławomir Gałka, Jan Cz Dobrowolski,
On dicyclopentadiene isomers,
Journal of Molecular Structure: THEOCHEM,
Volume 634, Issues 1–3, 5 September 2003,
Pages 225-233, ISSN 0166-1280,
<DOI|10.1016/S0166-1280(03)00348-8>
</ref>(at least when thermally initiated; photo initiation produces a racemic mixture of the two isomers<ref>
The Photosensitited Dimerization of Cyclopentadiene
Nicholas J. Turro and George S. Hammond
Journal of the American Chemical Society 1962 84 (14), 2841-2842
<DOI|10.1021/ja00873a050>
</ref>)
{| class="wikitable" border="1"

! rowspan="2" | Molecule
|style="text-align: center;" |Exo
|style="text-align: center;" |Endo
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbexodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Total E (kcal/mol)
|33.9975
|31.8764
|-
|}
[[file:Endoexoohb.bmp|thumb|left|500px]]
The small energy difference calculated by the MM2 forcefield does not highlight why the endo for is favoured over the exo form as it shows the exo form is lower in energy. While the difference between the two energies is relatively trivial, the high enationmeric excess of the products suggest that this is only part of the story, and suggest that this reaction is under kinetic rather than thermodynamic control.<ref> W.C.Herndon, C.R.Grayson, J.M.Manion; "Retro-Diels-Alder reactions. III. Kinetics of the thermal decompositions of exo- and endo-dicyclopentadiene" J. Org. Chem.; 1967, 32 (3); 526-529.DOI:10.1021/jo01278a003</ref> Being under kinetic control would imply the activation energy, and hence transition state, for the endo species is lower than the exo form and so the endo enantiomer is formed faster. This can be rationalised by looking at the orbital interactions in the two transition states.

The endo transition state is stabilised by the secondary favourable overlap whereas in the exo form there is no such overlap to stabilised the molecule meaning that the transition state is a higher energy, and so is less favourable. This cannot be handled by the simple MM2 calculation however.

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" colspan="2" |Different hydrogenation sites
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh3.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh4.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|1.2489
|1.1303
|-
!Bend
|19.1608
|13.10259
|-
!Torsion
|11.0730
|12.4118
|-
!VDW
|5.7962
|4.4398
|-
!Dipole-Dipole
|0.1622
|0.1410
|-
!Total E (kcal/mol)
|34.9643
|29.2475
|-
|}

The site of initial hydrogenation of the endo dimer can also be determined by calculating the energies of the two possible isomers. From these calculations it is clear that the second molecule is favoured more, as it is ~5.5kcalmol<sup>-1</sup> more stable. The bending energy in both of these molecules is the major difference. This manifests itself in the amount that the atoms are ebent away from their ideal positions, which is 109.5 for an sp3 carbon and 120 for an sp2 carbon. Across all of the key bonds, the second isomer has bond angles that are closer to the ideal than the first isomer; in particular the C-C=C bond angles; in the first molecule they are 107.6 and in the second 112.8. This difference of five degrees is enough to significantly stabilise the second isomer, making hydrogenation at that site the more preferable.

===Atropisomerism in an Intermediate related to the synthesis of Taxol===
In the complete synthesis of Taxol, and important cancer fighting drug, proposed by Pacquette <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 10.1016/S0040-4039(00)92617-0</ref> a key intermediate is either "Precursor 9" or "Precursor 10".

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" |Precursor 10
|style="text-align: center;" |Precursor 9
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol9.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol10.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|2.4687
|2.7846
|-
!Bend
|10.5555
|16.5411
|-
!Torsion
|17.4240
|18.2518
|-
!VDW
|13.1930
|13.1096
|-
!Dipole-Dipole
| -1.8818
| -1.7248
|-
!Total E (kcal/mol)
|39.1215
|47.8395
|-
|}
Precursor 9 and 10 are synthesised using a reversible oxy-Cope rearrangement as demonstrated below. As this process is in equilibrium that, with precursor 10 being more stable, it is predicted that this isomer will be the one produced as all of the molecules attempt to reduce the energy. As analysis of the individual energy componenets shows, this arrangement is a lot less strained than Precursor nine, which requires a lot more bending energy.

The molecule was then optimised with an MMFF94. Rather than rely on a large set of experimentally determined parameters like MM2, MMFF94 minimises the potential of each atom iteratively, attempting to minimise the whole molecule. Although the values produced for these two methods cannot be directly compared, they both correctly identify the correct altropisomer as being lower in energy.
{|class="wikitable" border="1"
! colspan="3" | Comparison of MMFF94 and MM2 minimisations
|-
!Molecule
| Precursor 9
| Precursor 10
|-
!MM2 minimised Energy (kJmol<sup><-1</sup>)
|39.1215
|47.8395
|-
!MMFF94 minimised Energy (kcalmol<sup><-1</sup>)
|58.7513
|70.5377
|-
|}

===Regioselective Addition of Dichlorocarbene to a diene===
Molecule A was initially optimised using a molecular mechanics (MM2) calculation

{| style="wikitable" border="1"
|<jmol>
<jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
It was then further optimised with a MOPAC calculation, which takes into effect stereoelectronic effects. The two were then compared.

{| class="wikitable" border="1"
!colspan="3" | Comparison of two optimisation calculations
|-
! Overlay of two optimised molecules !! MM2 optimised molecule !! MOPAC Optimised Molecule
|-
|[[file:Ohboverlaydiene.png|300px]]
The MM2 optimised molecule is coloured yellow for clarity
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1mopac.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! rowspan="6" | Distances between
corresponding atoms

on the overlaid molecules (Å)
|style="text-align: center;" | C(34)-C(9)
|0.5247
|-
|style="text-align: center;" | C(26)-C(1)
|0.5246
|-
|style="text-align: center;" | H(47)-H(22)
|0.8526
|-
|style="text-align: center;" | H(38)-H(13)
|0.8524
|-
|style="text-align: center;" | Cl(37)-Cl(12)
|0.0689
|}

As can be seen by the comparison above, when using the stereoelectronic interactions, the cyclohexadiene ring on the side with the Cl atom is moved further away from the Cl using the MOPAC calculation than the MM2. This is because the electronic effects included in this calculation include the repulsion between the electron rich Chlorine atom and the electron rich double bond, whereas the MM2 calculation doesn't include this and so a symmetrical molecule is formed.

====MOs====

The MOs of the previously MOPAC optimised molecule where then calculated using Guassian (B3LYP 6-31G)
{| style="wikitable" border="1"
! Homo-1 !! colspan="2" | Homo
|-
|[[File:Ohbclhomo-1.jpg|250px]]
| <jmol>
<jmolApplet>
<title>Orbital</title><color>white</color><size>250</size>
<script>isosurface color orange purple "images/f/f2/Ohbdienemo48.cub.jvxl" translucent; </script>
<uploadedFileContents>Ohbdienemo48.cub.xyz</uploadedFileContents>
</jmolApplet>
</jmol>
|[[File:Ohbclhomo.jpg|250px]]
|-
!Lumo !! Lumo+1 !! Lumo+2
|-
|[[File:Ohbcllumo.jpg|250px]]
|[[File:Ohbcllumo+1.jpg|250px]]
|[[File:Ohbcllumo+2.jpg|250px]]
|-
|colspan="2" | [[File:Ohbclmep.jpg|500px|rotate="90"]] Electrostatic diagram.
| [[File:Ohbclelevels.png|250px]]
|}

Molecule 2 was initially minimised using an MM2 calculation. The reactions of molecule A with an electrophile can be illustrated by taking a more advanced, quantum mechanical approach to modelling the molecule and its orbitals. This will also allow prediction of which C=C reacts with an electrophile.
Of the two alekenes, the endo is favoured rather than the exo because the cl-c sigma star orbital mixes with the exo alkene. This stabilises both orbitals, as shown by the frequency calculation having a higher value than the endo alkene, but reduces the pi bond character of the exo alkene. This is also shown by the comparative lengths of the alkene bonds - the exo is 1.3355A and the endo is 1.33190A. The cycloaddition of the carbene requires an alkene and so favours the endo alkene as it has a higher p character. The homo is also focused entirely on the endo side of the molecule, with the lumo focused mainly on the exo side. The Homo shows the high pi bond character of the endo alkene. The Homo-1 is mainly focused ont he exo alekene, so shows the pi bond character of the exo alekene. This is lower in energy and so is less likely to react with the carbene molecule.
The electrostatic diagram at the bottom displays how there is more negative charge on the endo alkene, which again is favourable to electrophillic attack.

====Glycosidation====

When the monosaccharide pyranose has an acetal in the 2 position, four different isomers can be formed, all of differing stability. These differing positions of the acetal group and its interactions with the neighbouring group means that it acts as a directing group to nucleophilic attack. With deprotonation to an oxenium cation being the initial step, the acetal group can then stabilise this to varying degrees depending on its position. Due to the Sn1 nature of the glycosidation nucleophilic attack occurring, the access of the nucleophile to the sigma* orbital of the carbon is crucial, and this depends on the Burgi-Dunitz angle of 107<ref> H. B. Bürgi, J. D. Dunitz, J. M. Lehn, G. Wipff (1974). "Stereochemistry of reaction paths at carbonyl centres". Tetrahedron 30 (12): 1563–1572. doi:10.1016/S0040-4020(01)90678-7</ref>.
Two sets of calculations were performed; initially using an MM2 forcefield, and then with using the MOPAC approach. While both approaches showed a similar trend, the benefit of the MOPAC, to make and break bond meant that the structures formed by this minimisation resembled the transition state a lot more closely than those formed by the MM2.
As shown by the table, below, all of the initial cations are at a lower energy than the intermediate forms, however the structures differ slightly depending on whether an MM2 or MOPAC minimisation was performed; the MOPAC structures much more closely resemble the transition states.
The differences in energy can be directly related to the amount of strain present within the molecule and the repulsion between the oxygen atoms. The large amount of strain present in the intermediates, particularly of molecule 2, mean that they have a lot higher energy. A notable differences is that the MM2 struggles to accurately deal with the oxenium cation, whereas the MOPAC produces a more lifelike picture in this area.
The glycosidation mainly produces the trans isomers, ie molecules going through the pathways of molecules 1 & 4. This is predicted well by the computational methods used, with both the initial molecules and the intermediates being lower in energy and having lower anomeric carbon-acetal oxygen distances.

=====Mechanisms=====

[[file:Ohbglymech.gif|800px]]

{|class="wikitable" border="2"
!rowspan="5" |Initial molecule
!colspan="2" | Conformation
|1
|2
|3
|4
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2amm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 11.5430
| 46.2672
| 35.5277
| 29.5144
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -90.51343
| -70.57703
| -72.56010
| -85.04737
|-
!rowspan="5" |Intermediate
!colspan="2" | Conformation
|chemdraw
|chemdraw
|chemdraw
|chemdraw
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2Bmm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 28.4913
| 43.2706
| 41.0918
| 31.8763
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -91.66112
| -66.72331
| -84.44899
| -88.08089

|-
|}

==Comparison of coumpational results to a molecule from literature.==

===Taxol intermediate===

Computational chemistry can be a powerful tool in the analysis and reproduction of spectra. in this exercise, literature values and spectra are compared to computed data and the effectiveness and accuracy of both methods is compared and contrasted.

A different intermediate in the synthesis of taxol was optimised using MM2 to produce the structure (right) with a total energy of 66.7072kcal<sup>-1</sup>
{| class="wikitable border="1"
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
This file was then optimised using Guassian and B3LYP 6-31G(d,p) basis set. The resulting file was then resubmitted to the SCAN cluster for computation of the nmr spectrum using these keywords # mpw1pw91/6-31G(d,p) NMR SCRF=(CPCM,Solvent=chloroform). These results were then compared to those found in the literature<ref>#L. Paquette, N. A. Pegg, D. Toops, G. D. Maynard, R. D. Rogers, ''J. Am. Chem. Soc.,'', '''1990''', ''112'', 277-283. {{DOI|10.1021/ja00157a043}}</ref>.
The results are below. As can be seen by this comparison chart, in general there is very good agreement between the predicted and measured shift values. With the only major discrepancy being at Carbon 16.

This however, can be resolved. The large distance is probably to do with this carbon being bonded to two sulphur atoms. The 6-31G(d,p) basis set is not very good at approximating, and hence optimising sulphur molecules. This is because Sulphur contains f type functions, of which there are 7. However there are 10<ref>SIMPLIFIED INTRODUCTION TO AB INITIO
BASIS SETS. TERMS AND NOTATION.
Jan K. Labanowski, Ohio Supercomputer Center,
1224 Kinnear Rd., Columbus, OH 43212-1163,</ref> possible Guassians, and so an element of contamination from the 4p orbitals is brought in. As the 6-31G(d,p) does not containg any f functions, it is not that good at predicting the behaviour of the sulphur molecule to the level required by the nmr calculation. Despite all of this, the shift values are still similar, and so the assignmnet of this molecule inth e literature can be deemed correct.
{|class="wikitable" border="2"
!Atom number !! Calculated ppm value !! Lit. ppm value
|-
| 1
| 27.5886
| 25.66
|-
| 2
| 31.6721
| 28.79
|-
| 3
| 52.6851
| 48.5
|-
| 4
| 146.8944
| 144.63
|-
| 5
| 51.4817
| 46.8
|-
| 6
| 20.6456
| 18.71
|-
| 7
| 27.0826
| 23.86
|-
| 8
| 125.7193
| 125.33
|-
| 9
| 50.5885
| 45.76
|-
| 10
| 218.6545
| 218.79
|-
| 11
| colspan="2" | Oxygen
|-
| 12
| 54.1882
| 52.52
|-
| 13
| 30.8219
| 28.29
|-
| 14
| 63.85
| 56.19
|-
| 15
| 29.5406
| 26.88
|-
| 16
| 89.99
| 72.88
|-
| 17
| 48.9728
| 39.8
|-
| 18
| 24.6905
| 20.96
|-
| 19
| 41.3115
| 32.66
|-
| 21
| 44.3139
| 35.85
|-
| 22
| 45.5337
| 38.81
|}

===Literature Molecule===

In the synthesis of molecule A (below), using Kobayashi aldol chemistry, two stereoisomers are produced. Initially, the syn isomer is formed, with a diasteromic ratio of 1:14, and via a similar synthetic route, the anti isomer is also produced, with a high dr of 1:>50. The high stereoselectivity of both of these reactions is an important step in the synthesis of enationmerically pure natural products.

{| class="wikitable border="1"
!Molecule A
! Syn
! Anti
|-
![[File:Ohbmol.gif|300px]]
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbsyn.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbanti.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
|}
Initiallyu the models were optimised using an MM2 optimisation within ChemBio 12.0. They were then further optimised using an RB3LYP-6-31G(d,p) method and basis set. After the optimisation, and checking to see that the the two molecules were still distinct, with one syn and one anti form, they were submitted for nmr analysis, to produce a predicted nmr. This was then compared with the reported nmr, with a view to see if the assignments and conclusions made in the literature were correct. There was a good correlations between the predicted and measured nmr peaks, with deviations, as show below, of less than 1ppm for the H nmr and less than 10ppm for the <sup>13</sup>C nmr.
[[File:Ohbccomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each carbon atom]]
[[File:Ohbhcomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each Hydrogen atom]]

This correlation helps confirm that the structures are correct; the different enantiomers are differentiated and assigned correctly. If they were not, and the calculated syn nmr is compared to the measured anti nmr, and vice versa, larger differences are noted. This is highlighted on the graph below. The blue and red graphs are the correctly assigned and matched nmrs, the green and purple nmrs are if they are assigned incorrectly. It can clearly be seen that the green and purple line are consistently higher than their counterparts.
[[file:Ohbcomparisonnmr.png|thumb|900px|none|left|Comparison of correct and incorrect assignment for the two conformers]]
Within the literature all of the hydrogens and carbons are assigned, with the exception of Hydrogen 48. This is because this is a labile proton and so does not show up on measured nmrs due to rapid exchange with the deuterium in the deuterated solvent. However the calculated spectra does not take this into account and so displays the shift value for this hydrogen.

The computed IR spectra are very similar for the two molecules. The OH stretch is increased by 30cm<sup>-1</sup> in the syn form of the molecule and the CH bend region between 1000-1500cm<sup>-1</sup> is also significantly different. This can be rationalised by the different atomic orbital overlaps that are occuring due to the different positioning of the methyl group. The literature does not supply data for the IR spectra of these two compounds, and it is understandable why as it would be impossible to differentiate between the two molecules through the IR, as they are so similar.

[[File:Irnzohb.png|thumb|900px|none|left|Comparison of the two computed IR spectra]]
[[File:Irzoomedohb.png|thumb|900px|none|left|Zoom showing main differences between spectra]]

As can be seen above, the differences, while there, are slight and insufficient to draw conclusions from.

As both molecules are chiral, they both rotate light in opposite directions. However due to the large size of this molecule and although it is relatively conformationally limited due to the double bond and ring, the calculation for the syn and anti variants did not converge after 48 a 48 hour run on the SCAN.

Despite the inconclusive IR I believe the correct assignments have been made in this case due to the close correlation between the predicted and measured <sup>13</sup>C and H nmr; this highlights the importance of computational chemistry, it can easily help corroborate results.

==References==
<references></references>

Rep:Mod:benton2

2013-02-08T16:11:42Z

Ohb09: /* MOs */

=Module 1 - Intro=
In this experiment, MM2 is compared to the more advanced MOPAC minimisation technique. A minimised molecule is then analysed and compared to literature.
Molecular mechanics, used here in its MM2 form is a very good first order approximation. Using data from previous experiments and breaking down the overall energy into different categories, such as van der Waals interaction, dipole-dipole, and bending before summing them to provide an overall energy is a very useful and more importantly quick method to calculate a molecules energy. The energy of molecule can then be iteratively reduced by tweaking the position of the atoms and conformations, providing a low energy structure. However it does have its limitations. Firstly, because of the large approximations used, the method is liable to fall, and remain, in an initial, smaller, potential well at a higher energy than the minimum possible. This can be overcome by carefully arranging the molecule by the user of the program to avoid these early, high energy minima, but requires a lot of rearrangement and prioir knowledge of low energy arrangements. As MM2 uses previously aquired data, it is also not that useful in determining new structures, or functional groups for which it does not have the data for.
MOPAC uses a different approach for minimisation. It uses semi empirical quantum chemistry functions to determine the energy of a molecule. This allows more advanced effects to be included in the calculation and allows for analysis of the neighbouring group effect in sacchardie chemistry and regioselectivity effects, as studied here.
Computational chemistry can also predict spectra, and in the last part of the experiment predicted spectra are compared to literature and the results analysed.

==Week 1==

===Hydrogenation of the Cyclopentadiene Dimer===
The endo dimer is primarily produced when cyclopentadiene dimerises, in a ratio of 99.5% to 0.5% <ref>
Małgorzata E Jamróz, Sławomir Gałka, Jan Cz Dobrowolski,
On dicyclopentadiene isomers,
Journal of Molecular Structure: THEOCHEM,
Volume 634, Issues 1–3, 5 September 2003,
Pages 225-233, ISSN 0166-1280,
<DOI|10.1016/S0166-1280(03)00348-8>
</ref>(at least when thermally initiated; photo initiation produces a racemic mixture of the two isomers<ref>
The Photosensitited Dimerization of Cyclopentadiene
Nicholas J. Turro and George S. Hammond
Journal of the American Chemical Society 1962 84 (14), 2841-2842
<DOI|10.1021/ja00873a050>
</ref>)
{| class="wikitable" border="1"

! rowspan="2" | Molecule
|style="text-align: center;" |Exo
|style="text-align: center;" |Endo
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbexodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Total E (kcal/mol)
|33.9975
|31.8764
|-
|}
[[file:Endoexoohb.bmp|thumb|left|500px]]
The small energy difference calculated by the MM2 forcefield does not highlight why the endo for is favoured over the exo form as it shows the exo form is lower in energy. While the difference between the two energies is relatively trivial, the high enationmeric excess of the products suggest that this is only part of the story, and suggest that this reaction is under kinetic rather than thermodynamic control.<ref> W.C.Herndon, C.R.Grayson, J.M.Manion; "Retro-Diels-Alder reactions. III. Kinetics of the thermal decompositions of exo- and endo-dicyclopentadiene" J. Org. Chem.; 1967, 32 (3); 526-529.DOI:10.1021/jo01278a003</ref> Being under kinetic control would imply the activation energy, and hence transition state, for the endo species is lower than the exo form and so the endo enantiomer is formed faster. This can be rationalised by looking at the orbital interactions in the two transition states.

The endo transition state is stabilised by the secondary favourable overlap whereas in the exo form there is no such overlap to stabilised the molecule meaning that the transition state is a higher energy, and so is less favourable. This cannot be handled by the simple MM2 calculation however.

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" colspan="2" |Different hydrogenation sites
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh3.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh4.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|1.2489
|1.1303
|-
!Bend
|19.1608
|13.10259
|-
!Torsion
|11.0730
|12.4118
|-
!VDW
|5.7962
|4.4398
|-
!Dipole-Dipole
|0.1622
|0.1410
|-
!Total E (kcal/mol)
|34.9643
|29.2475
|-
|}

The site of initial hydrogenation of the endo dimer can also be determined by calculating the energies of the two possible isomers. From these calculations it is clear that the second molecule is favoured more, as it is ~5.5kcalmol<sup>-1</sup> more stable. The bending energy in both of these molecules is the major difference. This manifests itself in the amount that the atoms are ebent away from their ideal positions, which is 109.5 for an sp3 carbon and 120 for an sp2 carbon. Across all of the key bonds, the second isomer has bond angles that are closer to the ideal than the first isomer; in particular the C-C=C bond angles; in the first molecule they are 107.6 and in the second 112.8. This difference of five degrees is enough to significantly stabilise the second isomer, making hydrogenation at that site the more preferable.

===Atropisomerism in an Intermediate related to the synthesis of Taxol===
In the complete synthesis of Taxol, and important cancer fighting drug, proposed by Pacquette <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 10.1016/S0040-4039(00)92617-0</ref> a key intermediate is either "Precursor 9" or "Precursor 10".

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" |Precursor 10
|style="text-align: center;" |Precursor 9
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol9.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol10.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|2.4687
|2.7846
|-
!Bend
|10.5555
|16.5411
|-
!Torsion
|17.4240
|18.2518
|-
!VDW
|13.1930
|13.1096
|-
!Dipole-Dipole
| -1.8818
| -1.7248
|-
!Total E (kcal/mol)
|39.1215
|47.8395
|-
|}
Precursor 9 and 10 are synthesised using a reversible oxy-Cope rearrangement as demonstrated below. As this process is in equilibrium that, with precursor 10 being more stable, it is predicted that this isomer will be the one produced as all of the molecules attempt to reduce the energy. As analysis of the individual energy componenets shows, this arrangement is a lot less strained than Precursor nine, which requires a lot more bending energy.

The molecule was then optimised with an MMFF94. Rather than rely on a large set of experimentally determined parameters like MM2, MMFF94 minimises the potential of each atom iteratively, attempting to minimise the whole molecule. Although the values produced for these two methods cannot be directly compared, they both correctly identify the correct altropisomer as being lower in energy.
{|class="wikitable" border="1"
! colspan="3" | Comparison of MMFF94 and MM2 minimisations
|-
!Molecule
| Precursor 9
| Precursor 10
|-
!MM2 minimised Energy (kJmol<sup><-1</sup>)
|39.1215
|47.8395
|-
!MMFF94 minimised Energy (kcalmol<sup><-1</sup>)
|58.7513
|70.5377
|-
|}

===Regioselective Addition of Dichlorocarbene to a diene===
Molecule A was initially optimised using a molecular mechanics (MM2) calculation

{| style="wikitable" border="1"
|<jmol>
<jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
It was then further optimised with a MOPAC calculation, which takes into effect stereoelectronic effects. The two were then compared.

{| class="wikitable" border="1"
!colspan="3" | Comparison of two optimisation calculations
|-
! Overlay of two optimised molecules !! MM2 optimised molecule !! MOPAC Optimised Molecule
|-
|[[file:Ohboverlaydiene.png|300px]]
The MM2 optimised molecule is coloured yellow for clarity
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1mopac.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! rowspan="6" | Distances between
corresponding atoms

on the overlaid molecules (Å)
|style="text-align: center;" | C(34)-C(9)
|0.5247
|-
|style="text-align: center;" | C(26)-C(1)
|0.5246
|-
|style="text-align: center;" | H(47)-H(22)
|0.8526
|-
|style="text-align: center;" | H(38)-H(13)
|0.8524
|-
|style="text-align: center;" | Cl(37)-Cl(12)
|0.0689
|}

As can be seen by the comparison above, when using the stereoelectronic interactions, the cyclohexadiene ring on the side with the Cl atom is moved further away from the Cl using the MOPAC calculation than the MM2. This is because the electronic effects included in this calculation include the repulsion between the electron rich Chlorine atom and the electron rich double bond, whereas the MM2 calculation doesn't include this and so a symmetrical molecule is formed.

====MOs====

The MOs of the previously MOPAC optimised molecule where then calculated using Guassian (B3LYP 6-31G)
{| style="wikitable" border="1"
! Homo-1 !! colspan="2" | Homo
|-
|[[File:Ohbclhomo-1.jpg|250px]]
| <jmol>
<jmolApplet>
<title>Orbital</title><color>white</color><size>250</size>
<script>isosurface color orange purple "images/f/f2/Ohbdienemo48.cub.jvxl" translucent; </script>
<uploadedFileContents>Ohbdienemo48.cub.xyz</uploadedFileContents>
</jmolApplet>
</jmol>
|[[File:Ohbclhomo.jpg|250px]]
|-
!Lumo !! Lumo+1 !! Lumo+2
|-
|[[File:Ohbcllumo.jpg|250px]]
|[[File:Ohbcllumo+1.jpg|250px]]
|[[File:Ohbcllumo+2.jpg|250px]]
|-
|colspan="2" | [[File:Ohbclmep.jpg|300px]] Electrostatic diagram.
| [[File:Ohbclelevels.png|250px]]
|}

Molecule 2 was initially minimised using an MM2 calculation. The reactions of molecule A with an electrophile can be illustrated by taking a more advanced, quantum mechanical approach to modelling the molecule and its orbitals. This will also allow prediction of which C=C reacts with an electrophile.
Of the two alekenes, the endo is favoured rather than the exo because the cl-c sigma star orbital mixes with the exo alkene. This stabilises both orbitals, as shown by the frequency calculation having a higher value than the endo alkene, but reduces the pi bond character of the exo alkene. This is also shown by the comparative lengths of the alkene bonds - the exo is 1.3355A and the endo is 1.33190A. The cycloaddition of the carbene requires an alkene and so favours the endo alkene as it has a higher p character. The homo is also focused entirely on the endo side of the molecule, with the lumo focused mainly on the exo side. The Homo shows the high pi bond character of the endo alkene. The Homo-1 is mainly focused ont he exo alekene, so shows the pi bond character of the exo alekene. This is lower in energy and so is less likely to react with the carbene molecule.
The electrostatic diagram at the bottom displays how there is more negative charge on the endo alkene, which again is favourable to electrophillic attack.

====Glycosidation====

When the monosaccharide pyranose has an acetal in the 2 position, four different isomers can be formed, all of differing stability. These differing positions of the acetal group and its interactions with the neighbouring group means that it acts as a directing group to nucleophilic attack. With deprotonation to an oxenium cation being the initial step, the acetal group can then stabilise this to varying degrees depending on its position. Due to the Sn1 nature of the glycosidation nucleophilic attack occurring, the access of the nucleophile to the sigma* orbital of the carbon is crucial, and this depends on the Burgi-Dunitz angle of 107<ref> H. B. Bürgi, J. D. Dunitz, J. M. Lehn, G. Wipff (1974). "Stereochemistry of reaction paths at carbonyl centres". Tetrahedron 30 (12): 1563–1572. doi:10.1016/S0040-4020(01)90678-7</ref>.
Two sets of calculations were performed; initially using an MM2 forcefield, and then with using the MOPAC approach. While both approaches showed a similar trend, the benefit of the MOPAC, to make and break bond meant that the structures formed by this minimisation resembled the transition state a lot more closely than those formed by the MM2.
As shown by the table, below, all of the initial cations are at a lower energy than the intermediate forms, however the structures differ slightly depending on whether an MM2 or MOPAC minimisation was performed; the MOPAC structures much more closely resemble the transition states.
The differences in energy can be directly related to the amount of strain present within the molecule and the repulsion between the oxygen atoms. The large amount of strain present in the intermediates, particularly of molecule 2, mean that they have a lot higher energy. A notable differences is that the MM2 struggles to accurately deal with the oxenium cation, whereas the MOPAC produces a more lifelike picture in this area.
The glycosidation mainly produces the trans isomers, ie molecules going through the pathways of molecules 1 & 4. This is predicted well by the computational methods used, with both the initial molecules and the intermediates being lower in energy and having lower anomeric carbon-acetal oxygen distances.

=====Mechanisms=====

[[file:Ohbglymech.gif|800px]]

{|class="wikitable" border="2"
!rowspan="5" |Initial molecule
!colspan="2" | Conformation
|1
|2
|3
|4
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2amm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 11.5430
| 46.2672
| 35.5277
| 29.5144
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -90.51343
| -70.57703
| -72.56010
| -85.04737
|-
!rowspan="5" |Intermediate
!colspan="2" | Conformation
|chemdraw
|chemdraw
|chemdraw
|chemdraw
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2Bmm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 28.4913
| 43.2706
| 41.0918
| 31.8763
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -91.66112
| -66.72331
| -84.44899
| -88.08089

|-
|}

==Comparison of coumpational results to a molecule from literature.==

===Taxol intermediate===

Computational chemistry can be a powerful tool in the analysis and reproduction of spectra. in this exercise, literature values and spectra are compared to computed data and the effectiveness and accuracy of both methods is compared and contrasted.

A different intermediate in the synthesis of taxol was optimised using MM2 to produce the structure (right) with a total energy of 66.7072kcal<sup>-1</sup>
{| class="wikitable border="1"
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
This file was then optimised using Guassian and B3LYP 6-31G(d,p) basis set. The resulting file was then resubmitted to the SCAN cluster for computation of the nmr spectrum using these keywords # mpw1pw91/6-31G(d,p) NMR SCRF=(CPCM,Solvent=chloroform). These results were then compared to those found in the literature<ref>#L. Paquette, N. A. Pegg, D. Toops, G. D. Maynard, R. D. Rogers, ''J. Am. Chem. Soc.,'', '''1990''', ''112'', 277-283. {{DOI|10.1021/ja00157a043}}</ref>.
The results are below. As can be seen by this comparison chart, in general there is very good agreement between the predicted and measured shift values. With the only major discrepancy being at Carbon 16.

This however, can be resolved. The large distance is probably to do with this carbon being bonded to two sulphur atoms. The 6-31G(d,p) basis set is not very good at approximating, and hence optimising sulphur molecules. This is because Sulphur contains f type functions, of which there are 7. However there are 10<ref>SIMPLIFIED INTRODUCTION TO AB INITIO
BASIS SETS. TERMS AND NOTATION.
Jan K. Labanowski, Ohio Supercomputer Center,
1224 Kinnear Rd., Columbus, OH 43212-1163,</ref> possible Guassians, and so an element of contamination from the 4p orbitals is brought in. As the 6-31G(d,p) does not containg any f functions, it is not that good at predicting the behaviour of the sulphur molecule to the level required by the nmr calculation. Despite all of this, the shift values are still similar, and so the assignmnet of this molecule inth e literature can be deemed correct.
{|class="wikitable" border="2"
!Atom number !! Calculated ppm value !! Lit. ppm value
|-
| 1
| 27.5886
| 25.66
|-
| 2
| 31.6721
| 28.79
|-
| 3
| 52.6851
| 48.5
|-
| 4
| 146.8944
| 144.63
|-
| 5
| 51.4817
| 46.8
|-
| 6
| 20.6456
| 18.71
|-
| 7
| 27.0826
| 23.86
|-
| 8
| 125.7193
| 125.33
|-
| 9
| 50.5885
| 45.76
|-
| 10
| 218.6545
| 218.79
|-
| 11
| colspan="2" | Oxygen
|-
| 12
| 54.1882
| 52.52
|-
| 13
| 30.8219
| 28.29
|-
| 14
| 63.85
| 56.19
|-
| 15
| 29.5406
| 26.88
|-
| 16
| 89.99
| 72.88
|-
| 17
| 48.9728
| 39.8
|-
| 18
| 24.6905
| 20.96
|-
| 19
| 41.3115
| 32.66
|-
| 21
| 44.3139
| 35.85
|-
| 22
| 45.5337
| 38.81
|}

===Literature Molecule===

In the synthesis of molecule A (below), using Kobayashi aldol chemistry, two stereoisomers are produced. Initially, the syn isomer is formed, with a diasteromic ratio of 1:14, and via a similar synthetic route, the anti isomer is also produced, with a high dr of 1:>50. The high stereoselectivity of both of these reactions is an important step in the synthesis of enationmerically pure natural products.

{| class="wikitable border="1"
!Molecule A
! Syn
! Anti
|-
![[File:Ohbmol.gif|300px]]
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbsyn.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbanti.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
|}
Initiallyu the models were optimised using an MM2 optimisation within ChemBio 12.0. They were then further optimised using an RB3LYP-6-31G(d,p) method and basis set. After the optimisation, and checking to see that the the two molecules were still distinct, with one syn and one anti form, they were submitted for nmr analysis, to produce a predicted nmr. This was then compared with the reported nmr, with a view to see if the assignments and conclusions made in the literature were correct. There was a good correlations between the predicted and measured nmr peaks, with deviations, as show below, of less than 1ppm for the H nmr and less than 10ppm for the <sup>13</sup>C nmr.
[[File:Ohbccomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each carbon atom]]
[[File:Ohbhcomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each Hydrogen atom]]

This correlation helps confirm that the structures are correct; the different enantiomers are differentiated and assigned correctly. If they were not, and the calculated syn nmr is compared to the measured anti nmr, and vice versa, larger differences are noted. This is highlighted on the graph below. The blue and red graphs are the correctly assigned and matched nmrs, the green and purple nmrs are if they are assigned incorrectly. It can clearly be seen that the green and purple line are consistently higher than their counterparts.
[[file:Ohbcomparisonnmr.png|thumb|900px|none|left|Comparison of correct and incorrect assignment for the two conformers]]
Within the literature all of the hydrogens and carbons are assigned, with the exception of Hydrogen 48. This is because this is a labile proton and so does not show up on measured nmrs due to rapid exchange with the deuterium in the deuterated solvent. However the calculated spectra does not take this into account and so displays the shift value for this hydrogen.

The computed IR spectra are very similar for the two molecules. The OH stretch is increased by 30cm<sup>-1</sup> in the syn form of the molecule and the CH bend region between 1000-1500cm<sup>-1</sup> is also significantly different. This can be rationalised by the different atomic orbital overlaps that are occuring due to the different positioning of the methyl group. The literature does not supply data for the IR spectra of these two compounds, and it is understandable why as it would be impossible to differentiate between the two molecules through the IR, as they are so similar.

[[File:Irnzohb.png|thumb|900px|none|left|Comparison of the two computed IR spectra]]
[[File:Irzoomedohb.png|thumb|900px|none|left|Zoom showing main differences between spectra]]

As can be seen above, the differences, while there, are slight and insufficient to draw conclusions from.

As both molecules are chiral, they both rotate light in opposite directions. However due to the large size of this molecule and although it is relatively conformationally limited due to the double bond and ring, the calculation for the syn and anti variants did not converge after 48 a 48 hour run on the SCAN.

Despite the inconclusive IR I believe the correct assignments have been made in this case due to the close correlation between the predicted and measured <sup>13</sup>C and H nmr; this highlights the importance of computational chemistry, it can easily help corroborate results.

==References==
<references></references>

Rep:Mod:benton2

2013-02-08T16:04:32Z

Ohb09: /* Literature Molecule */

=Module 1 - Intro=
In this experiment, MM2 is compared to the more advanced MOPAC minimisation technique. A minimised molecule is then analysed and compared to literature.
Molecular mechanics, used here in its MM2 form is a very good first order approximation. Using data from previous experiments and breaking down the overall energy into different categories, such as van der Waals interaction, dipole-dipole, and bending before summing them to provide an overall energy is a very useful and more importantly quick method to calculate a molecules energy. The energy of molecule can then be iteratively reduced by tweaking the position of the atoms and conformations, providing a low energy structure. However it does have its limitations. Firstly, because of the large approximations used, the method is liable to fall, and remain, in an initial, smaller, potential well at a higher energy than the minimum possible. This can be overcome by carefully arranging the molecule by the user of the program to avoid these early, high energy minima, but requires a lot of rearrangement and prioir knowledge of low energy arrangements. As MM2 uses previously aquired data, it is also not that useful in determining new structures, or functional groups for which it does not have the data for.
MOPAC uses a different approach for minimisation. It uses semi empirical quantum chemistry functions to determine the energy of a molecule. This allows more advanced effects to be included in the calculation and allows for analysis of the neighbouring group effect in sacchardie chemistry and regioselectivity effects, as studied here.
Computational chemistry can also predict spectra, and in the last part of the experiment predicted spectra are compared to literature and the results analysed.

==Week 1==

===Hydrogenation of the Cyclopentadiene Dimer===
The endo dimer is primarily produced when cyclopentadiene dimerises, in a ratio of 99.5% to 0.5% <ref>
Małgorzata E Jamróz, Sławomir Gałka, Jan Cz Dobrowolski,
On dicyclopentadiene isomers,
Journal of Molecular Structure: THEOCHEM,
Volume 634, Issues 1–3, 5 September 2003,
Pages 225-233, ISSN 0166-1280,
<DOI|10.1016/S0166-1280(03)00348-8>
</ref>(at least when thermally initiated; photo initiation produces a racemic mixture of the two isomers<ref>
The Photosensitited Dimerization of Cyclopentadiene
Nicholas J. Turro and George S. Hammond
Journal of the American Chemical Society 1962 84 (14), 2841-2842
<DOI|10.1021/ja00873a050>
</ref>)
{| class="wikitable" border="1"

! rowspan="2" | Molecule
|style="text-align: center;" |Exo
|style="text-align: center;" |Endo
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbexodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Total E (kcal/mol)
|33.9975
|31.8764
|-
|}
[[file:Endoexoohb.bmp|thumb|left|500px]]
The small energy difference calculated by the MM2 forcefield does not highlight why the endo for is favoured over the exo form as it shows the exo form is lower in energy. While the difference between the two energies is relatively trivial, the high enationmeric excess of the products suggest that this is only part of the story, and suggest that this reaction is under kinetic rather than thermodynamic control.<ref> W.C.Herndon, C.R.Grayson, J.M.Manion; "Retro-Diels-Alder reactions. III. Kinetics of the thermal decompositions of exo- and endo-dicyclopentadiene" J. Org. Chem.; 1967, 32 (3); 526-529.DOI:10.1021/jo01278a003</ref> Being under kinetic control would imply the activation energy, and hence transition state, for the endo species is lower than the exo form and so the endo enantiomer is formed faster. This can be rationalised by looking at the orbital interactions in the two transition states.

The endo transition state is stabilised by the secondary favourable overlap whereas in the exo form there is no such overlap to stabilised the molecule meaning that the transition state is a higher energy, and so is less favourable. This cannot be handled by the simple MM2 calculation however.

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" colspan="2" |Different hydrogenation sites
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh3.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh4.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|1.2489
|1.1303
|-
!Bend
|19.1608
|13.10259
|-
!Torsion
|11.0730
|12.4118
|-
!VDW
|5.7962
|4.4398
|-
!Dipole-Dipole
|0.1622
|0.1410
|-
!Total E (kcal/mol)
|34.9643
|29.2475
|-
|}

The site of initial hydrogenation of the endo dimer can also be determined by calculating the energies of the two possible isomers. From these calculations it is clear that the second molecule is favoured more, as it is ~5.5kcalmol<sup>-1</sup> more stable. The bending energy in both of these molecules is the major difference. This manifests itself in the amount that the atoms are ebent away from their ideal positions, which is 109.5 for an sp3 carbon and 120 for an sp2 carbon. Across all of the key bonds, the second isomer has bond angles that are closer to the ideal than the first isomer; in particular the C-C=C bond angles; in the first molecule they are 107.6 and in the second 112.8. This difference of five degrees is enough to significantly stabilise the second isomer, making hydrogenation at that site the more preferable.

===Atropisomerism in an Intermediate related to the synthesis of Taxol===
In the complete synthesis of Taxol, and important cancer fighting drug, proposed by Pacquette <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 10.1016/S0040-4039(00)92617-0</ref> a key intermediate is either "Precursor 9" or "Precursor 10".

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" |Precursor 10
|style="text-align: center;" |Precursor 9
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol9.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol10.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|2.4687
|2.7846
|-
!Bend
|10.5555
|16.5411
|-
!Torsion
|17.4240
|18.2518
|-
!VDW
|13.1930
|13.1096
|-
!Dipole-Dipole
| -1.8818
| -1.7248
|-
!Total E (kcal/mol)
|39.1215
|47.8395
|-
|}
Precursor 9 and 10 are synthesised using a reversible oxy-Cope rearrangement as demonstrated below. As this process is in equilibrium that, with precursor 10 being more stable, it is predicted that this isomer will be the one produced as all of the molecules attempt to reduce the energy. As analysis of the individual energy componenets shows, this arrangement is a lot less strained than Precursor nine, which requires a lot more bending energy.

The molecule was then optimised with an MMFF94. Rather than rely on a large set of experimentally determined parameters like MM2, MMFF94 minimises the potential of each atom iteratively, attempting to minimise the whole molecule. Although the values produced for these two methods cannot be directly compared, they both correctly identify the correct altropisomer as being lower in energy.
{|class="wikitable" border="1"
! colspan="3" | Comparison of MMFF94 and MM2 minimisations
|-
!Molecule
| Precursor 9
| Precursor 10
|-
!MM2 minimised Energy (kJmol<sup><-1</sup>)
|39.1215
|47.8395
|-
!MMFF94 minimised Energy (kcalmol<sup><-1</sup>)
|58.7513
|70.5377
|-
|}

===Regioselective Addition of Dichlorocarbene to a diene===
Molecule A was initially optimised using a molecular mechanics (MM2) calculation

{| style="wikitable" border="1"
|<jmol>
<jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
It was then further optimised with a MOPAC calculation, which takes into effect stereoelectronic effects. The two were then compared.

{| class="wikitable" border="1"
!colspan="3" | Comparison of two optimisation calculations
|-
! Overlay of two optimised molecules !! MM2 optimised molecule !! MOPAC Optimised Molecule
|-
|[[file:Ohboverlaydiene.png|300px]]
The MM2 optimised molecule is coloured yellow for clarity
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1mopac.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! rowspan="6" | Distances between
corresponding atoms

on the overlaid molecules (Å)
|style="text-align: center;" | C(34)-C(9)
|0.5247
|-
|style="text-align: center;" | C(26)-C(1)
|0.5246
|-
|style="text-align: center;" | H(47)-H(22)
|0.8526
|-
|style="text-align: center;" | H(38)-H(13)
|0.8524
|-
|style="text-align: center;" | Cl(37)-Cl(12)
|0.0689
|}

As can be seen by the comparison above, when using the stereoelectronic interactions, the cyclohexadiene ring on the side with the Cl atom is moved further away from the Cl using the MOPAC calculation than the MM2. This is because the electronic effects included in this calculation include the repulsion between the electron rich Chlorine atom and the electron rich double bond, whereas the MM2 calculation doesn't include this and so a symmetrical molecule is formed.

====MOs====

The MOs of the previously MOPAC optimised molecule where then calculated using Guassian (B3LYP 6-31G)
{| style="wikitable" border="1"
! Homo-1 !! colspan="2" | Homo
|-
|[[File:Ohbclhomo-1.jpg|250px]]
| <jmol>
<jmolApplet>
<title>Orbital</title><color>white</color><size>250</size>
<script>isosurface color orange purple "images/f/f2/Ohbdienemo48.cub.jvxl" translucent; </script>
<uploadedFileContents>Ohbdienemo48.cub.xyz</uploadedFileContents>
</jmolApplet>
</jmol>
|[[File:Ohbclhomo.jpg|250px]]
|-
!Lumo !! Lumo+1 !! Lumo+2
|-
|[[File:Ohbcllumo.jpg|250px]]
|[[File:Ohbcllumo+1.jpg|250px]]
|[[File:Ohbcllumo+2.jpg|250px]]
|-
|colspan="2" | [[File:Ohbclmep.jpg|300px rotate="90"]]
| [[File:Ohbclelevels.png|250px]]
|}

Molecule 2 was initially minimised using an MM2 calculation. The reactions of molecule A with an electrophile can be illustrated by taking a more advanced, quantum mechanical approach to modelling the molecule and its orbitals. This will also allow prediction of which C=C reacts with an electrophile.
Of the two alekenes, the endo is favoured rather than the exo because the cl-c sigma star orbital mixes with the exo alkene. This stabilises both orbitals, as shown by the frequency calculation having a higher value than the endo alkene, but reduces the pi bond character of the exo alkene. This is also shown by the comparative lengths of the alkene bonds - the exo is 1.3355A and the endo is 1.33190A. The cycloaddition of the carbene requires an alkene and so favours the endo alkene as it has a higher p character. The homo is also focused entirely on the endo side of the molecule, with the lumo focused mainly on the exo side. The Homo shows the high pi bond character of the endo alkene. The Homo-1 is mainly focused ont he exo alekene, so shows the pi bond character of the exo alekene. This is lower in energy and so is less likely to react with the carbene molecule.

====Glycosidation====

When the monosaccharide pyranose has an acetal in the 2 position, four different isomers can be formed, all of differing stability. These differing positions of the acetal group and its interactions with the neighbouring group means that it acts as a directing group to nucleophilic attack. With deprotonation to an oxenium cation being the initial step, the acetal group can then stabilise this to varying degrees depending on its position. Due to the Sn1 nature of the glycosidation nucleophilic attack occurring, the access of the nucleophile to the sigma* orbital of the carbon is crucial, and this depends on the Burgi-Dunitz angle of 107<ref> H. B. Bürgi, J. D. Dunitz, J. M. Lehn, G. Wipff (1974). "Stereochemistry of reaction paths at carbonyl centres". Tetrahedron 30 (12): 1563–1572. doi:10.1016/S0040-4020(01)90678-7</ref>.
Two sets of calculations were performed; initially using an MM2 forcefield, and then with using the MOPAC approach. While both approaches showed a similar trend, the benefit of the MOPAC, to make and break bond meant that the structures formed by this minimisation resembled the transition state a lot more closely than those formed by the MM2.
As shown by the table, below, all of the initial cations are at a lower energy than the intermediate forms, however the structures differ slightly depending on whether an MM2 or MOPAC minimisation was performed; the MOPAC structures much more closely resemble the transition states.
The differences in energy can be directly related to the amount of strain present within the molecule and the repulsion between the oxygen atoms. The large amount of strain present in the intermediates, particularly of molecule 2, mean that they have a lot higher energy. A notable differences is that the MM2 struggles to accurately deal with the oxenium cation, whereas the MOPAC produces a more lifelike picture in this area.
The glycosidation mainly produces the trans isomers, ie molecules going through the pathways of molecules 1 & 4. This is predicted well by the computational methods used, with both the initial molecules and the intermediates being lower in energy and having lower anomeric carbon-acetal oxygen distances.

=====Mechanisms=====

[[file:Ohbglymech.gif|800px]]

{|class="wikitable" border="2"
!rowspan="5" |Initial molecule
!colspan="2" | Conformation
|1
|2
|3
|4
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2amm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 11.5430
| 46.2672
| 35.5277
| 29.5144
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -90.51343
| -70.57703
| -72.56010
| -85.04737
|-
!rowspan="5" |Intermediate
!colspan="2" | Conformation
|chemdraw
|chemdraw
|chemdraw
|chemdraw
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2Bmm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 28.4913
| 43.2706
| 41.0918
| 31.8763
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -91.66112
| -66.72331
| -84.44899
| -88.08089

|-
|}

==Comparison of coumpational results to a molecule from literature.==

===Taxol intermediate===

Computational chemistry can be a powerful tool in the analysis and reproduction of spectra. in this exercise, literature values and spectra are compared to computed data and the effectiveness and accuracy of both methods is compared and contrasted.

A different intermediate in the synthesis of taxol was optimised using MM2 to produce the structure (right) with a total energy of 66.7072kcal<sup>-1</sup>
{| class="wikitable border="1"
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
This file was then optimised using Guassian and B3LYP 6-31G(d,p) basis set. The resulting file was then resubmitted to the SCAN cluster for computation of the nmr spectrum using these keywords # mpw1pw91/6-31G(d,p) NMR SCRF=(CPCM,Solvent=chloroform). These results were then compared to those found in the literature<ref>#L. Paquette, N. A. Pegg, D. Toops, G. D. Maynard, R. D. Rogers, ''J. Am. Chem. Soc.,'', '''1990''', ''112'', 277-283. {{DOI|10.1021/ja00157a043}}</ref>.
The results are below. As can be seen by this comparison chart, in general there is very good agreement between the predicted and measured shift values. With the only major discrepancy being at Carbon 16.

This however, can be resolved. The large distance is probably to do with this carbon being bonded to two sulphur atoms. The 6-31G(d,p) basis set is not very good at approximating, and hence optimising sulphur molecules. This is because Sulphur contains f type functions, of which there are 7. However there are 10<ref>SIMPLIFIED INTRODUCTION TO AB INITIO
BASIS SETS. TERMS AND NOTATION.
Jan K. Labanowski, Ohio Supercomputer Center,
1224 Kinnear Rd., Columbus, OH 43212-1163,</ref> possible Guassians, and so an element of contamination from the 4p orbitals is brought in. As the 6-31G(d,p) does not containg any f functions, it is not that good at predicting the behaviour of the sulphur molecule to the level required by the nmr calculation. Despite all of this, the shift values are still similar, and so the assignmnet of this molecule inth e literature can be deemed correct.
{|class="wikitable" border="2"
!Atom number !! Calculated ppm value !! Lit. ppm value
|-
| 1
| 27.5886
| 25.66
|-
| 2
| 31.6721
| 28.79
|-
| 3
| 52.6851
| 48.5
|-
| 4
| 146.8944
| 144.63
|-
| 5
| 51.4817
| 46.8
|-
| 6
| 20.6456
| 18.71
|-
| 7
| 27.0826
| 23.86
|-
| 8
| 125.7193
| 125.33
|-
| 9
| 50.5885
| 45.76
|-
| 10
| 218.6545
| 218.79
|-
| 11
| colspan="2" | Oxygen
|-
| 12
| 54.1882
| 52.52
|-
| 13
| 30.8219
| 28.29
|-
| 14
| 63.85
| 56.19
|-
| 15
| 29.5406
| 26.88
|-
| 16
| 89.99
| 72.88
|-
| 17
| 48.9728
| 39.8
|-
| 18
| 24.6905
| 20.96
|-
| 19
| 41.3115
| 32.66
|-
| 21
| 44.3139
| 35.85
|-
| 22
| 45.5337
| 38.81
|}

===Literature Molecule===

In the synthesis of molecule A (below), using Kobayashi aldol chemistry, two stereoisomers are produced. Initially, the syn isomer is formed, with a diasteromic ratio of 1:14, and via a similar synthetic route, the anti isomer is also produced, with a high dr of 1:>50. The high stereoselectivity of both of these reactions is an important step in the synthesis of enationmerically pure natural products.

{| class="wikitable border="1"
!Molecule A
! Syn
! Anti
|-
![[File:Ohbmol.gif|300px]]
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbsyn.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbanti.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
|}
Initiallyu the models were optimised using an MM2 optimisation within ChemBio 12.0. They were then further optimised using an RB3LYP-6-31G(d,p) method and basis set. After the optimisation, and checking to see that the the two molecules were still distinct, with one syn and one anti form, they were submitted for nmr analysis, to produce a predicted nmr. This was then compared with the reported nmr, with a view to see if the assignments and conclusions made in the literature were correct. There was a good correlations between the predicted and measured nmr peaks, with deviations, as show below, of less than 1ppm for the H nmr and less than 10ppm for the <sup>13</sup>C nmr.
[[File:Ohbccomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each carbon atom]]
[[File:Ohbhcomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each Hydrogen atom]]

This correlation helps confirm that the structures are correct; the different enantiomers are differentiated and assigned correctly. If they were not, and the calculated syn nmr is compared to the measured anti nmr, and vice versa, larger differences are noted. This is highlighted on the graph below. The blue and red graphs are the correctly assigned and matched nmrs, the green and purple nmrs are if they are assigned incorrectly. It can clearly be seen that the green and purple line are consistently higher than their counterparts.
[[file:Ohbcomparisonnmr.png|thumb|900px|none|left|Comparison of correct and incorrect assignment for the two conformers]]
Within the literature all of the hydrogens and carbons are assigned, with the exception of Hydrogen 48. This is because this is a labile proton and so does not show up on measured nmrs due to rapid exchange with the deuterium in the deuterated solvent. However the calculated spectra does not take this into account and so displays the shift value for this hydrogen.

The computed IR spectra are very similar for the two molecules. The OH stretch is increased by 30cm<sup>-1</sup> in the syn form of the molecule and the CH bend region between 1000-1500cm<sup>-1</sup> is also significantly different. This can be rationalised by the different atomic orbital overlaps that are occuring due to the different positioning of the methyl group. The literature does not supply data for the IR spectra of these two compounds, and it is understandable why as it would be impossible to differentiate between the two molecules through the IR, as they are so similar.

[[File:Irnzohb.png|thumb|900px|none|left|Comparison of the two computed IR spectra]]
[[File:Irzoomedohb.png|thumb|900px|none|left|Zoom showing main differences between spectra]]

As can be seen above, the differences, while there, are slight and insufficient to draw conclusions from.

As both molecules are chiral, they both rotate light in opposite directions. However due to the large size of this molecule and although it is relatively conformationally limited due to the double bond and ring, the calculation for the syn and anti variants did not converge after 48 a 48 hour run on the SCAN.

Despite the inconclusive IR I believe the correct assignments have been made in this case due to the close correlation between the predicted and measured <sup>13</sup>C and H nmr; this highlights the importance of computational chemistry, it can easily help corroborate results.

==References==
<references></references>

Rep:Mod:benton2

2013-02-08T16:03:33Z

Ohb09: /* Literature Molecule */

=Module 1 - Intro=
In this experiment, MM2 is compared to the more advanced MOPAC minimisation technique. A minimised molecule is then analysed and compared to literature.
Molecular mechanics, used here in its MM2 form is a very good first order approximation. Using data from previous experiments and breaking down the overall energy into different categories, such as van der Waals interaction, dipole-dipole, and bending before summing them to provide an overall energy is a very useful and more importantly quick method to calculate a molecules energy. The energy of molecule can then be iteratively reduced by tweaking the position of the atoms and conformations, providing a low energy structure. However it does have its limitations. Firstly, because of the large approximations used, the method is liable to fall, and remain, in an initial, smaller, potential well at a higher energy than the minimum possible. This can be overcome by carefully arranging the molecule by the user of the program to avoid these early, high energy minima, but requires a lot of rearrangement and prioir knowledge of low energy arrangements. As MM2 uses previously aquired data, it is also not that useful in determining new structures, or functional groups for which it does not have the data for.
MOPAC uses a different approach for minimisation. It uses semi empirical quantum chemistry functions to determine the energy of a molecule. This allows more advanced effects to be included in the calculation and allows for analysis of the neighbouring group effect in sacchardie chemistry and regioselectivity effects, as studied here.
Computational chemistry can also predict spectra, and in the last part of the experiment predicted spectra are compared to literature and the results analysed.

==Week 1==

===Hydrogenation of the Cyclopentadiene Dimer===
The endo dimer is primarily produced when cyclopentadiene dimerises, in a ratio of 99.5% to 0.5% <ref>
Małgorzata E Jamróz, Sławomir Gałka, Jan Cz Dobrowolski,
On dicyclopentadiene isomers,
Journal of Molecular Structure: THEOCHEM,
Volume 634, Issues 1–3, 5 September 2003,
Pages 225-233, ISSN 0166-1280,
<DOI|10.1016/S0166-1280(03)00348-8>
</ref>(at least when thermally initiated; photo initiation produces a racemic mixture of the two isomers<ref>
The Photosensitited Dimerization of Cyclopentadiene
Nicholas J. Turro and George S. Hammond
Journal of the American Chemical Society 1962 84 (14), 2841-2842
<DOI|10.1021/ja00873a050>
</ref>)
{| class="wikitable" border="1"

! rowspan="2" | Molecule
|style="text-align: center;" |Exo
|style="text-align: center;" |Endo
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbexodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Total E (kcal/mol)
|33.9975
|31.8764
|-
|}
[[file:Endoexoohb.bmp|thumb|left|500px]]
The small energy difference calculated by the MM2 forcefield does not highlight why the endo for is favoured over the exo form as it shows the exo form is lower in energy. While the difference between the two energies is relatively trivial, the high enationmeric excess of the products suggest that this is only part of the story, and suggest that this reaction is under kinetic rather than thermodynamic control.<ref> W.C.Herndon, C.R.Grayson, J.M.Manion; "Retro-Diels-Alder reactions. III. Kinetics of the thermal decompositions of exo- and endo-dicyclopentadiene" J. Org. Chem.; 1967, 32 (3); 526-529.DOI:10.1021/jo01278a003</ref> Being under kinetic control would imply the activation energy, and hence transition state, for the endo species is lower than the exo form and so the endo enantiomer is formed faster. This can be rationalised by looking at the orbital interactions in the two transition states.

The endo transition state is stabilised by the secondary favourable overlap whereas in the exo form there is no such overlap to stabilised the molecule meaning that the transition state is a higher energy, and so is less favourable. This cannot be handled by the simple MM2 calculation however.

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" colspan="2" |Different hydrogenation sites
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh3.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh4.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|1.2489
|1.1303
|-
!Bend
|19.1608
|13.10259
|-
!Torsion
|11.0730
|12.4118
|-
!VDW
|5.7962
|4.4398
|-
!Dipole-Dipole
|0.1622
|0.1410
|-
!Total E (kcal/mol)
|34.9643
|29.2475
|-
|}

The site of initial hydrogenation of the endo dimer can also be determined by calculating the energies of the two possible isomers. From these calculations it is clear that the second molecule is favoured more, as it is ~5.5kcalmol<sup>-1</sup> more stable. The bending energy in both of these molecules is the major difference. This manifests itself in the amount that the atoms are ebent away from their ideal positions, which is 109.5 for an sp3 carbon and 120 for an sp2 carbon. Across all of the key bonds, the second isomer has bond angles that are closer to the ideal than the first isomer; in particular the C-C=C bond angles; in the first molecule they are 107.6 and in the second 112.8. This difference of five degrees is enough to significantly stabilise the second isomer, making hydrogenation at that site the more preferable.

===Atropisomerism in an Intermediate related to the synthesis of Taxol===
In the complete synthesis of Taxol, and important cancer fighting drug, proposed by Pacquette <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 10.1016/S0040-4039(00)92617-0</ref> a key intermediate is either "Precursor 9" or "Precursor 10".

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" |Precursor 10
|style="text-align: center;" |Precursor 9
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol9.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol10.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|2.4687
|2.7846
|-
!Bend
|10.5555
|16.5411
|-
!Torsion
|17.4240
|18.2518
|-
!VDW
|13.1930
|13.1096
|-
!Dipole-Dipole
| -1.8818
| -1.7248
|-
!Total E (kcal/mol)
|39.1215
|47.8395
|-
|}
Precursor 9 and 10 are synthesised using a reversible oxy-Cope rearrangement as demonstrated below. As this process is in equilibrium that, with precursor 10 being more stable, it is predicted that this isomer will be the one produced as all of the molecules attempt to reduce the energy. As analysis of the individual energy componenets shows, this arrangement is a lot less strained than Precursor nine, which requires a lot more bending energy.

The molecule was then optimised with an MMFF94. Rather than rely on a large set of experimentally determined parameters like MM2, MMFF94 minimises the potential of each atom iteratively, attempting to minimise the whole molecule. Although the values produced for these two methods cannot be directly compared, they both correctly identify the correct altropisomer as being lower in energy.
{|class="wikitable" border="1"
! colspan="3" | Comparison of MMFF94 and MM2 minimisations
|-
!Molecule
| Precursor 9
| Precursor 10
|-
!MM2 minimised Energy (kJmol<sup><-1</sup>)
|39.1215
|47.8395
|-
!MMFF94 minimised Energy (kcalmol<sup><-1</sup>)
|58.7513
|70.5377
|-
|}

===Regioselective Addition of Dichlorocarbene to a diene===
Molecule A was initially optimised using a molecular mechanics (MM2) calculation

{| style="wikitable" border="1"
|<jmol>
<jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
It was then further optimised with a MOPAC calculation, which takes into effect stereoelectronic effects. The two were then compared.

{| class="wikitable" border="1"
!colspan="3" | Comparison of two optimisation calculations
|-
! Overlay of two optimised molecules !! MM2 optimised molecule !! MOPAC Optimised Molecule
|-
|[[file:Ohboverlaydiene.png|300px]]
The MM2 optimised molecule is coloured yellow for clarity
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1mopac.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! rowspan="6" | Distances between
corresponding atoms

on the overlaid molecules (Å)
|style="text-align: center;" | C(34)-C(9)
|0.5247
|-
|style="text-align: center;" | C(26)-C(1)
|0.5246
|-
|style="text-align: center;" | H(47)-H(22)
|0.8526
|-
|style="text-align: center;" | H(38)-H(13)
|0.8524
|-
|style="text-align: center;" | Cl(37)-Cl(12)
|0.0689
|}

As can be seen by the comparison above, when using the stereoelectronic interactions, the cyclohexadiene ring on the side with the Cl atom is moved further away from the Cl using the MOPAC calculation than the MM2. This is because the electronic effects included in this calculation include the repulsion between the electron rich Chlorine atom and the electron rich double bond, whereas the MM2 calculation doesn't include this and so a symmetrical molecule is formed.

====MOs====

The MOs of the previously MOPAC optimised molecule where then calculated using Guassian (B3LYP 6-31G)
{| style="wikitable" border="1"
! Homo-1 !! colspan="2" | Homo
|-
|[[File:Ohbclhomo-1.jpg|250px]]
| <jmol>
<jmolApplet>
<title>Orbital</title><color>white</color><size>250</size>
<script>isosurface color orange purple "images/f/f2/Ohbdienemo48.cub.jvxl" translucent; </script>
<uploadedFileContents>Ohbdienemo48.cub.xyz</uploadedFileContents>
</jmolApplet>
</jmol>
|[[File:Ohbclhomo.jpg|250px]]
|-
!Lumo !! Lumo+1 !! Lumo+2
|-
|[[File:Ohbcllumo.jpg|250px]]
|[[File:Ohbcllumo+1.jpg|250px]]
|[[File:Ohbcllumo+2.jpg|250px]]
|-
|colspan="2" | [[File:Ohbclmep.jpg|300px rotate="90"]]
| [[File:Ohbclelevels.png|250px]]
|}

Molecule 2 was initially minimised using an MM2 calculation. The reactions of molecule A with an electrophile can be illustrated by taking a more advanced, quantum mechanical approach to modelling the molecule and its orbitals. This will also allow prediction of which C=C reacts with an electrophile.
Of the two alekenes, the endo is favoured rather than the exo because the cl-c sigma star orbital mixes with the exo alkene. This stabilises both orbitals, as shown by the frequency calculation having a higher value than the endo alkene, but reduces the pi bond character of the exo alkene. This is also shown by the comparative lengths of the alkene bonds - the exo is 1.3355A and the endo is 1.33190A. The cycloaddition of the carbene requires an alkene and so favours the endo alkene as it has a higher p character. The homo is also focused entirely on the endo side of the molecule, with the lumo focused mainly on the exo side. The Homo shows the high pi bond character of the endo alkene. The Homo-1 is mainly focused ont he exo alekene, so shows the pi bond character of the exo alekene. This is lower in energy and so is less likely to react with the carbene molecule.

====Glycosidation====

When the monosaccharide pyranose has an acetal in the 2 position, four different isomers can be formed, all of differing stability. These differing positions of the acetal group and its interactions with the neighbouring group means that it acts as a directing group to nucleophilic attack. With deprotonation to an oxenium cation being the initial step, the acetal group can then stabilise this to varying degrees depending on its position. Due to the Sn1 nature of the glycosidation nucleophilic attack occurring, the access of the nucleophile to the sigma* orbital of the carbon is crucial, and this depends on the Burgi-Dunitz angle of 107<ref> H. B. Bürgi, J. D. Dunitz, J. M. Lehn, G. Wipff (1974). "Stereochemistry of reaction paths at carbonyl centres". Tetrahedron 30 (12): 1563–1572. doi:10.1016/S0040-4020(01)90678-7</ref>.
Two sets of calculations were performed; initially using an MM2 forcefield, and then with using the MOPAC approach. While both approaches showed a similar trend, the benefit of the MOPAC, to make and break bond meant that the structures formed by this minimisation resembled the transition state a lot more closely than those formed by the MM2.
As shown by the table, below, all of the initial cations are at a lower energy than the intermediate forms, however the structures differ slightly depending on whether an MM2 or MOPAC minimisation was performed; the MOPAC structures much more closely resemble the transition states.
The differences in energy can be directly related to the amount of strain present within the molecule and the repulsion between the oxygen atoms. The large amount of strain present in the intermediates, particularly of molecule 2, mean that they have a lot higher energy. A notable differences is that the MM2 struggles to accurately deal with the oxenium cation, whereas the MOPAC produces a more lifelike picture in this area.
The glycosidation mainly produces the trans isomers, ie molecules going through the pathways of molecules 1 & 4. This is predicted well by the computational methods used, with both the initial molecules and the intermediates being lower in energy and having lower anomeric carbon-acetal oxygen distances.

=====Mechanisms=====

[[file:Ohbglymech.gif|800px]]

{|class="wikitable" border="2"
!rowspan="5" |Initial molecule
!colspan="2" | Conformation
|1
|2
|3
|4
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2amm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 11.5430
| 46.2672
| 35.5277
| 29.5144
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -90.51343
| -70.57703
| -72.56010
| -85.04737
|-
!rowspan="5" |Intermediate
!colspan="2" | Conformation
|chemdraw
|chemdraw
|chemdraw
|chemdraw
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2Bmm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 28.4913
| 43.2706
| 41.0918
| 31.8763
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -91.66112
| -66.72331
| -84.44899
| -88.08089

|-
|}

==Comparison of coumpational results to a molecule from literature.==

===Taxol intermediate===

Computational chemistry can be a powerful tool in the analysis and reproduction of spectra. in this exercise, literature values and spectra are compared to computed data and the effectiveness and accuracy of both methods is compared and contrasted.

A different intermediate in the synthesis of taxol was optimised using MM2 to produce the structure (right) with a total energy of 66.7072kcal<sup>-1</sup>
{| class="wikitable border="1"
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
This file was then optimised using Guassian and B3LYP 6-31G(d,p) basis set. The resulting file was then resubmitted to the SCAN cluster for computation of the nmr spectrum using these keywords # mpw1pw91/6-31G(d,p) NMR SCRF=(CPCM,Solvent=chloroform). These results were then compared to those found in the literature<ref>#L. Paquette, N. A. Pegg, D. Toops, G. D. Maynard, R. D. Rogers, ''J. Am. Chem. Soc.,'', '''1990''', ''112'', 277-283. {{DOI|10.1021/ja00157a043}}</ref>.
The results are below. As can be seen by this comparison chart, in general there is very good agreement between the predicted and measured shift values. With the only major discrepancy being at Carbon 16.

This however, can be resolved. The large distance is probably to do with this carbon being bonded to two sulphur atoms. The 6-31G(d,p) basis set is not very good at approximating, and hence optimising sulphur molecules. This is because Sulphur contains f type functions, of which there are 7. However there are 10<ref>SIMPLIFIED INTRODUCTION TO AB INITIO
BASIS SETS. TERMS AND NOTATION.
Jan K. Labanowski, Ohio Supercomputer Center,
1224 Kinnear Rd., Columbus, OH 43212-1163,</ref> possible Guassians, and so an element of contamination from the 4p orbitals is brought in. As the 6-31G(d,p) does not containg any f functions, it is not that good at predicting the behaviour of the sulphur molecule to the level required by the nmr calculation. Despite all of this, the shift values are still similar, and so the assignmnet of this molecule inth e literature can be deemed correct.
{|class="wikitable" border="2"
!Atom number !! Calculated ppm value !! Lit. ppm value
|-
| 1
| 27.5886
| 25.66
|-
| 2
| 31.6721
| 28.79
|-
| 3
| 52.6851
| 48.5
|-
| 4
| 146.8944
| 144.63
|-
| 5
| 51.4817
| 46.8
|-
| 6
| 20.6456
| 18.71
|-
| 7
| 27.0826
| 23.86
|-
| 8
| 125.7193
| 125.33
|-
| 9
| 50.5885
| 45.76
|-
| 10
| 218.6545
| 218.79
|-
| 11
| colspan="2" | Oxygen
|-
| 12
| 54.1882
| 52.52
|-
| 13
| 30.8219
| 28.29
|-
| 14
| 63.85
| 56.19
|-
| 15
| 29.5406
| 26.88
|-
| 16
| 89.99
| 72.88
|-
| 17
| 48.9728
| 39.8
|-
| 18
| 24.6905
| 20.96
|-
| 19
| 41.3115
| 32.66
|-
| 21
| 44.3139
| 35.85
|-
| 22
| 45.5337
| 38.81
|}

===Literature Molecule===

In the synthesis of molecule A (below), using Kobayashi aldol chemistry, two stereoisomers are produced. Initially, the syn isomer is formed, with a diasteromic ratio of 1:14, and via a similar synthetic route, the anti isomer is also produced, with a high dr of 1:>50. The high stereoselectivity of both of these reactions is an important step in the synthesis of enationmerically pure natural products.

{| class="wikitable border="1"
!Molecule A
! Syn
! Anti
|-
![[File:Ohbmol.gif|300px]]
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbsyn.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbanti.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
|}
Initiallyu the models were optimised using an MM2 optimisation within ChemBio 12.0. They were then further optimised using an RB3LYP-6-31G(d,p) method and basis set. After the optimisation, and checking to see that the the two molecules were still distinct, with one syn and one anti form, they were submitted for nmr analysis, to produce a predicted nmr. This was then compared with the reported nmr, with a view to see if the assignments and conclusions made in the literature were correct. There was a good correlations between the predicted and measured nmr peaks, with deviations, as show below, of less than 1ppm for the H nmr and less than 10ppm for the <sup>13</sup>C nmr.
[[File:Ohbccomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each carbon atom]]
[[File:Ohbhcomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each Hydrogen atom]]

This correlation helps confirm that the structures are correct; the different enantiomers are differentiated and assigned correctly. If they were not, and the calculated syn nmr is compared to the measured anti nmr, and vice versa, larger differences are noted. This is highlighted on the graph below. The blue and red graphs are the correctly assigned and matched nmrs, the green and purple nmrs are if they are assigned incorrectly. It can clearly be seen that the green and purple line are consistently higher than their counterparts.
[[file:Ohbcomparisonnmr.png|thumb|900px|none|left|Comparison of correct and incorrect assignment for the two conformers]]
Within the literature all of the hydrogens and carbons are assigned, with the exception of Hydrogen 48. This is because this is a labile proton and so does not show up on measured nmrs due to rapid exchange with the deuterium in the deuterated solvent. However the calculated spectra does not take this into account and so displays the shift value for this hydrogen.

The computed IR spectra are very similar for the two molecules. The OH stretch is increased by 30cm<sup>-1</sup> in the syn form of the molecule and the CH bend region between 1000-1500cm<sup>-1</sup> is also significantly different. This can be rationalised by the different atomic orbital overlaps that are occuring due to the different positioning of the methyl group. The literature does not supply data for the IR spectra of these two compounds, and it is understandable why as it would be impossible to differentiate between the two molecules through the IR, as they are so similar.

[[File:Irnzohb.png|thumb|900px|none|left|Comparison of the two computed IR spectra]]
[[File:Irzoomedohb.png|thumb|900px|none|left|Zoom showing main differences between spectra]]

As can be seen above, the differences, while there, are slight and insufficient to draw conclusions from.

As both molecules are chiral, they both rotate light in opposite directions. However due to the large size of this molecule and although it is relatively conformationally limited due to the double bond and ring, the calculation for the syn and anti variants did not converge after 48 a 48 hour run on the SCAN.

Despite the inconclusive IR I believe the correct assignments have been made in this case due to the close correlation between the predicted and measured <sup>13</sup>C and H nmr.

==References==
<references></references>

Rep:Mod:benton2

2013-02-08T16:00:41Z

Ohb09: /* Literature Molecule */

=Module 1 - Intro=
In this experiment, MM2 is compared to the more advanced MOPAC minimisation technique. A minimised molecule is then analysed and compared to literature.
Molecular mechanics, used here in its MM2 form is a very good first order approximation. Using data from previous experiments and breaking down the overall energy into different categories, such as van der Waals interaction, dipole-dipole, and bending before summing them to provide an overall energy is a very useful and more importantly quick method to calculate a molecules energy. The energy of molecule can then be iteratively reduced by tweaking the position of the atoms and conformations, providing a low energy structure. However it does have its limitations. Firstly, because of the large approximations used, the method is liable to fall, and remain, in an initial, smaller, potential well at a higher energy than the minimum possible. This can be overcome by carefully arranging the molecule by the user of the program to avoid these early, high energy minima, but requires a lot of rearrangement and prioir knowledge of low energy arrangements. As MM2 uses previously aquired data, it is also not that useful in determining new structures, or functional groups for which it does not have the data for.
MOPAC uses a different approach for minimisation. It uses semi empirical quantum chemistry functions to determine the energy of a molecule. This allows more advanced effects to be included in the calculation and allows for analysis of the neighbouring group effect in sacchardie chemistry and regioselectivity effects, as studied here.
Computational chemistry can also predict spectra, and in the last part of the experiment predicted spectra are compared to literature and the results analysed.

==Week 1==

===Hydrogenation of the Cyclopentadiene Dimer===
The endo dimer is primarily produced when cyclopentadiene dimerises, in a ratio of 99.5% to 0.5% <ref>
Małgorzata E Jamróz, Sławomir Gałka, Jan Cz Dobrowolski,
On dicyclopentadiene isomers,
Journal of Molecular Structure: THEOCHEM,
Volume 634, Issues 1–3, 5 September 2003,
Pages 225-233, ISSN 0166-1280,
<DOI|10.1016/S0166-1280(03)00348-8>
</ref>(at least when thermally initiated; photo initiation produces a racemic mixture of the two isomers<ref>
The Photosensitited Dimerization of Cyclopentadiene
Nicholas J. Turro and George S. Hammond
Journal of the American Chemical Society 1962 84 (14), 2841-2842
<DOI|10.1021/ja00873a050>
</ref>)
{| class="wikitable" border="1"

! rowspan="2" | Molecule
|style="text-align: center;" |Exo
|style="text-align: center;" |Endo
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbexodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Total E (kcal/mol)
|33.9975
|31.8764
|-
|}
[[file:Endoexoohb.bmp|thumb|left|500px]]
The small energy difference calculated by the MM2 forcefield does not highlight why the endo for is favoured over the exo form as it shows the exo form is lower in energy. While the difference between the two energies is relatively trivial, the high enationmeric excess of the products suggest that this is only part of the story, and suggest that this reaction is under kinetic rather than thermodynamic control.<ref> W.C.Herndon, C.R.Grayson, J.M.Manion; "Retro-Diels-Alder reactions. III. Kinetics of the thermal decompositions of exo- and endo-dicyclopentadiene" J. Org. Chem.; 1967, 32 (3); 526-529.DOI:10.1021/jo01278a003</ref> Being under kinetic control would imply the activation energy, and hence transition state, for the endo species is lower than the exo form and so the endo enantiomer is formed faster. This can be rationalised by looking at the orbital interactions in the two transition states.

The endo transition state is stabilised by the secondary favourable overlap whereas in the exo form there is no such overlap to stabilised the molecule meaning that the transition state is a higher energy, and so is less favourable. This cannot be handled by the simple MM2 calculation however.

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" colspan="2" |Different hydrogenation sites
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh3.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh4.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|1.2489
|1.1303
|-
!Bend
|19.1608
|13.10259
|-
!Torsion
|11.0730
|12.4118
|-
!VDW
|5.7962
|4.4398
|-
!Dipole-Dipole
|0.1622
|0.1410
|-
!Total E (kcal/mol)
|34.9643
|29.2475
|-
|}

The site of initial hydrogenation of the endo dimer can also be determined by calculating the energies of the two possible isomers. From these calculations it is clear that the second molecule is favoured more, as it is ~5.5kcalmol<sup>-1</sup> more stable. The bending energy in both of these molecules is the major difference. This manifests itself in the amount that the atoms are ebent away from their ideal positions, which is 109.5 for an sp3 carbon and 120 for an sp2 carbon. Across all of the key bonds, the second isomer has bond angles that are closer to the ideal than the first isomer; in particular the C-C=C bond angles; in the first molecule they are 107.6 and in the second 112.8. This difference of five degrees is enough to significantly stabilise the second isomer, making hydrogenation at that site the more preferable.

===Atropisomerism in an Intermediate related to the synthesis of Taxol===
In the complete synthesis of Taxol, and important cancer fighting drug, proposed by Pacquette <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 10.1016/S0040-4039(00)92617-0</ref> a key intermediate is either "Precursor 9" or "Precursor 10".

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" |Precursor 10
|style="text-align: center;" |Precursor 9
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol9.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol10.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|2.4687
|2.7846
|-
!Bend
|10.5555
|16.5411
|-
!Torsion
|17.4240
|18.2518
|-
!VDW
|13.1930
|13.1096
|-
!Dipole-Dipole
| -1.8818
| -1.7248
|-
!Total E (kcal/mol)
|39.1215
|47.8395
|-
|}
Precursor 9 and 10 are synthesised using a reversible oxy-Cope rearrangement as demonstrated below. As this process is in equilibrium that, with precursor 10 being more stable, it is predicted that this isomer will be the one produced as all of the molecules attempt to reduce the energy. As analysis of the individual energy componenets shows, this arrangement is a lot less strained than Precursor nine, which requires a lot more bending energy.

The molecule was then optimised with an MMFF94. Rather than rely on a large set of experimentally determined parameters like MM2, MMFF94 minimises the potential of each atom iteratively, attempting to minimise the whole molecule. Although the values produced for these two methods cannot be directly compared, they both correctly identify the correct altropisomer as being lower in energy.
{|class="wikitable" border="1"
! colspan="3" | Comparison of MMFF94 and MM2 minimisations
|-
!Molecule
| Precursor 9
| Precursor 10
|-
!MM2 minimised Energy (kJmol<sup><-1</sup>)
|39.1215
|47.8395
|-
!MMFF94 minimised Energy (kcalmol<sup><-1</sup>)
|58.7513
|70.5377
|-
|}

===Regioselective Addition of Dichlorocarbene to a diene===
Molecule A was initially optimised using a molecular mechanics (MM2) calculation

{| style="wikitable" border="1"
|<jmol>
<jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
It was then further optimised with a MOPAC calculation, which takes into effect stereoelectronic effects. The two were then compared.

{| class="wikitable" border="1"
!colspan="3" | Comparison of two optimisation calculations
|-
! Overlay of two optimised molecules !! MM2 optimised molecule !! MOPAC Optimised Molecule
|-
|[[file:Ohboverlaydiene.png|300px]]
The MM2 optimised molecule is coloured yellow for clarity
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1mopac.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! rowspan="6" | Distances between
corresponding atoms

on the overlaid molecules (Å)
|style="text-align: center;" | C(34)-C(9)
|0.5247
|-
|style="text-align: center;" | C(26)-C(1)
|0.5246
|-
|style="text-align: center;" | H(47)-H(22)
|0.8526
|-
|style="text-align: center;" | H(38)-H(13)
|0.8524
|-
|style="text-align: center;" | Cl(37)-Cl(12)
|0.0689
|}

As can be seen by the comparison above, when using the stereoelectronic interactions, the cyclohexadiene ring on the side with the Cl atom is moved further away from the Cl using the MOPAC calculation than the MM2. This is because the electronic effects included in this calculation include the repulsion between the electron rich Chlorine atom and the electron rich double bond, whereas the MM2 calculation doesn't include this and so a symmetrical molecule is formed.

====MOs====

The MOs of the previously MOPAC optimised molecule where then calculated using Guassian (B3LYP 6-31G)
{| style="wikitable" border="1"
! Homo-1 !! colspan="2" | Homo
|-
|[[File:Ohbclhomo-1.jpg|250px]]
| <jmol>
<jmolApplet>
<title>Orbital</title><color>white</color><size>250</size>
<script>isosurface color orange purple "images/f/f2/Ohbdienemo48.cub.jvxl" translucent; </script>
<uploadedFileContents>Ohbdienemo48.cub.xyz</uploadedFileContents>
</jmolApplet>
</jmol>
|[[File:Ohbclhomo.jpg|250px]]
|-
!Lumo !! Lumo+1 !! Lumo+2
|-
|[[File:Ohbcllumo.jpg|250px]]
|[[File:Ohbcllumo+1.jpg|250px]]
|[[File:Ohbcllumo+2.jpg|250px]]
|-
|colspan="2" | [[File:Ohbclmep.jpg|300px rotate="90"]]
| [[File:Ohbclelevels.png|250px]]
|}

Molecule 2 was initially minimised using an MM2 calculation. The reactions of molecule A with an electrophile can be illustrated by taking a more advanced, quantum mechanical approach to modelling the molecule and its orbitals. This will also allow prediction of which C=C reacts with an electrophile.
Of the two alekenes, the endo is favoured rather than the exo because the cl-c sigma star orbital mixes with the exo alkene. This stabilises both orbitals, as shown by the frequency calculation having a higher value than the endo alkene, but reduces the pi bond character of the exo alkene. This is also shown by the comparative lengths of the alkene bonds - the exo is 1.3355A and the endo is 1.33190A. The cycloaddition of the carbene requires an alkene and so favours the endo alkene as it has a higher p character. The homo is also focused entirely on the endo side of the molecule, with the lumo focused mainly on the exo side. The Homo shows the high pi bond character of the endo alkene. The Homo-1 is mainly focused ont he exo alekene, so shows the pi bond character of the exo alekene. This is lower in energy and so is less likely to react with the carbene molecule.

====Glycosidation====

When the monosaccharide pyranose has an acetal in the 2 position, four different isomers can be formed, all of differing stability. These differing positions of the acetal group and its interactions with the neighbouring group means that it acts as a directing group to nucleophilic attack. With deprotonation to an oxenium cation being the initial step, the acetal group can then stabilise this to varying degrees depending on its position. Due to the Sn1 nature of the glycosidation nucleophilic attack occurring, the access of the nucleophile to the sigma* orbital of the carbon is crucial, and this depends on the Burgi-Dunitz angle of 107<ref> H. B. Bürgi, J. D. Dunitz, J. M. Lehn, G. Wipff (1974). "Stereochemistry of reaction paths at carbonyl centres". Tetrahedron 30 (12): 1563–1572. doi:10.1016/S0040-4020(01)90678-7</ref>.
Two sets of calculations were performed; initially using an MM2 forcefield, and then with using the MOPAC approach. While both approaches showed a similar trend, the benefit of the MOPAC, to make and break bond meant that the structures formed by this minimisation resembled the transition state a lot more closely than those formed by the MM2.
As shown by the table, below, all of the initial cations are at a lower energy than the intermediate forms, however the structures differ slightly depending on whether an MM2 or MOPAC minimisation was performed; the MOPAC structures much more closely resemble the transition states.
The differences in energy can be directly related to the amount of strain present within the molecule and the repulsion between the oxygen atoms. The large amount of strain present in the intermediates, particularly of molecule 2, mean that they have a lot higher energy. A notable differences is that the MM2 struggles to accurately deal with the oxenium cation, whereas the MOPAC produces a more lifelike picture in this area.
The glycosidation mainly produces the trans isomers, ie molecules going through the pathways of molecules 1 & 4. This is predicted well by the computational methods used, with both the initial molecules and the intermediates being lower in energy and having lower anomeric carbon-acetal oxygen distances.

=====Mechanisms=====

[[file:Ohbglymech.gif|800px]]

{|class="wikitable" border="2"
!rowspan="5" |Initial molecule
!colspan="2" | Conformation
|1
|2
|3
|4
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2amm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 11.5430
| 46.2672
| 35.5277
| 29.5144
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -90.51343
| -70.57703
| -72.56010
| -85.04737
|-
!rowspan="5" |Intermediate
!colspan="2" | Conformation
|chemdraw
|chemdraw
|chemdraw
|chemdraw
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2Bmm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 28.4913
| 43.2706
| 41.0918
| 31.8763
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -91.66112
| -66.72331
| -84.44899
| -88.08089

|-
|}

==Comparison of coumpational results to a molecule from literature.==

===Taxol intermediate===

Computational chemistry can be a powerful tool in the analysis and reproduction of spectra. in this exercise, literature values and spectra are compared to computed data and the effectiveness and accuracy of both methods is compared and contrasted.

A different intermediate in the synthesis of taxol was optimised using MM2 to produce the structure (right) with a total energy of 66.7072kcal<sup>-1</sup>
{| class="wikitable border="1"
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
This file was then optimised using Guassian and B3LYP 6-31G(d,p) basis set. The resulting file was then resubmitted to the SCAN cluster for computation of the nmr spectrum using these keywords # mpw1pw91/6-31G(d,p) NMR SCRF=(CPCM,Solvent=chloroform). These results were then compared to those found in the literature<ref>#L. Paquette, N. A. Pegg, D. Toops, G. D. Maynard, R. D. Rogers, ''J. Am. Chem. Soc.,'', '''1990''', ''112'', 277-283. {{DOI|10.1021/ja00157a043}}</ref>.
The results are below. As can be seen by this comparison chart, in general there is very good agreement between the predicted and measured shift values. With the only major discrepancy being at Carbon 16.

This however, can be resolved. The large distance is probably to do with this carbon being bonded to two sulphur atoms. The 6-31G(d,p) basis set is not very good at approximating, and hence optimising sulphur molecules. This is because Sulphur contains f type functions, of which there are 7. However there are 10<ref>SIMPLIFIED INTRODUCTION TO AB INITIO
BASIS SETS. TERMS AND NOTATION.
Jan K. Labanowski, Ohio Supercomputer Center,
1224 Kinnear Rd., Columbus, OH 43212-1163,</ref> possible Guassians, and so an element of contamination from the 4p orbitals is brought in. As the 6-31G(d,p) does not containg any f functions, it is not that good at predicting the behaviour of the sulphur molecule to the level required by the nmr calculation. Despite all of this, the shift values are still similar, and so the assignmnet of this molecule inth e literature can be deemed correct.
{|class="wikitable" border="2"
!Atom number !! Calculated ppm value !! Lit. ppm value
|-
| 1
| 27.5886
| 25.66
|-
| 2
| 31.6721
| 28.79
|-
| 3
| 52.6851
| 48.5
|-
| 4
| 146.8944
| 144.63
|-
| 5
| 51.4817
| 46.8
|-
| 6
| 20.6456
| 18.71
|-
| 7
| 27.0826
| 23.86
|-
| 8
| 125.7193
| 125.33
|-
| 9
| 50.5885
| 45.76
|-
| 10
| 218.6545
| 218.79
|-
| 11
| colspan="2" | Oxygen
|-
| 12
| 54.1882
| 52.52
|-
| 13
| 30.8219
| 28.29
|-
| 14
| 63.85
| 56.19
|-
| 15
| 29.5406
| 26.88
|-
| 16
| 89.99
| 72.88
|-
| 17
| 48.9728
| 39.8
|-
| 18
| 24.6905
| 20.96
|-
| 19
| 41.3115
| 32.66
|-
| 21
| 44.3139
| 35.85
|-
| 22
| 45.5337
| 38.81
|}

===Literature Molecule===

In the synthesis of molecule A (below), using Kobayashi aldol chemistry, two stereoisomers are produced. Initially, the syn isomer is formed, with a diasteromic ratio of 1:14, and via a similar synthetic route, the anti isomer is also produced, with a high dr of 1:>50. The high stereoselectivity of both of these reactions is an important step in the synthesis of enationmerically pure natural products.

{| class="wikitable border="1"
!Molecule A
! Syn
! Anti
|-
![[File:Ohbmol.gif|300px]]
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbsyn.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbanti.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
|}
Initiallyu the models were optimised using an MM2 optimisation within ChemBio 12.0. They were then further optimised using an RB3LYP-6-31G(d,p) method and basis set. After the optimisation, and checking to see that the the two molecules were still distinct, with one syn and one anti form, they were submitted for nmr analysis, to produce a predicted nmr. This was then compared with the reported nmr, with a view to see if the assignments and conclusions made in the literature were correct. There was a good correlations between the predicted and measured nmr peaks, with deviations, as show below, of less than 1ppm for the H nmr and less than 10ppm for the <sup>13</sup>C nmr.
[[File:Ohbccomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each carbon atom]]
[[File:Ohbhcomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each Hydrogen atom]]

This correlation helps confirm that the structures are correct; the different enantiomers are differentiated and assigned correctly. If they were not, and the calculated syn nmr is compared to the measured anti nmr, and vice versa, larger differences are noted. This is highlighted on the graph below. The blue and red graphs are the correctly assigned and matched nmrs, the green and purple nmrs are if they are assigned incorrectly. It can clearly be seen that the green and purple line are consistently higher than their counterparts.
[[file:Ohbcomparisonnmr.png|thumb|900px|none|left|Comparison of correct and incorrect assignment for the two conformers]]
Within the literature all of the hydrogens and carbons are assigned, with the exception of Hydrogen 48. This is because this is a labile proton and so does not show up on measured nmrs due to rapid exchange with the deuterium in the deuterated solvent. However the calculated spectra does not take this into account and so displays the shift value for this hydrogen.

The computed IR spectra are very similar for the two molecules. The OH stretch is increased by 30cm<sup>-1</sup> in the syn form of the molecule and the CH bend region between 1000-1500cm<sup>-1</sup> is also significantly different. This can be rationalised by the different atomic orbital overlaps that are occuring due to the different positioning of the methyl group. The literature does not supply data for the IR spectra of these two compounds, and it is understandable why as it would be impossible to differentiate between the two molecules through the IR, as they are so similar.

[[File:Irnzohb.png|thumb|900px|none|left|Comparison of the two computed IR spectra]]
[[File:Irzoomedohb.png|thumb|900px|none|left|Zoom showing main differences between spectra]]

As both molecules are chiral, they both rotate light in opposite directions. However due to the large size of this molecule and although it is relatively conformationally limited due to the double bond and ring, the calculation for the syn and anti variants did not converge after 48 a 48 hour run on the SCAN.

==References==
<references></references>

File:Irzoomedohb.png

2013-02-08T15:59:42Z

Ohb09:

File:Irnzohb.png

2013-02-08T15:59:41Z

Ohb09:

Rep:Mod:benton2

2013-02-08T15:52:22Z

Ohb09: /* Literature Molecule */

=Module 1 - Intro=
In this experiment, MM2 is compared to the more advanced MOPAC minimisation technique. A minimised molecule is then analysed and compared to literature.
Molecular mechanics, used here in its MM2 form is a very good first order approximation. Using data from previous experiments and breaking down the overall energy into different categories, such as van der Waals interaction, dipole-dipole, and bending before summing them to provide an overall energy is a very useful and more importantly quick method to calculate a molecules energy. The energy of molecule can then be iteratively reduced by tweaking the position of the atoms and conformations, providing a low energy structure. However it does have its limitations. Firstly, because of the large approximations used, the method is liable to fall, and remain, in an initial, smaller, potential well at a higher energy than the minimum possible. This can be overcome by carefully arranging the molecule by the user of the program to avoid these early, high energy minima, but requires a lot of rearrangement and prioir knowledge of low energy arrangements. As MM2 uses previously aquired data, it is also not that useful in determining new structures, or functional groups for which it does not have the data for.
MOPAC uses a different approach for minimisation. It uses semi empirical quantum chemistry functions to determine the energy of a molecule. This allows more advanced effects to be included in the calculation and allows for analysis of the neighbouring group effect in sacchardie chemistry and regioselectivity effects, as studied here.
Computational chemistry can also predict spectra, and in the last part of the experiment predicted spectra are compared to literature and the results analysed.

==Week 1==

===Hydrogenation of the Cyclopentadiene Dimer===
The endo dimer is primarily produced when cyclopentadiene dimerises, in a ratio of 99.5% to 0.5% <ref>
Małgorzata E Jamróz, Sławomir Gałka, Jan Cz Dobrowolski,
On dicyclopentadiene isomers,
Journal of Molecular Structure: THEOCHEM,
Volume 634, Issues 1–3, 5 September 2003,
Pages 225-233, ISSN 0166-1280,
<DOI|10.1016/S0166-1280(03)00348-8>
</ref>(at least when thermally initiated; photo initiation produces a racemic mixture of the two isomers<ref>
The Photosensitited Dimerization of Cyclopentadiene
Nicholas J. Turro and George S. Hammond
Journal of the American Chemical Society 1962 84 (14), 2841-2842
<DOI|10.1021/ja00873a050>
</ref>)
{| class="wikitable" border="1"

! rowspan="2" | Molecule
|style="text-align: center;" |Exo
|style="text-align: center;" |Endo
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbexodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Total E (kcal/mol)
|33.9975
|31.8764
|-
|}
[[file:Endoexoohb.bmp|thumb|left|500px]]
The small energy difference calculated by the MM2 forcefield does not highlight why the endo for is favoured over the exo form as it shows the exo form is lower in energy. While the difference between the two energies is relatively trivial, the high enationmeric excess of the products suggest that this is only part of the story, and suggest that this reaction is under kinetic rather than thermodynamic control.<ref> W.C.Herndon, C.R.Grayson, J.M.Manion; "Retro-Diels-Alder reactions. III. Kinetics of the thermal decompositions of exo- and endo-dicyclopentadiene" J. Org. Chem.; 1967, 32 (3); 526-529.DOI:10.1021/jo01278a003</ref> Being under kinetic control would imply the activation energy, and hence transition state, for the endo species is lower than the exo form and so the endo enantiomer is formed faster. This can be rationalised by looking at the orbital interactions in the two transition states.

The endo transition state is stabilised by the secondary favourable overlap whereas in the exo form there is no such overlap to stabilised the molecule meaning that the transition state is a higher energy, and so is less favourable. This cannot be handled by the simple MM2 calculation however.

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" colspan="2" |Different hydrogenation sites
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh3.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh4.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|1.2489
|1.1303
|-
!Bend
|19.1608
|13.10259
|-
!Torsion
|11.0730
|12.4118
|-
!VDW
|5.7962
|4.4398
|-
!Dipole-Dipole
|0.1622
|0.1410
|-
!Total E (kcal/mol)
|34.9643
|29.2475
|-
|}

The site of initial hydrogenation of the endo dimer can also be determined by calculating the energies of the two possible isomers. From these calculations it is clear that the second molecule is favoured more, as it is ~5.5kcalmol<sup>-1</sup> more stable. The bending energy in both of these molecules is the major difference. This manifests itself in the amount that the atoms are ebent away from their ideal positions, which is 109.5 for an sp3 carbon and 120 for an sp2 carbon. Across all of the key bonds, the second isomer has bond angles that are closer to the ideal than the first isomer; in particular the C-C=C bond angles; in the first molecule they are 107.6 and in the second 112.8. This difference of five degrees is enough to significantly stabilise the second isomer, making hydrogenation at that site the more preferable.

===Atropisomerism in an Intermediate related to the synthesis of Taxol===
In the complete synthesis of Taxol, and important cancer fighting drug, proposed by Pacquette <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 10.1016/S0040-4039(00)92617-0</ref> a key intermediate is either "Precursor 9" or "Precursor 10".

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" |Precursor 10
|style="text-align: center;" |Precursor 9
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol9.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol10.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|2.4687
|2.7846
|-
!Bend
|10.5555
|16.5411
|-
!Torsion
|17.4240
|18.2518
|-
!VDW
|13.1930
|13.1096
|-
!Dipole-Dipole
| -1.8818
| -1.7248
|-
!Total E (kcal/mol)
|39.1215
|47.8395
|-
|}
Precursor 9 and 10 are synthesised using a reversible oxy-Cope rearrangement as demonstrated below. As this process is in equilibrium that, with precursor 10 being more stable, it is predicted that this isomer will be the one produced as all of the molecules attempt to reduce the energy. As analysis of the individual energy componenets shows, this arrangement is a lot less strained than Precursor nine, which requires a lot more bending energy.

The molecule was then optimised with an MMFF94. Rather than rely on a large set of experimentally determined parameters like MM2, MMFF94 minimises the potential of each atom iteratively, attempting to minimise the whole molecule. Although the values produced for these two methods cannot be directly compared, they both correctly identify the correct altropisomer as being lower in energy.
{|class="wikitable" border="1"
! colspan="3" | Comparison of MMFF94 and MM2 minimisations
|-
!Molecule
| Precursor 9
| Precursor 10
|-
!MM2 minimised Energy (kJmol<sup><-1</sup>)
|39.1215
|47.8395
|-
!MMFF94 minimised Energy (kcalmol<sup><-1</sup>)
|58.7513
|70.5377
|-
|}

===Regioselective Addition of Dichlorocarbene to a diene===
Molecule A was initially optimised using a molecular mechanics (MM2) calculation

{| style="wikitable" border="1"
|<jmol>
<jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
It was then further optimised with a MOPAC calculation, which takes into effect stereoelectronic effects. The two were then compared.

{| class="wikitable" border="1"
!colspan="3" | Comparison of two optimisation calculations
|-
! Overlay of two optimised molecules !! MM2 optimised molecule !! MOPAC Optimised Molecule
|-
|[[file:Ohboverlaydiene.png|300px]]
The MM2 optimised molecule is coloured yellow for clarity
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1mopac.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! rowspan="6" | Distances between
corresponding atoms

on the overlaid molecules (Å)
|style="text-align: center;" | C(34)-C(9)
|0.5247
|-
|style="text-align: center;" | C(26)-C(1)
|0.5246
|-
|style="text-align: center;" | H(47)-H(22)
|0.8526
|-
|style="text-align: center;" | H(38)-H(13)
|0.8524
|-
|style="text-align: center;" | Cl(37)-Cl(12)
|0.0689
|}

As can be seen by the comparison above, when using the stereoelectronic interactions, the cyclohexadiene ring on the side with the Cl atom is moved further away from the Cl using the MOPAC calculation than the MM2. This is because the electronic effects included in this calculation include the repulsion between the electron rich Chlorine atom and the electron rich double bond, whereas the MM2 calculation doesn't include this and so a symmetrical molecule is formed.

====MOs====

The MOs of the previously MOPAC optimised molecule where then calculated using Guassian (B3LYP 6-31G)
{| style="wikitable" border="1"
! Homo-1 !! colspan="2" | Homo
|-
|[[File:Ohbclhomo-1.jpg|250px]]
| <jmol>
<jmolApplet>
<title>Orbital</title><color>white</color><size>250</size>
<script>isosurface color orange purple "images/f/f2/Ohbdienemo48.cub.jvxl" translucent; </script>
<uploadedFileContents>Ohbdienemo48.cub.xyz</uploadedFileContents>
</jmolApplet>
</jmol>
|[[File:Ohbclhomo.jpg|250px]]
|-
!Lumo !! Lumo+1 !! Lumo+2
|-
|[[File:Ohbcllumo.jpg|250px]]
|[[File:Ohbcllumo+1.jpg|250px]]
|[[File:Ohbcllumo+2.jpg|250px]]
|-
|colspan="2" | [[File:Ohbclmep.jpg|300px rotate="90"]]
| [[File:Ohbclelevels.png|250px]]
|}

Molecule 2 was initially minimised using an MM2 calculation. The reactions of molecule A with an electrophile can be illustrated by taking a more advanced, quantum mechanical approach to modelling the molecule and its orbitals. This will also allow prediction of which C=C reacts with an electrophile.
Of the two alekenes, the endo is favoured rather than the exo because the cl-c sigma star orbital mixes with the exo alkene. This stabilises both orbitals, as shown by the frequency calculation having a higher value than the endo alkene, but reduces the pi bond character of the exo alkene. This is also shown by the comparative lengths of the alkene bonds - the exo is 1.3355A and the endo is 1.33190A. The cycloaddition of the carbene requires an alkene and so favours the endo alkene as it has a higher p character. The homo is also focused entirely on the endo side of the molecule, with the lumo focused mainly on the exo side. The Homo shows the high pi bond character of the endo alkene. The Homo-1 is mainly focused ont he exo alekene, so shows the pi bond character of the exo alekene. This is lower in energy and so is less likely to react with the carbene molecule.

====Glycosidation====

When the monosaccharide pyranose has an acetal in the 2 position, four different isomers can be formed, all of differing stability. These differing positions of the acetal group and its interactions with the neighbouring group means that it acts as a directing group to nucleophilic attack. With deprotonation to an oxenium cation being the initial step, the acetal group can then stabilise this to varying degrees depending on its position. Due to the Sn1 nature of the glycosidation nucleophilic attack occurring, the access of the nucleophile to the sigma* orbital of the carbon is crucial, and this depends on the Burgi-Dunitz angle of 107<ref> H. B. Bürgi, J. D. Dunitz, J. M. Lehn, G. Wipff (1974). "Stereochemistry of reaction paths at carbonyl centres". Tetrahedron 30 (12): 1563–1572. doi:10.1016/S0040-4020(01)90678-7</ref>.
Two sets of calculations were performed; initially using an MM2 forcefield, and then with using the MOPAC approach. While both approaches showed a similar trend, the benefit of the MOPAC, to make and break bond meant that the structures formed by this minimisation resembled the transition state a lot more closely than those formed by the MM2.
As shown by the table, below, all of the initial cations are at a lower energy than the intermediate forms, however the structures differ slightly depending on whether an MM2 or MOPAC minimisation was performed; the MOPAC structures much more closely resemble the transition states.
The differences in energy can be directly related to the amount of strain present within the molecule and the repulsion between the oxygen atoms. The large amount of strain present in the intermediates, particularly of molecule 2, mean that they have a lot higher energy. A notable differences is that the MM2 struggles to accurately deal with the oxenium cation, whereas the MOPAC produces a more lifelike picture in this area.
The glycosidation mainly produces the trans isomers, ie molecules going through the pathways of molecules 1 & 4. This is predicted well by the computational methods used, with both the initial molecules and the intermediates being lower in energy and having lower anomeric carbon-acetal oxygen distances.

=====Mechanisms=====

[[file:Ohbglymech.gif|800px]]

{|class="wikitable" border="2"
!rowspan="5" |Initial molecule
!colspan="2" | Conformation
|1
|2
|3
|4
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2amm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 11.5430
| 46.2672
| 35.5277
| 29.5144
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -90.51343
| -70.57703
| -72.56010
| -85.04737
|-
!rowspan="5" |Intermediate
!colspan="2" | Conformation
|chemdraw
|chemdraw
|chemdraw
|chemdraw
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2Bmm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 28.4913
| 43.2706
| 41.0918
| 31.8763
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -91.66112
| -66.72331
| -84.44899
| -88.08089

|-
|}

==Comparison of coumpational results to a molecule from literature.==

===Taxol intermediate===

Computational chemistry can be a powerful tool in the analysis and reproduction of spectra. in this exercise, literature values and spectra are compared to computed data and the effectiveness and accuracy of both methods is compared and contrasted.

A different intermediate in the synthesis of taxol was optimised using MM2 to produce the structure (right) with a total energy of 66.7072kcal<sup>-1</sup>
{| class="wikitable border="1"
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
This file was then optimised using Guassian and B3LYP 6-31G(d,p) basis set. The resulting file was then resubmitted to the SCAN cluster for computation of the nmr spectrum using these keywords # mpw1pw91/6-31G(d,p) NMR SCRF=(CPCM,Solvent=chloroform). These results were then compared to those found in the literature<ref>#L. Paquette, N. A. Pegg, D. Toops, G. D. Maynard, R. D. Rogers, ''J. Am. Chem. Soc.,'', '''1990''', ''112'', 277-283. {{DOI|10.1021/ja00157a043}}</ref>.
The results are below. As can be seen by this comparison chart, in general there is very good agreement between the predicted and measured shift values. With the only major discrepancy being at Carbon 16.

This however, can be resolved. The large distance is probably to do with this carbon being bonded to two sulphur atoms. The 6-31G(d,p) basis set is not very good at approximating, and hence optimising sulphur molecules. This is because Sulphur contains f type functions, of which there are 7. However there are 10<ref>SIMPLIFIED INTRODUCTION TO AB INITIO
BASIS SETS. TERMS AND NOTATION.
Jan K. Labanowski, Ohio Supercomputer Center,
1224 Kinnear Rd., Columbus, OH 43212-1163,</ref> possible Guassians, and so an element of contamination from the 4p orbitals is brought in. As the 6-31G(d,p) does not containg any f functions, it is not that good at predicting the behaviour of the sulphur molecule to the level required by the nmr calculation. Despite all of this, the shift values are still similar, and so the assignmnet of this molecule inth e literature can be deemed correct.
{|class="wikitable" border="2"
!Atom number !! Calculated ppm value !! Lit. ppm value
|-
| 1
| 27.5886
| 25.66
|-
| 2
| 31.6721
| 28.79
|-
| 3
| 52.6851
| 48.5
|-
| 4
| 146.8944
| 144.63
|-
| 5
| 51.4817
| 46.8
|-
| 6
| 20.6456
| 18.71
|-
| 7
| 27.0826
| 23.86
|-
| 8
| 125.7193
| 125.33
|-
| 9
| 50.5885
| 45.76
|-
| 10
| 218.6545
| 218.79
|-
| 11
| colspan="2" | Oxygen
|-
| 12
| 54.1882
| 52.52
|-
| 13
| 30.8219
| 28.29
|-
| 14
| 63.85
| 56.19
|-
| 15
| 29.5406
| 26.88
|-
| 16
| 89.99
| 72.88
|-
| 17
| 48.9728
| 39.8
|-
| 18
| 24.6905
| 20.96
|-
| 19
| 41.3115
| 32.66
|-
| 21
| 44.3139
| 35.85
|-
| 22
| 45.5337
| 38.81
|}

===Literature Molecule===

In the synthesis of molecule A (below), using Kobayashi aldol chemistry, two stereoisomers are produced. Initially, the syn isomer is formed, with a diasteromic ratio of 1:14, and via a similar synthetic route, the anti isomer is also produced, with a high dr of 1:>50. The high stereoselectivity of both of these reactions is an important step in the synthesis of enationmerically pure natural products.

{| class="wikitable border="1"
!Molecule A
! Syn
! Anti
|-
![[File:Ohbmol.gif|300px]]
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbsyn.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbanti.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
|}
Initiallyu the models were optimised using an MM2 optimisation within ChemBio 12.0. They were then further optimised using an RB3LYP-6-31G(d,p) method and basis set. After the optimisation, and checking to see that the the two molecules were still distinct, with one syn and one anti form, they were submitted for nmr analysis, to produce a predicted nmr. This was then compared with the reported nmr, with a view to see if the assignments and conclusions made in the literature were correct. There was a good correlations between the predicted and measured nmr peaks, with deviations, as show below, of less than 1ppm for the H nmr and less than 10ppm for the <sup>13</sup>C nmr.
[[File:Ohbccomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each carbon atom]]
[[File:Ohbhcomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each Hydrogen atom]]

This correlation helps confirm that the structures are correct; the different enantiomers are differentiated and assigned correctly. If they were not, and the calculated syn nmr is compared to the measured anti nmr, and vice versa, larger differences are noted. This is highlighted on the graph below. The blue and red graphs are the correctly assigned and matched nmrs, the green and purple nmrs are if they are assigned incorrectly. It can clearly be seen that the green and purple line are consistently higher than their counterparts.
[[file:Ohbcomparisonnmr.png|thumb|900px|none|left|Comparison of correct and incorrect assignment for the two conformers]]
Within the literature all of the hydrogens and carbons are assigned, with the exception of Hydrogen 48. This is because this is a labile proton and so does not show up on measured nmrs due to rapid exchange with the deuterium in the deuterated solvent. However the calculated spectra does not take this into account and so displays the shift value for this hydrogen.

The computed IR spectra are very similar for the two molecules. The OH stretch is increased by 30cm<sup>-1</sup> in the syn form of the molecule and the CH bend region between 1000-1500cm<sup>-1</sup> is also significantly different. This can be rationalised by the different atomic orbital overlaps that are occuring due to the different positioning of the methyl group. The literature does not supply data for the IR spectra of these two compounds, and it is understandable why as it would be impossible to differentiate between the two molecules through the IR, as they are so similar.

[[File:synir.png|thumb|900px|none|left|Anti conformer IR]]
[[File:antiir.png|thumb|900px|none|left|Syn Conformer IR]]

As both molecules are chiral, they both rotate light in opposite directions. However due to the large size of this molecule and although it is relatively conformationally limited due to the double bond and ring, the calculation for the syn and anti variants did not converge after 48 a 48 hour run on the SCAN.

==References==
<references></references>

Rep:Mod:benton2

2013-02-08T15:50:04Z

Ohb09: /* Literature Molecule */

=Module 1 - Intro=
In this experiment, MM2 is compared to the more advanced MOPAC minimisation technique. A minimised molecule is then analysed and compared to literature.
Molecular mechanics, used here in its MM2 form is a very good first order approximation. Using data from previous experiments and breaking down the overall energy into different categories, such as van der Waals interaction, dipole-dipole, and bending before summing them to provide an overall energy is a very useful and more importantly quick method to calculate a molecules energy. The energy of molecule can then be iteratively reduced by tweaking the position of the atoms and conformations, providing a low energy structure. However it does have its limitations. Firstly, because of the large approximations used, the method is liable to fall, and remain, in an initial, smaller, potential well at a higher energy than the minimum possible. This can be overcome by carefully arranging the molecule by the user of the program to avoid these early, high energy minima, but requires a lot of rearrangement and prioir knowledge of low energy arrangements. As MM2 uses previously aquired data, it is also not that useful in determining new structures, or functional groups for which it does not have the data for.
MOPAC uses a different approach for minimisation. It uses semi empirical quantum chemistry functions to determine the energy of a molecule. This allows more advanced effects to be included in the calculation and allows for analysis of the neighbouring group effect in sacchardie chemistry and regioselectivity effects, as studied here.
Computational chemistry can also predict spectra, and in the last part of the experiment predicted spectra are compared to literature and the results analysed.

==Week 1==

===Hydrogenation of the Cyclopentadiene Dimer===
The endo dimer is primarily produced when cyclopentadiene dimerises, in a ratio of 99.5% to 0.5% <ref>
Małgorzata E Jamróz, Sławomir Gałka, Jan Cz Dobrowolski,
On dicyclopentadiene isomers,
Journal of Molecular Structure: THEOCHEM,
Volume 634, Issues 1–3, 5 September 2003,
Pages 225-233, ISSN 0166-1280,
<DOI|10.1016/S0166-1280(03)00348-8>
</ref>(at least when thermally initiated; photo initiation produces a racemic mixture of the two isomers<ref>
The Photosensitited Dimerization of Cyclopentadiene
Nicholas J. Turro and George S. Hammond
Journal of the American Chemical Society 1962 84 (14), 2841-2842
<DOI|10.1021/ja00873a050>
</ref>)
{| class="wikitable" border="1"

! rowspan="2" | Molecule
|style="text-align: center;" |Exo
|style="text-align: center;" |Endo
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbexodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Total E (kcal/mol)
|33.9975
|31.8764
|-
|}
[[file:Endoexoohb.bmp|thumb|left|500px]]
The small energy difference calculated by the MM2 forcefield does not highlight why the endo for is favoured over the exo form as it shows the exo form is lower in energy. While the difference between the two energies is relatively trivial, the high enationmeric excess of the products suggest that this is only part of the story, and suggest that this reaction is under kinetic rather than thermodynamic control.<ref> W.C.Herndon, C.R.Grayson, J.M.Manion; "Retro-Diels-Alder reactions. III. Kinetics of the thermal decompositions of exo- and endo-dicyclopentadiene" J. Org. Chem.; 1967, 32 (3); 526-529.DOI:10.1021/jo01278a003</ref> Being under kinetic control would imply the activation energy, and hence transition state, for the endo species is lower than the exo form and so the endo enantiomer is formed faster. This can be rationalised by looking at the orbital interactions in the two transition states.

The endo transition state is stabilised by the secondary favourable overlap whereas in the exo form there is no such overlap to stabilised the molecule meaning that the transition state is a higher energy, and so is less favourable. This cannot be handled by the simple MM2 calculation however.

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" colspan="2" |Different hydrogenation sites
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh3.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh4.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|1.2489
|1.1303
|-
!Bend
|19.1608
|13.10259
|-
!Torsion
|11.0730
|12.4118
|-
!VDW
|5.7962
|4.4398
|-
!Dipole-Dipole
|0.1622
|0.1410
|-
!Total E (kcal/mol)
|34.9643
|29.2475
|-
|}

The site of initial hydrogenation of the endo dimer can also be determined by calculating the energies of the two possible isomers. From these calculations it is clear that the second molecule is favoured more, as it is ~5.5kcalmol<sup>-1</sup> more stable. The bending energy in both of these molecules is the major difference. This manifests itself in the amount that the atoms are ebent away from their ideal positions, which is 109.5 for an sp3 carbon and 120 for an sp2 carbon. Across all of the key bonds, the second isomer has bond angles that are closer to the ideal than the first isomer; in particular the C-C=C bond angles; in the first molecule they are 107.6 and in the second 112.8. This difference of five degrees is enough to significantly stabilise the second isomer, making hydrogenation at that site the more preferable.

===Atropisomerism in an Intermediate related to the synthesis of Taxol===
In the complete synthesis of Taxol, and important cancer fighting drug, proposed by Pacquette <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 10.1016/S0040-4039(00)92617-0</ref> a key intermediate is either "Precursor 9" or "Precursor 10".

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" |Precursor 10
|style="text-align: center;" |Precursor 9
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol9.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol10.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|2.4687
|2.7846
|-
!Bend
|10.5555
|16.5411
|-
!Torsion
|17.4240
|18.2518
|-
!VDW
|13.1930
|13.1096
|-
!Dipole-Dipole
| -1.8818
| -1.7248
|-
!Total E (kcal/mol)
|39.1215
|47.8395
|-
|}
Precursor 9 and 10 are synthesised using a reversible oxy-Cope rearrangement as demonstrated below. As this process is in equilibrium that, with precursor 10 being more stable, it is predicted that this isomer will be the one produced as all of the molecules attempt to reduce the energy. As analysis of the individual energy componenets shows, this arrangement is a lot less strained than Precursor nine, which requires a lot more bending energy.

The molecule was then optimised with an MMFF94. Rather than rely on a large set of experimentally determined parameters like MM2, MMFF94 minimises the potential of each atom iteratively, attempting to minimise the whole molecule. Although the values produced for these two methods cannot be directly compared, they both correctly identify the correct altropisomer as being lower in energy.
{|class="wikitable" border="1"
! colspan="3" | Comparison of MMFF94 and MM2 minimisations
|-
!Molecule
| Precursor 9
| Precursor 10
|-
!MM2 minimised Energy (kJmol<sup><-1</sup>)
|39.1215
|47.8395
|-
!MMFF94 minimised Energy (kcalmol<sup><-1</sup>)
|58.7513
|70.5377
|-
|}

===Regioselective Addition of Dichlorocarbene to a diene===
Molecule A was initially optimised using a molecular mechanics (MM2) calculation

{| style="wikitable" border="1"
|<jmol>
<jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
It was then further optimised with a MOPAC calculation, which takes into effect stereoelectronic effects. The two were then compared.

{| class="wikitable" border="1"
!colspan="3" | Comparison of two optimisation calculations
|-
! Overlay of two optimised molecules !! MM2 optimised molecule !! MOPAC Optimised Molecule
|-
|[[file:Ohboverlaydiene.png|300px]]
The MM2 optimised molecule is coloured yellow for clarity
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1mopac.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! rowspan="6" | Distances between
corresponding atoms

on the overlaid molecules (Å)
|style="text-align: center;" | C(34)-C(9)
|0.5247
|-
|style="text-align: center;" | C(26)-C(1)
|0.5246
|-
|style="text-align: center;" | H(47)-H(22)
|0.8526
|-
|style="text-align: center;" | H(38)-H(13)
|0.8524
|-
|style="text-align: center;" | Cl(37)-Cl(12)
|0.0689
|}

As can be seen by the comparison above, when using the stereoelectronic interactions, the cyclohexadiene ring on the side with the Cl atom is moved further away from the Cl using the MOPAC calculation than the MM2. This is because the electronic effects included in this calculation include the repulsion between the electron rich Chlorine atom and the electron rich double bond, whereas the MM2 calculation doesn't include this and so a symmetrical molecule is formed.

====MOs====

The MOs of the previously MOPAC optimised molecule where then calculated using Guassian (B3LYP 6-31G)
{| style="wikitable" border="1"
! Homo-1 !! colspan="2" | Homo
|-
|[[File:Ohbclhomo-1.jpg|250px]]
| <jmol>
<jmolApplet>
<title>Orbital</title><color>white</color><size>250</size>
<script>isosurface color orange purple "images/f/f2/Ohbdienemo48.cub.jvxl" translucent; </script>
<uploadedFileContents>Ohbdienemo48.cub.xyz</uploadedFileContents>
</jmolApplet>
</jmol>
|[[File:Ohbclhomo.jpg|250px]]
|-
!Lumo !! Lumo+1 !! Lumo+2
|-
|[[File:Ohbcllumo.jpg|250px]]
|[[File:Ohbcllumo+1.jpg|250px]]
|[[File:Ohbcllumo+2.jpg|250px]]
|-
|colspan="2" | [[File:Ohbclmep.jpg|300px rotate="90"]]
| [[File:Ohbclelevels.png|250px]]
|}

Molecule 2 was initially minimised using an MM2 calculation. The reactions of molecule A with an electrophile can be illustrated by taking a more advanced, quantum mechanical approach to modelling the molecule and its orbitals. This will also allow prediction of which C=C reacts with an electrophile.
Of the two alekenes, the endo is favoured rather than the exo because the cl-c sigma star orbital mixes with the exo alkene. This stabilises both orbitals, as shown by the frequency calculation having a higher value than the endo alkene, but reduces the pi bond character of the exo alkene. This is also shown by the comparative lengths of the alkene bonds - the exo is 1.3355A and the endo is 1.33190A. The cycloaddition of the carbene requires an alkene and so favours the endo alkene as it has a higher p character. The homo is also focused entirely on the endo side of the molecule, with the lumo focused mainly on the exo side. The Homo shows the high pi bond character of the endo alkene. The Homo-1 is mainly focused ont he exo alekene, so shows the pi bond character of the exo alekene. This is lower in energy and so is less likely to react with the carbene molecule.

====Glycosidation====

When the monosaccharide pyranose has an acetal in the 2 position, four different isomers can be formed, all of differing stability. These differing positions of the acetal group and its interactions with the neighbouring group means that it acts as a directing group to nucleophilic attack. With deprotonation to an oxenium cation being the initial step, the acetal group can then stabilise this to varying degrees depending on its position. Due to the Sn1 nature of the glycosidation nucleophilic attack occurring, the access of the nucleophile to the sigma* orbital of the carbon is crucial, and this depends on the Burgi-Dunitz angle of 107<ref> H. B. Bürgi, J. D. Dunitz, J. M. Lehn, G. Wipff (1974). "Stereochemistry of reaction paths at carbonyl centres". Tetrahedron 30 (12): 1563–1572. doi:10.1016/S0040-4020(01)90678-7</ref>.
Two sets of calculations were performed; initially using an MM2 forcefield, and then with using the MOPAC approach. While both approaches showed a similar trend, the benefit of the MOPAC, to make and break bond meant that the structures formed by this minimisation resembled the transition state a lot more closely than those formed by the MM2.
As shown by the table, below, all of the initial cations are at a lower energy than the intermediate forms, however the structures differ slightly depending on whether an MM2 or MOPAC minimisation was performed; the MOPAC structures much more closely resemble the transition states.
The differences in energy can be directly related to the amount of strain present within the molecule and the repulsion between the oxygen atoms. The large amount of strain present in the intermediates, particularly of molecule 2, mean that they have a lot higher energy. A notable differences is that the MM2 struggles to accurately deal with the oxenium cation, whereas the MOPAC produces a more lifelike picture in this area.
The glycosidation mainly produces the trans isomers, ie molecules going through the pathways of molecules 1 & 4. This is predicted well by the computational methods used, with both the initial molecules and the intermediates being lower in energy and having lower anomeric carbon-acetal oxygen distances.

=====Mechanisms=====

[[file:Ohbglymech.gif|800px]]

{|class="wikitable" border="2"
!rowspan="5" |Initial molecule
!colspan="2" | Conformation
|1
|2
|3
|4
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2amm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 11.5430
| 46.2672
| 35.5277
| 29.5144
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -90.51343
| -70.57703
| -72.56010
| -85.04737
|-
!rowspan="5" |Intermediate
!colspan="2" | Conformation
|chemdraw
|chemdraw
|chemdraw
|chemdraw
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2Bmm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 28.4913
| 43.2706
| 41.0918
| 31.8763
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -91.66112
| -66.72331
| -84.44899
| -88.08089

|-
|}

==Comparison of coumpational results to a molecule from literature.==

===Taxol intermediate===

Computational chemistry can be a powerful tool in the analysis and reproduction of spectra. in this exercise, literature values and spectra are compared to computed data and the effectiveness and accuracy of both methods is compared and contrasted.

A different intermediate in the synthesis of taxol was optimised using MM2 to produce the structure (right) with a total energy of 66.7072kcal<sup>-1</sup>
{| class="wikitable border="1"
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
This file was then optimised using Guassian and B3LYP 6-31G(d,p) basis set. The resulting file was then resubmitted to the SCAN cluster for computation of the nmr spectrum using these keywords # mpw1pw91/6-31G(d,p) NMR SCRF=(CPCM,Solvent=chloroform). These results were then compared to those found in the literature<ref>#L. Paquette, N. A. Pegg, D. Toops, G. D. Maynard, R. D. Rogers, ''J. Am. Chem. Soc.,'', '''1990''', ''112'', 277-283. {{DOI|10.1021/ja00157a043}}</ref>.
The results are below. As can be seen by this comparison chart, in general there is very good agreement between the predicted and measured shift values. With the only major discrepancy being at Carbon 16.

This however, can be resolved. The large distance is probably to do with this carbon being bonded to two sulphur atoms. The 6-31G(d,p) basis set is not very good at approximating, and hence optimising sulphur molecules. This is because Sulphur contains f type functions, of which there are 7. However there are 10<ref>SIMPLIFIED INTRODUCTION TO AB INITIO
BASIS SETS. TERMS AND NOTATION.
Jan K. Labanowski, Ohio Supercomputer Center,
1224 Kinnear Rd., Columbus, OH 43212-1163,</ref> possible Guassians, and so an element of contamination from the 4p orbitals is brought in. As the 6-31G(d,p) does not containg any f functions, it is not that good at predicting the behaviour of the sulphur molecule to the level required by the nmr calculation. Despite all of this, the shift values are still similar, and so the assignmnet of this molecule inth e literature can be deemed correct.
{|class="wikitable" border="2"
!Atom number !! Calculated ppm value !! Lit. ppm value
|-
| 1
| 27.5886
| 25.66
|-
| 2
| 31.6721
| 28.79
|-
| 3
| 52.6851
| 48.5
|-
| 4
| 146.8944
| 144.63
|-
| 5
| 51.4817
| 46.8
|-
| 6
| 20.6456
| 18.71
|-
| 7
| 27.0826
| 23.86
|-
| 8
| 125.7193
| 125.33
|-
| 9
| 50.5885
| 45.76
|-
| 10
| 218.6545
| 218.79
|-
| 11
| colspan="2" | Oxygen
|-
| 12
| 54.1882
| 52.52
|-
| 13
| 30.8219
| 28.29
|-
| 14
| 63.85
| 56.19
|-
| 15
| 29.5406
| 26.88
|-
| 16
| 89.99
| 72.88
|-
| 17
| 48.9728
| 39.8
|-
| 18
| 24.6905
| 20.96
|-
| 19
| 41.3115
| 32.66
|-
| 21
| 44.3139
| 35.85
|-
| 22
| 45.5337
| 38.81
|}

===Literature Molecule===

In the synthesis of molecule A (below), using Kobayashi aldol chemistry, two stereoisomers are produced. Initially, the syn isomer is formed, with a diasteromic ratio of 1:14, and via a similar synthetic route, the anti isomer is also produced, with a high dr of 1:>50. The high stereoselectivity of both of these reactions is an important step in the synthesis of enationmerically pure natural products.

{| class="wikitable border="1"
!Molecule A
! Syn
! Anti
|-
![[File:Ohbmol.gif|300px]]
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbsyn.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbanti.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
|}
Initiallyu the models were optimised using an MM2 optimisation within ChemBio 12.0. They were then further optimised using an RB3LYP-6-31G(d,p) method and basis set. After the optimisation, and checking to see that the the two molecules were still distinct, with one syn and one anti form, they were submitted for nmr analysis, to produce a predicted nmr. This was then compared with the reported nmr, with a view to see if the assignments and conclusions made in the literature were correct. There was a good correlations between the predicted and measured nmr peaks, with deviations, as show below, of less than 1ppm for the H nmr and less than 10ppm for the <sup>13</sup>C nmr.
[[File:Ohbccomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each carbon atom]]
[[File:Ohbhcomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each Hydrogen atom]]

This correlation helps confirm that the structures are correct; the different enantiomers are differentiated and assigned correctly. If they were not, and the calculated syn nmr is compared to the measured anti nmr, and vice versa, larger differences are noted. This is highlighted on the graph below. The blue and red graphs are the correctly assigned and matched nmrs, the green and purple nmrs are if they are assigned incorrectly. It can clearly be seen that the green and purple line are consistently higher than their counterparts.
[[file:Ohbcomparisonnmr.png|thumb|900px|none|left|Comparison of correct and incorrect assignment for the two conformers]]
Within the literature all of the hydrogens and carbons are assigned, with the exception of Hydrogen 48. This is because this is a labile proton and so does not show up on measured nmrs due to rapid exchange with the deuterium in the deuterated solvent. However the calculated spectra does not take this into account and so displays the shift value for this hydrogen.

The computed IR spectra are very similar for the two molecules. The OH stretch is increased by 30cm<sup>-1</sup> in the syn form of the molecule and the CH bend region between 1000-1500cm<sup>-1</sup> is also significantly different. This acsn be rationalised by the different atomic orbital overlaps that are occuring due to the different positioning of the methyl group.

[[File:synir.png|thumb|900px|none|left|Anti conformer IR]]
[[File:antiir.png|thumb|900px|none|left|Syn Conformer IR]]

As both molecules are chiral, they both rotate light in opposite directions. However due to the large size of this molecule and although it is relatively conformationally limited due to the double bond and ring, the calculation for the syn and anti variants did not converge after 48 a 48 hour run on the SCAN.

==References==
<references></references>

Rep:Mod:benton2

2013-02-08T15:45:49Z

Ohb09: /* Literature Molecule */

=Module 1 - Intro=
In this experiment, MM2 is compared to the more advanced MOPAC minimisation technique. A minimised molecule is then analysed and compared to literature.
Molecular mechanics, used here in its MM2 form is a very good first order approximation. Using data from previous experiments and breaking down the overall energy into different categories, such as van der Waals interaction, dipole-dipole, and bending before summing them to provide an overall energy is a very useful and more importantly quick method to calculate a molecules energy. The energy of molecule can then be iteratively reduced by tweaking the position of the atoms and conformations, providing a low energy structure. However it does have its limitations. Firstly, because of the large approximations used, the method is liable to fall, and remain, in an initial, smaller, potential well at a higher energy than the minimum possible. This can be overcome by carefully arranging the molecule by the user of the program to avoid these early, high energy minima, but requires a lot of rearrangement and prioir knowledge of low energy arrangements. As MM2 uses previously aquired data, it is also not that useful in determining new structures, or functional groups for which it does not have the data for.
MOPAC uses a different approach for minimisation. It uses semi empirical quantum chemistry functions to determine the energy of a molecule. This allows more advanced effects to be included in the calculation and allows for analysis of the neighbouring group effect in sacchardie chemistry and regioselectivity effects, as studied here.
Computational chemistry can also predict spectra, and in the last part of the experiment predicted spectra are compared to literature and the results analysed.

==Week 1==

===Hydrogenation of the Cyclopentadiene Dimer===
The endo dimer is primarily produced when cyclopentadiene dimerises, in a ratio of 99.5% to 0.5% <ref>
Małgorzata E Jamróz, Sławomir Gałka, Jan Cz Dobrowolski,
On dicyclopentadiene isomers,
Journal of Molecular Structure: THEOCHEM,
Volume 634, Issues 1–3, 5 September 2003,
Pages 225-233, ISSN 0166-1280,
<DOI|10.1016/S0166-1280(03)00348-8>
</ref>(at least when thermally initiated; photo initiation produces a racemic mixture of the two isomers<ref>
The Photosensitited Dimerization of Cyclopentadiene
Nicholas J. Turro and George S. Hammond
Journal of the American Chemical Society 1962 84 (14), 2841-2842
<DOI|10.1021/ja00873a050>
</ref>)
{| class="wikitable" border="1"

! rowspan="2" | Molecule
|style="text-align: center;" |Exo
|style="text-align: center;" |Endo
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbexodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Total E (kcal/mol)
|33.9975
|31.8764
|-
|}
[[file:Endoexoohb.bmp|thumb|left|500px]]
The small energy difference calculated by the MM2 forcefield does not highlight why the endo for is favoured over the exo form as it shows the exo form is lower in energy. While the difference between the two energies is relatively trivial, the high enationmeric excess of the products suggest that this is only part of the story, and suggest that this reaction is under kinetic rather than thermodynamic control.<ref> W.C.Herndon, C.R.Grayson, J.M.Manion; "Retro-Diels-Alder reactions. III. Kinetics of the thermal decompositions of exo- and endo-dicyclopentadiene" J. Org. Chem.; 1967, 32 (3); 526-529.DOI:10.1021/jo01278a003</ref> Being under kinetic control would imply the activation energy, and hence transition state, for the endo species is lower than the exo form and so the endo enantiomer is formed faster. This can be rationalised by looking at the orbital interactions in the two transition states.

The endo transition state is stabilised by the secondary favourable overlap whereas in the exo form there is no such overlap to stabilised the molecule meaning that the transition state is a higher energy, and so is less favourable. This cannot be handled by the simple MM2 calculation however.

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" colspan="2" |Different hydrogenation sites
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh3.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh4.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|1.2489
|1.1303
|-
!Bend
|19.1608
|13.10259
|-
!Torsion
|11.0730
|12.4118
|-
!VDW
|5.7962
|4.4398
|-
!Dipole-Dipole
|0.1622
|0.1410
|-
!Total E (kcal/mol)
|34.9643
|29.2475
|-
|}

The site of initial hydrogenation of the endo dimer can also be determined by calculating the energies of the two possible isomers. From these calculations it is clear that the second molecule is favoured more, as it is ~5.5kcalmol<sup>-1</sup> more stable. The bending energy in both of these molecules is the major difference. This manifests itself in the amount that the atoms are ebent away from their ideal positions, which is 109.5 for an sp3 carbon and 120 for an sp2 carbon. Across all of the key bonds, the second isomer has bond angles that are closer to the ideal than the first isomer; in particular the C-C=C bond angles; in the first molecule they are 107.6 and in the second 112.8. This difference of five degrees is enough to significantly stabilise the second isomer, making hydrogenation at that site the more preferable.

===Atropisomerism in an Intermediate related to the synthesis of Taxol===
In the complete synthesis of Taxol, and important cancer fighting drug, proposed by Pacquette <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 10.1016/S0040-4039(00)92617-0</ref> a key intermediate is either "Precursor 9" or "Precursor 10".

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" |Precursor 10
|style="text-align: center;" |Precursor 9
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol9.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol10.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|2.4687
|2.7846
|-
!Bend
|10.5555
|16.5411
|-
!Torsion
|17.4240
|18.2518
|-
!VDW
|13.1930
|13.1096
|-
!Dipole-Dipole
| -1.8818
| -1.7248
|-
!Total E (kcal/mol)
|39.1215
|47.8395
|-
|}
Precursor 9 and 10 are synthesised using a reversible oxy-Cope rearrangement as demonstrated below. As this process is in equilibrium that, with precursor 10 being more stable, it is predicted that this isomer will be the one produced as all of the molecules attempt to reduce the energy. As analysis of the individual energy componenets shows, this arrangement is a lot less strained than Precursor nine, which requires a lot more bending energy.

The molecule was then optimised with an MMFF94. Rather than rely on a large set of experimentally determined parameters like MM2, MMFF94 minimises the potential of each atom iteratively, attempting to minimise the whole molecule. Although the values produced for these two methods cannot be directly compared, they both correctly identify the correct altropisomer as being lower in energy.
{|class="wikitable" border="1"
! colspan="3" | Comparison of MMFF94 and MM2 minimisations
|-
!Molecule
| Precursor 9
| Precursor 10
|-
!MM2 minimised Energy (kJmol<sup><-1</sup>)
|39.1215
|47.8395
|-
!MMFF94 minimised Energy (kcalmol<sup><-1</sup>)
|58.7513
|70.5377
|-
|}

===Regioselective Addition of Dichlorocarbene to a diene===
Molecule A was initially optimised using a molecular mechanics (MM2) calculation

{| style="wikitable" border="1"
|<jmol>
<jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
It was then further optimised with a MOPAC calculation, which takes into effect stereoelectronic effects. The two were then compared.

{| class="wikitable" border="1"
!colspan="3" | Comparison of two optimisation calculations
|-
! Overlay of two optimised molecules !! MM2 optimised molecule !! MOPAC Optimised Molecule
|-
|[[file:Ohboverlaydiene.png|300px]]
The MM2 optimised molecule is coloured yellow for clarity
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1mopac.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! rowspan="6" | Distances between
corresponding atoms

on the overlaid molecules (Å)
|style="text-align: center;" | C(34)-C(9)
|0.5247
|-
|style="text-align: center;" | C(26)-C(1)
|0.5246
|-
|style="text-align: center;" | H(47)-H(22)
|0.8526
|-
|style="text-align: center;" | H(38)-H(13)
|0.8524
|-
|style="text-align: center;" | Cl(37)-Cl(12)
|0.0689
|}

As can be seen by the comparison above, when using the stereoelectronic interactions, the cyclohexadiene ring on the side with the Cl atom is moved further away from the Cl using the MOPAC calculation than the MM2. This is because the electronic effects included in this calculation include the repulsion between the electron rich Chlorine atom and the electron rich double bond, whereas the MM2 calculation doesn't include this and so a symmetrical molecule is formed.

====MOs====

The MOs of the previously MOPAC optimised molecule where then calculated using Guassian (B3LYP 6-31G)
{| style="wikitable" border="1"
! Homo-1 !! colspan="2" | Homo
|-
|[[File:Ohbclhomo-1.jpg|250px]]
| <jmol>
<jmolApplet>
<title>Orbital</title><color>white</color><size>250</size>
<script>isosurface color orange purple "images/f/f2/Ohbdienemo48.cub.jvxl" translucent; </script>
<uploadedFileContents>Ohbdienemo48.cub.xyz</uploadedFileContents>
</jmolApplet>
</jmol>
|[[File:Ohbclhomo.jpg|250px]]
|-
!Lumo !! Lumo+1 !! Lumo+2
|-
|[[File:Ohbcllumo.jpg|250px]]
|[[File:Ohbcllumo+1.jpg|250px]]
|[[File:Ohbcllumo+2.jpg|250px]]
|-
|colspan="2" | [[File:Ohbclmep.jpg|300px rotate="90"]]
| [[File:Ohbclelevels.png|250px]]
|}

Molecule 2 was initially minimised using an MM2 calculation. The reactions of molecule A with an electrophile can be illustrated by taking a more advanced, quantum mechanical approach to modelling the molecule and its orbitals. This will also allow prediction of which C=C reacts with an electrophile.
Of the two alekenes, the endo is favoured rather than the exo because the cl-c sigma star orbital mixes with the exo alkene. This stabilises both orbitals, as shown by the frequency calculation having a higher value than the endo alkene, but reduces the pi bond character of the exo alkene. This is also shown by the comparative lengths of the alkene bonds - the exo is 1.3355A and the endo is 1.33190A. The cycloaddition of the carbene requires an alkene and so favours the endo alkene as it has a higher p character. The homo is also focused entirely on the endo side of the molecule, with the lumo focused mainly on the exo side. The Homo shows the high pi bond character of the endo alkene. The Homo-1 is mainly focused ont he exo alekene, so shows the pi bond character of the exo alekene. This is lower in energy and so is less likely to react with the carbene molecule.

====Glycosidation====

When the monosaccharide pyranose has an acetal in the 2 position, four different isomers can be formed, all of differing stability. These differing positions of the acetal group and its interactions with the neighbouring group means that it acts as a directing group to nucleophilic attack. With deprotonation to an oxenium cation being the initial step, the acetal group can then stabilise this to varying degrees depending on its position. Due to the Sn1 nature of the glycosidation nucleophilic attack occurring, the access of the nucleophile to the sigma* orbital of the carbon is crucial, and this depends on the Burgi-Dunitz angle of 107<ref> H. B. Bürgi, J. D. Dunitz, J. M. Lehn, G. Wipff (1974). "Stereochemistry of reaction paths at carbonyl centres". Tetrahedron 30 (12): 1563–1572. doi:10.1016/S0040-4020(01)90678-7</ref>.
Two sets of calculations were performed; initially using an MM2 forcefield, and then with using the MOPAC approach. While both approaches showed a similar trend, the benefit of the MOPAC, to make and break bond meant that the structures formed by this minimisation resembled the transition state a lot more closely than those formed by the MM2.
As shown by the table, below, all of the initial cations are at a lower energy than the intermediate forms, however the structures differ slightly depending on whether an MM2 or MOPAC minimisation was performed; the MOPAC structures much more closely resemble the transition states.
The differences in energy can be directly related to the amount of strain present within the molecule and the repulsion between the oxygen atoms. The large amount of strain present in the intermediates, particularly of molecule 2, mean that they have a lot higher energy. A notable differences is that the MM2 struggles to accurately deal with the oxenium cation, whereas the MOPAC produces a more lifelike picture in this area.
The glycosidation mainly produces the trans isomers, ie molecules going through the pathways of molecules 1 & 4. This is predicted well by the computational methods used, with both the initial molecules and the intermediates being lower in energy and having lower anomeric carbon-acetal oxygen distances.

=====Mechanisms=====

[[file:Ohbglymech.gif|800px]]

{|class="wikitable" border="2"
!rowspan="5" |Initial molecule
!colspan="2" | Conformation
|1
|2
|3
|4
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2amm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 11.5430
| 46.2672
| 35.5277
| 29.5144
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -90.51343
| -70.57703
| -72.56010
| -85.04737
|-
!rowspan="5" |Intermediate
!colspan="2" | Conformation
|chemdraw
|chemdraw
|chemdraw
|chemdraw
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2Bmm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 28.4913
| 43.2706
| 41.0918
| 31.8763
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -91.66112
| -66.72331
| -84.44899
| -88.08089

|-
|}

==Comparison of coumpational results to a molecule from literature.==

===Taxol intermediate===

Computational chemistry can be a powerful tool in the analysis and reproduction of spectra. in this exercise, literature values and spectra are compared to computed data and the effectiveness and accuracy of both methods is compared and contrasted.

A different intermediate in the synthesis of taxol was optimised using MM2 to produce the structure (right) with a total energy of 66.7072kcal<sup>-1</sup>
{| class="wikitable border="1"
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
This file was then optimised using Guassian and B3LYP 6-31G(d,p) basis set. The resulting file was then resubmitted to the SCAN cluster for computation of the nmr spectrum using these keywords # mpw1pw91/6-31G(d,p) NMR SCRF=(CPCM,Solvent=chloroform). These results were then compared to those found in the literature<ref>#L. Paquette, N. A. Pegg, D. Toops, G. D. Maynard, R. D. Rogers, ''J. Am. Chem. Soc.,'', '''1990''', ''112'', 277-283. {{DOI|10.1021/ja00157a043}}</ref>.
The results are below. As can be seen by this comparison chart, in general there is very good agreement between the predicted and measured shift values. With the only major discrepancy being at Carbon 16.

This however, can be resolved. The large distance is probably to do with this carbon being bonded to two sulphur atoms. The 6-31G(d,p) basis set is not very good at approximating, and hence optimising sulphur molecules. This is because Sulphur contains f type functions, of which there are 7. However there are 10<ref>SIMPLIFIED INTRODUCTION TO AB INITIO
BASIS SETS. TERMS AND NOTATION.
Jan K. Labanowski, Ohio Supercomputer Center,
1224 Kinnear Rd., Columbus, OH 43212-1163,</ref> possible Guassians, and so an element of contamination from the 4p orbitals is brought in. As the 6-31G(d,p) does not containg any f functions, it is not that good at predicting the behaviour of the sulphur molecule to the level required by the nmr calculation. Despite all of this, the shift values are still similar, and so the assignmnet of this molecule inth e literature can be deemed correct.
{|class="wikitable" border="2"
!Atom number !! Calculated ppm value !! Lit. ppm value
|-
| 1
| 27.5886
| 25.66
|-
| 2
| 31.6721
| 28.79
|-
| 3
| 52.6851
| 48.5
|-
| 4
| 146.8944
| 144.63
|-
| 5
| 51.4817
| 46.8
|-
| 6
| 20.6456
| 18.71
|-
| 7
| 27.0826
| 23.86
|-
| 8
| 125.7193
| 125.33
|-
| 9
| 50.5885
| 45.76
|-
| 10
| 218.6545
| 218.79
|-
| 11
| colspan="2" | Oxygen
|-
| 12
| 54.1882
| 52.52
|-
| 13
| 30.8219
| 28.29
|-
| 14
| 63.85
| 56.19
|-
| 15
| 29.5406
| 26.88
|-
| 16
| 89.99
| 72.88
|-
| 17
| 48.9728
| 39.8
|-
| 18
| 24.6905
| 20.96
|-
| 19
| 41.3115
| 32.66
|-
| 21
| 44.3139
| 35.85
|-
| 22
| 45.5337
| 38.81
|}

===Literature Molecule===

In the synthesis of molecule A (below), using Kobayashi aldol chemistry, two stereoisomers are produced. Initially, the syn isomer is formed, with a diasteromic ratio of 1:14, and via a similar synthetic route, the anti isomer is also produced, with a high dr of 1:>50. The high stereoselectivity of both of these reactions is an important step in the synthesis of enationmerically pure natural products.

{| class="wikitable border="1"
!Molecule A
! Syn
! Anti
|-
![[File:Ohbmol.gif|300px]]
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbsyn.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbanti.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
|}
Initiallyu the models were optimised using an MM2 optimisation within ChemBio 12.0. They were then further optimised using an RB3LYP-6-31G(d,p) method and basis set. After the optimisation, and checking to see that the the two molecules were still distinct, with one syn and one anti form, they were submitted for nmr analysis, to produce a predicted nmr. This was then compared with the reported nmr, with a view to see if the assignments and conclusions made in the literature were correct. There was a good correlations between the predicted and measured nmr peaks, with deviations, as show below, of less than 1ppm for the H nmr and less than 10ppm for the <sup>13</sup>C nmr.
[[File:Ohbccomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each carbon atom]]
[[File:Ohbhcomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each Hydrogen atom]]

This correlation helps confirm that the structures are correct; the different enantiomers are differentiated and assigned correctly. If they were not, and the calculated syn nmr is compared to the measured anti nmr, and vice versa, larger differences are noted. This is highlighted on the graph below. The blue and red graphs are the correctly assigned and matched nmrs, the green and purple nmrs are if they are assigned incorrectly. It can clearly be seen that the green and purple line are consistently higher than their counterparts.
[[file:Ohbcomparisonnmr.png|thumb|900px|none|left|Comparison of correct and incorrect assignment for the two conformers]]
Within the literature all of the hydrogens and carbons are assigned, with the exception of Hydrogen 48. This is because this is a labile proton and so does not show up on measured nmrs due to rapid exchange with the deuterium in the deuterated solvent. However the calculated spectra does not take this into account and so displays the shift value for this hydrogen.

The computed IR spectra are very similar for the two molecules. The OH stretch is increased by 30cm<sup>-1</sup> in the syn form of the molecule and the CH bend region between 1000-1500cm<sup>-1</sup> is also significantly different. This acsn be rationalised by the different atomic orbital overlaps that are occuring due to the different positioning of the methyl group.

As both molecules are chiral, they both rotate light in opposite directions. However due to the large size of this molecule and although it is relatively conformationally limited due to the double bond and ring, the calculation for the syn and anti variants did not converge after 48 a 48 hour run on the SCAN.

==References==
<references></references>

Rep:Mod:benton2

2013-02-08T15:44:48Z

Ohb09: /* Comparison of coumpational results to a molecule from literature. */

=Module 1 - Intro=
In this experiment, MM2 is compared to the more advanced MOPAC minimisation technique. A minimised molecule is then analysed and compared to literature.
Molecular mechanics, used here in its MM2 form is a very good first order approximation. Using data from previous experiments and breaking down the overall energy into different categories, such as van der Waals interaction, dipole-dipole, and bending before summing them to provide an overall energy is a very useful and more importantly quick method to calculate a molecules energy. The energy of molecule can then be iteratively reduced by tweaking the position of the atoms and conformations, providing a low energy structure. However it does have its limitations. Firstly, because of the large approximations used, the method is liable to fall, and remain, in an initial, smaller, potential well at a higher energy than the minimum possible. This can be overcome by carefully arranging the molecule by the user of the program to avoid these early, high energy minima, but requires a lot of rearrangement and prioir knowledge of low energy arrangements. As MM2 uses previously aquired data, it is also not that useful in determining new structures, or functional groups for which it does not have the data for.
MOPAC uses a different approach for minimisation. It uses semi empirical quantum chemistry functions to determine the energy of a molecule. This allows more advanced effects to be included in the calculation and allows for analysis of the neighbouring group effect in sacchardie chemistry and regioselectivity effects, as studied here.
Computational chemistry can also predict spectra, and in the last part of the experiment predicted spectra are compared to literature and the results analysed.

==Week 1==

===Hydrogenation of the Cyclopentadiene Dimer===
The endo dimer is primarily produced when cyclopentadiene dimerises, in a ratio of 99.5% to 0.5% <ref>
Małgorzata E Jamróz, Sławomir Gałka, Jan Cz Dobrowolski,
On dicyclopentadiene isomers,
Journal of Molecular Structure: THEOCHEM,
Volume 634, Issues 1–3, 5 September 2003,
Pages 225-233, ISSN 0166-1280,
<DOI|10.1016/S0166-1280(03)00348-8>
</ref>(at least when thermally initiated; photo initiation produces a racemic mixture of the two isomers<ref>
The Photosensitited Dimerization of Cyclopentadiene
Nicholas J. Turro and George S. Hammond
Journal of the American Chemical Society 1962 84 (14), 2841-2842
<DOI|10.1021/ja00873a050>
</ref>)
{| class="wikitable" border="1"

! rowspan="2" | Molecule
|style="text-align: center;" |Exo
|style="text-align: center;" |Endo
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbexodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Total E (kcal/mol)
|33.9975
|31.8764
|-
|}
[[file:Endoexoohb.bmp|thumb|left|500px]]
The small energy difference calculated by the MM2 forcefield does not highlight why the endo for is favoured over the exo form as it shows the exo form is lower in energy. While the difference between the two energies is relatively trivial, the high enationmeric excess of the products suggest that this is only part of the story, and suggest that this reaction is under kinetic rather than thermodynamic control.<ref> W.C.Herndon, C.R.Grayson, J.M.Manion; "Retro-Diels-Alder reactions. III. Kinetics of the thermal decompositions of exo- and endo-dicyclopentadiene" J. Org. Chem.; 1967, 32 (3); 526-529.DOI:10.1021/jo01278a003</ref> Being under kinetic control would imply the activation energy, and hence transition state, for the endo species is lower than the exo form and so the endo enantiomer is formed faster. This can be rationalised by looking at the orbital interactions in the two transition states.

The endo transition state is stabilised by the secondary favourable overlap whereas in the exo form there is no such overlap to stabilised the molecule meaning that the transition state is a higher energy, and so is less favourable. This cannot be handled by the simple MM2 calculation however.

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" colspan="2" |Different hydrogenation sites
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh3.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh4.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|1.2489
|1.1303
|-
!Bend
|19.1608
|13.10259
|-
!Torsion
|11.0730
|12.4118
|-
!VDW
|5.7962
|4.4398
|-
!Dipole-Dipole
|0.1622
|0.1410
|-
!Total E (kcal/mol)
|34.9643
|29.2475
|-
|}

The site of initial hydrogenation of the endo dimer can also be determined by calculating the energies of the two possible isomers. From these calculations it is clear that the second molecule is favoured more, as it is ~5.5kcalmol<sup>-1</sup> more stable. The bending energy in both of these molecules is the major difference. This manifests itself in the amount that the atoms are ebent away from their ideal positions, which is 109.5 for an sp3 carbon and 120 for an sp2 carbon. Across all of the key bonds, the second isomer has bond angles that are closer to the ideal than the first isomer; in particular the C-C=C bond angles; in the first molecule they are 107.6 and in the second 112.8. This difference of five degrees is enough to significantly stabilise the second isomer, making hydrogenation at that site the more preferable.

===Atropisomerism in an Intermediate related to the synthesis of Taxol===
In the complete synthesis of Taxol, and important cancer fighting drug, proposed by Pacquette <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 10.1016/S0040-4039(00)92617-0</ref> a key intermediate is either "Precursor 9" or "Precursor 10".

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" |Precursor 10
|style="text-align: center;" |Precursor 9
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol9.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol10.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|2.4687
|2.7846
|-
!Bend
|10.5555
|16.5411
|-
!Torsion
|17.4240
|18.2518
|-
!VDW
|13.1930
|13.1096
|-
!Dipole-Dipole
| -1.8818
| -1.7248
|-
!Total E (kcal/mol)
|39.1215
|47.8395
|-
|}
Precursor 9 and 10 are synthesised using a reversible oxy-Cope rearrangement as demonstrated below. As this process is in equilibrium that, with precursor 10 being more stable, it is predicted that this isomer will be the one produced as all of the molecules attempt to reduce the energy. As analysis of the individual energy componenets shows, this arrangement is a lot less strained than Precursor nine, which requires a lot more bending energy.

The molecule was then optimised with an MMFF94. Rather than rely on a large set of experimentally determined parameters like MM2, MMFF94 minimises the potential of each atom iteratively, attempting to minimise the whole molecule. Although the values produced for these two methods cannot be directly compared, they both correctly identify the correct altropisomer as being lower in energy.
{|class="wikitable" border="1"
! colspan="3" | Comparison of MMFF94 and MM2 minimisations
|-
!Molecule
| Precursor 9
| Precursor 10
|-
!MM2 minimised Energy (kJmol<sup><-1</sup>)
|39.1215
|47.8395
|-
!MMFF94 minimised Energy (kcalmol<sup><-1</sup>)
|58.7513
|70.5377
|-
|}

===Regioselective Addition of Dichlorocarbene to a diene===
Molecule A was initially optimised using a molecular mechanics (MM2) calculation

{| style="wikitable" border="1"
|<jmol>
<jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
It was then further optimised with a MOPAC calculation, which takes into effect stereoelectronic effects. The two were then compared.

{| class="wikitable" border="1"
!colspan="3" | Comparison of two optimisation calculations
|-
! Overlay of two optimised molecules !! MM2 optimised molecule !! MOPAC Optimised Molecule
|-
|[[file:Ohboverlaydiene.png|300px]]
The MM2 optimised molecule is coloured yellow for clarity
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1mopac.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! rowspan="6" | Distances between
corresponding atoms

on the overlaid molecules (Å)
|style="text-align: center;" | C(34)-C(9)
|0.5247
|-
|style="text-align: center;" | C(26)-C(1)
|0.5246
|-
|style="text-align: center;" | H(47)-H(22)
|0.8526
|-
|style="text-align: center;" | H(38)-H(13)
|0.8524
|-
|style="text-align: center;" | Cl(37)-Cl(12)
|0.0689
|}

As can be seen by the comparison above, when using the stereoelectronic interactions, the cyclohexadiene ring on the side with the Cl atom is moved further away from the Cl using the MOPAC calculation than the MM2. This is because the electronic effects included in this calculation include the repulsion between the electron rich Chlorine atom and the electron rich double bond, whereas the MM2 calculation doesn't include this and so a symmetrical molecule is formed.

====MOs====

The MOs of the previously MOPAC optimised molecule where then calculated using Guassian (B3LYP 6-31G)
{| style="wikitable" border="1"
! Homo-1 !! colspan="2" | Homo
|-
|[[File:Ohbclhomo-1.jpg|250px]]
| <jmol>
<jmolApplet>
<title>Orbital</title><color>white</color><size>250</size>
<script>isosurface color orange purple "images/f/f2/Ohbdienemo48.cub.jvxl" translucent; </script>
<uploadedFileContents>Ohbdienemo48.cub.xyz</uploadedFileContents>
</jmolApplet>
</jmol>
|[[File:Ohbclhomo.jpg|250px]]
|-
!Lumo !! Lumo+1 !! Lumo+2
|-
|[[File:Ohbcllumo.jpg|250px]]
|[[File:Ohbcllumo+1.jpg|250px]]
|[[File:Ohbcllumo+2.jpg|250px]]
|-
|colspan="2" | [[File:Ohbclmep.jpg|300px rotate="90"]]
| [[File:Ohbclelevels.png|250px]]
|}

Molecule 2 was initially minimised using an MM2 calculation. The reactions of molecule A with an electrophile can be illustrated by taking a more advanced, quantum mechanical approach to modelling the molecule and its orbitals. This will also allow prediction of which C=C reacts with an electrophile.
Of the two alekenes, the endo is favoured rather than the exo because the cl-c sigma star orbital mixes with the exo alkene. This stabilises both orbitals, as shown by the frequency calculation having a higher value than the endo alkene, but reduces the pi bond character of the exo alkene. This is also shown by the comparative lengths of the alkene bonds - the exo is 1.3355A and the endo is 1.33190A. The cycloaddition of the carbene requires an alkene and so favours the endo alkene as it has a higher p character. The homo is also focused entirely on the endo side of the molecule, with the lumo focused mainly on the exo side. The Homo shows the high pi bond character of the endo alkene. The Homo-1 is mainly focused ont he exo alekene, so shows the pi bond character of the exo alekene. This is lower in energy and so is less likely to react with the carbene molecule.

====Glycosidation====

When the monosaccharide pyranose has an acetal in the 2 position, four different isomers can be formed, all of differing stability. These differing positions of the acetal group and its interactions with the neighbouring group means that it acts as a directing group to nucleophilic attack. With deprotonation to an oxenium cation being the initial step, the acetal group can then stabilise this to varying degrees depending on its position. Due to the Sn1 nature of the glycosidation nucleophilic attack occurring, the access of the nucleophile to the sigma* orbital of the carbon is crucial, and this depends on the Burgi-Dunitz angle of 107<ref> H. B. Bürgi, J. D. Dunitz, J. M. Lehn, G. Wipff (1974). "Stereochemistry of reaction paths at carbonyl centres". Tetrahedron 30 (12): 1563–1572. doi:10.1016/S0040-4020(01)90678-7</ref>.
Two sets of calculations were performed; initially using an MM2 forcefield, and then with using the MOPAC approach. While both approaches showed a similar trend, the benefit of the MOPAC, to make and break bond meant that the structures formed by this minimisation resembled the transition state a lot more closely than those formed by the MM2.
As shown by the table, below, all of the initial cations are at a lower energy than the intermediate forms, however the structures differ slightly depending on whether an MM2 or MOPAC minimisation was performed; the MOPAC structures much more closely resemble the transition states.
The differences in energy can be directly related to the amount of strain present within the molecule and the repulsion between the oxygen atoms. The large amount of strain present in the intermediates, particularly of molecule 2, mean that they have a lot higher energy. A notable differences is that the MM2 struggles to accurately deal with the oxenium cation, whereas the MOPAC produces a more lifelike picture in this area.
The glycosidation mainly produces the trans isomers, ie molecules going through the pathways of molecules 1 & 4. This is predicted well by the computational methods used, with both the initial molecules and the intermediates being lower in energy and having lower anomeric carbon-acetal oxygen distances.

=====Mechanisms=====

[[file:Ohbglymech.gif|800px]]

{|class="wikitable" border="2"
!rowspan="5" |Initial molecule
!colspan="2" | Conformation
|1
|2
|3
|4
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2amm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 11.5430
| 46.2672
| 35.5277
| 29.5144
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -90.51343
| -70.57703
| -72.56010
| -85.04737
|-
!rowspan="5" |Intermediate
!colspan="2" | Conformation
|chemdraw
|chemdraw
|chemdraw
|chemdraw
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2Bmm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 28.4913
| 43.2706
| 41.0918
| 31.8763
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -91.66112
| -66.72331
| -84.44899
| -88.08089

|-
|}

==Comparison of coumpational results to a molecule from literature.==

===Taxol intermediate===

Computational chemistry can be a powerful tool in the analysis and reproduction of spectra. in this exercise, literature values and spectra are compared to computed data and the effectiveness and accuracy of both methods is compared and contrasted.

A different intermediate in the synthesis of taxol was optimised using MM2 to produce the structure (right) with a total energy of 66.7072kcal<sup>-1</sup>
{| class="wikitable border="1"
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
This file was then optimised using Guassian and B3LYP 6-31G(d,p) basis set. The resulting file was then resubmitted to the SCAN cluster for computation of the nmr spectrum using these keywords # mpw1pw91/6-31G(d,p) NMR SCRF=(CPCM,Solvent=chloroform). These results were then compared to those found in the literature<ref>#L. Paquette, N. A. Pegg, D. Toops, G. D. Maynard, R. D. Rogers, ''J. Am. Chem. Soc.,'', '''1990''', ''112'', 277-283. {{DOI|10.1021/ja00157a043}}</ref>.
The results are below. As can be seen by this comparison chart, in general there is very good agreement between the predicted and measured shift values. With the only major discrepancy being at Carbon 16.

This however, can be resolved. The large distance is probably to do with this carbon being bonded to two sulphur atoms. The 6-31G(d,p) basis set is not very good at approximating, and hence optimising sulphur molecules. This is because Sulphur contains f type functions, of which there are 7. However there are 10<ref>SIMPLIFIED INTRODUCTION TO AB INITIO
BASIS SETS. TERMS AND NOTATION.
Jan K. Labanowski, Ohio Supercomputer Center,
1224 Kinnear Rd., Columbus, OH 43212-1163,</ref> possible Guassians, and so an element of contamination from the 4p orbitals is brought in. As the 6-31G(d,p) does not containg any f functions, it is not that good at predicting the behaviour of the sulphur molecule to the level required by the nmr calculation. Despite all of this, the shift values are still similar, and so the assignmnet of this molecule inth e literature can be deemed correct.
{|class="wikitable" border="2"
!Atom number !! Calculated ppm value !! Lit. ppm value
|-
| 1
| 27.5886
| 25.66
|-
| 2
| 31.6721
| 28.79
|-
| 3
| 52.6851
| 48.5
|-
| 4
| 146.8944
| 144.63
|-
| 5
| 51.4817
| 46.8
|-
| 6
| 20.6456
| 18.71
|-
| 7
| 27.0826
| 23.86
|-
| 8
| 125.7193
| 125.33
|-
| 9
| 50.5885
| 45.76
|-
| 10
| 218.6545
| 218.79
|-
| 11
| colspan="2" | Oxygen
|-
| 12
| 54.1882
| 52.52
|-
| 13
| 30.8219
| 28.29
|-
| 14
| 63.85
| 56.19
|-
| 15
| 29.5406
| 26.88
|-
| 16
| 89.99
| 72.88
|-
| 17
| 48.9728
| 39.8
|-
| 18
| 24.6905
| 20.96
|-
| 19
| 41.3115
| 32.66
|-
| 21
| 44.3139
| 35.85
|-
| 22
| 45.5337
| 38.81
|}

===Literature Molecule===

In the synthesis of molecule A (below), using Kobayashi aldol chemistry, two stereoisomers are produced. Initially, the syn isomer is formed, with a diasteromic ratio of 1:14, and via a similar synthetic route, the anti isomer is also produced, with a high dr of 1:>50. The high stereoselectivity of both of these reactions is an important step in the synthesis of enationmerically pure natural products.

{| class="wikitable border="1"
!Syn ! Anti
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbsyn.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbanti.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
|}
Initiallyu the models were optimised using an MM2 optimisation within ChemBio 12.0. They were then further optimised using an RB3LYP-6-31G(d,p) method and basis set. After the optimisation, and checking to see that the the two molecules were still distinct, with one syn and one anti form, they were submitted for nmr analysis, to produce a predicted nmr. This was then compared with the reported nmr, with a view to see if the assignments and conclusions made in the literature were correct. There was a good correlations between the predicted and measured nmr peaks, with deviations, as show below, of less than 1ppm for the H nmr and less than 10ppm for the <sup>13</sup>C nmr.
[[File:Ohbccomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each carbon atom]]
[[File:Ohbhcomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each Hydrogen atom]]

This correlation helps confirm that the structures are correct; the different enantiomers are differentiated and assigned correctly. If they were not, and the calculated syn nmr is compared to the measured anti nmr, and vice versa, larger differences are noted. This is highlighted on the graph below. The blue and red graphs are the correctly assigned and matched nmrs, the green and purple nmrs are if they are assigned incorrectly. It can clearly be seen that the green and purple line are consistently higher than their counterparts.
[[file:Ohbcomparisonnmr.png|thumb|900px|none|left|Comparison of correct and incorrect assignment for the two conformers]]
Within the literature all of the hydrogens and carbons are assigned, with the exception of Hydrogen 48. This is because this is a labile proton and so does not show up on measured nmrs due to rapid exchange with the deuterium in the deuterated solvent. However the calculated spectra does not take this into account and so displays the shift value for this hydrogen.

The computed IR spectra are very similar for the two molecules. The OH stretch is increased by 30cm<sup>-1</sup> in the syn form of the molecule and the CH bend region between 1000-1500cm<sup>-1</sup> is also significantly different. This acsn be rationalised by the different atomic orbital overlaps that are occuring due to the different positioning of the methyl group.

As both molecules are chiral, they both rotate light in opposite directions. However due to the large size of this molecule and although it is relatively conformationally limited due to the double bond and ring, the calculation for the syn and anti variants did not converge after 48 a 48 hour run on the SCAN.

==References==
<references></references>

File:Ohbsyn.mol

2013-02-08T15:44:10Z

Ohb09:

File:Ohbmol.gif

2013-02-08T15:44:10Z

Ohb09:

File:Ohbanti.mol

2013-02-08T15:44:09Z

Ohb09:

File:Synir.png

2013-02-08T15:44:09Z

Ohb09: uploaded a new version of "File:Synir.png"

File:Antiir.png

2013-02-08T15:44:08Z

Ohb09: uploaded a new version of "File:Antiir.png"

Rep:Mod:benton2

2013-02-08T14:39:32Z

Ohb09: /* Taxol intermediate */

=Module 1 - Intro=
In this experiment, MM2 is compared to the more advanced MOPAC minimisation technique. A minimised molecule is then analysed and compared to literature.
Molecular mechanics, used here in its MM2 form is a very good first order approximation. Using data from previous experiments and breaking down the overall energy into different categories, such as van der Waals interaction, dipole-dipole, and bending before summing them to provide an overall energy is a very useful and more importantly quick method to calculate a molecules energy. The energy of molecule can then be iteratively reduced by tweaking the position of the atoms and conformations, providing a low energy structure. However it does have its limitations. Firstly, because of the large approximations used, the method is liable to fall, and remain, in an initial, smaller, potential well at a higher energy than the minimum possible. This can be overcome by carefully arranging the molecule by the user of the program to avoid these early, high energy minima, but requires a lot of rearrangement and prioir knowledge of low energy arrangements. As MM2 uses previously aquired data, it is also not that useful in determining new structures, or functional groups for which it does not have the data for.
MOPAC uses a different approach for minimisation. It uses semi empirical quantum chemistry functions to determine the energy of a molecule. This allows more advanced effects to be included in the calculation and allows for analysis of the neighbouring group effect in sacchardie chemistry and regioselectivity effects, as studied here.
Computational chemistry can also predict spectra, and in the last part of the experiment predicted spectra are compared to literature and the results analysed.

==Week 1==

===Hydrogenation of the Cyclopentadiene Dimer===
The endo dimer is primarily produced when cyclopentadiene dimerises, in a ratio of 99.5% to 0.5% <ref>
Małgorzata E Jamróz, Sławomir Gałka, Jan Cz Dobrowolski,
On dicyclopentadiene isomers,
Journal of Molecular Structure: THEOCHEM,
Volume 634, Issues 1–3, 5 September 2003,
Pages 225-233, ISSN 0166-1280,
<DOI|10.1016/S0166-1280(03)00348-8>
</ref>(at least when thermally initiated; photo initiation produces a racemic mixture of the two isomers<ref>
The Photosensitited Dimerization of Cyclopentadiene
Nicholas J. Turro and George S. Hammond
Journal of the American Chemical Society 1962 84 (14), 2841-2842
<DOI|10.1021/ja00873a050>
</ref>)
{| class="wikitable" border="1"

! rowspan="2" | Molecule
|style="text-align: center;" |Exo
|style="text-align: center;" |Endo
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbexodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Total E (kcal/mol)
|33.9975
|31.8764
|-
|}
[[file:Endoexoohb.bmp|thumb|left|500px]]
The small energy difference calculated by the MM2 forcefield does not highlight why the endo for is favoured over the exo form as it shows the exo form is lower in energy. While the difference between the two energies is relatively trivial, the high enationmeric excess of the products suggest that this is only part of the story, and suggest that this reaction is under kinetic rather than thermodynamic control.<ref> W.C.Herndon, C.R.Grayson, J.M.Manion; "Retro-Diels-Alder reactions. III. Kinetics of the thermal decompositions of exo- and endo-dicyclopentadiene" J. Org. Chem.; 1967, 32 (3); 526-529.DOI:10.1021/jo01278a003</ref> Being under kinetic control would imply the activation energy, and hence transition state, for the endo species is lower than the exo form and so the endo enantiomer is formed faster. This can be rationalised by looking at the orbital interactions in the two transition states.

The endo transition state is stabilised by the secondary favourable overlap whereas in the exo form there is no such overlap to stabilised the molecule meaning that the transition state is a higher energy, and so is less favourable. This cannot be handled by the simple MM2 calculation however.

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" colspan="2" |Different hydrogenation sites
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh3.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh4.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|1.2489
|1.1303
|-
!Bend
|19.1608
|13.10259
|-
!Torsion
|11.0730
|12.4118
|-
!VDW
|5.7962
|4.4398
|-
!Dipole-Dipole
|0.1622
|0.1410
|-
!Total E (kcal/mol)
|34.9643
|29.2475
|-
|}

The site of initial hydrogenation of the endo dimer can also be determined by calculating the energies of the two possible isomers. From these calculations it is clear that the second molecule is favoured more, as it is ~5.5kcalmol<sup>-1</sup> more stable. The bending energy in both of these molecules is the major difference. This manifests itself in the amount that the atoms are ebent away from their ideal positions, which is 109.5 for an sp3 carbon and 120 for an sp2 carbon. Across all of the key bonds, the second isomer has bond angles that are closer to the ideal than the first isomer; in particular the C-C=C bond angles; in the first molecule they are 107.6 and in the second 112.8. This difference of five degrees is enough to significantly stabilise the second isomer, making hydrogenation at that site the more preferable.

===Atropisomerism in an Intermediate related to the synthesis of Taxol===
In the complete synthesis of Taxol, and important cancer fighting drug, proposed by Pacquette <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 10.1016/S0040-4039(00)92617-0</ref> a key intermediate is either "Precursor 9" or "Precursor 10".

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" |Precursor 10
|style="text-align: center;" |Precursor 9
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol9.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol10.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|2.4687
|2.7846
|-
!Bend
|10.5555
|16.5411
|-
!Torsion
|17.4240
|18.2518
|-
!VDW
|13.1930
|13.1096
|-
!Dipole-Dipole
| -1.8818
| -1.7248
|-
!Total E (kcal/mol)
|39.1215
|47.8395
|-
|}
Precursor 9 and 10 are synthesised using a reversible oxy-Cope rearrangement as demonstrated below. As this process is in equilibrium that, with precursor 10 being more stable, it is predicted that this isomer will be the one produced as all of the molecules attempt to reduce the energy. As analysis of the individual energy componenets shows, this arrangement is a lot less strained than Precursor nine, which requires a lot more bending energy.

The molecule was then optimised with an MMFF94. Rather than rely on a large set of experimentally determined parameters like MM2, MMFF94 minimises the potential of each atom iteratively, attempting to minimise the whole molecule. Although the values produced for these two methods cannot be directly compared, they both correctly identify the correct altropisomer as being lower in energy.
{|class="wikitable" border="1"
! colspan="3" | Comparison of MMFF94 and MM2 minimisations
|-
!Molecule
| Precursor 9
| Precursor 10
|-
!MM2 minimised Energy (kJmol<sup><-1</sup>)
|39.1215
|47.8395
|-
!MMFF94 minimised Energy (kcalmol<sup><-1</sup>)
|58.7513
|70.5377
|-
|}

===Regioselective Addition of Dichlorocarbene to a diene===
Molecule A was initially optimised using a molecular mechanics (MM2) calculation

{| style="wikitable" border="1"
|<jmol>
<jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
It was then further optimised with a MOPAC calculation, which takes into effect stereoelectronic effects. The two were then compared.

{| class="wikitable" border="1"
!colspan="3" | Comparison of two optimisation calculations
|-
! Overlay of two optimised molecules !! MM2 optimised molecule !! MOPAC Optimised Molecule
|-
|[[file:Ohboverlaydiene.png|300px]]
The MM2 optimised molecule is coloured yellow for clarity
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1mopac.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! rowspan="6" | Distances between
corresponding atoms

on the overlaid molecules (Å)
|style="text-align: center;" | C(34)-C(9)
|0.5247
|-
|style="text-align: center;" | C(26)-C(1)
|0.5246
|-
|style="text-align: center;" | H(47)-H(22)
|0.8526
|-
|style="text-align: center;" | H(38)-H(13)
|0.8524
|-
|style="text-align: center;" | Cl(37)-Cl(12)
|0.0689
|}

As can be seen by the comparison above, when using the stereoelectronic interactions, the cyclohexadiene ring on the side with the Cl atom is moved further away from the Cl using the MOPAC calculation than the MM2. This is because the electronic effects included in this calculation include the repulsion between the electron rich Chlorine atom and the electron rich double bond, whereas the MM2 calculation doesn't include this and so a symmetrical molecule is formed.

====MOs====

The MOs of the previously MOPAC optimised molecule where then calculated using Guassian (B3LYP 6-31G)
{| style="wikitable" border="1"
! Homo-1 !! colspan="2" | Homo
|-
|[[File:Ohbclhomo-1.jpg|250px]]
| <jmol>
<jmolApplet>
<title>Orbital</title><color>white</color><size>250</size>
<script>isosurface color orange purple "images/f/f2/Ohbdienemo48.cub.jvxl" translucent; </script>
<uploadedFileContents>Ohbdienemo48.cub.xyz</uploadedFileContents>
</jmolApplet>
</jmol>
|[[File:Ohbclhomo.jpg|250px]]
|-
!Lumo !! Lumo+1 !! Lumo+2
|-
|[[File:Ohbcllumo.jpg|250px]]
|[[File:Ohbcllumo+1.jpg|250px]]
|[[File:Ohbcllumo+2.jpg|250px]]
|-
|colspan="2" | [[File:Ohbclmep.jpg|300px rotate="90"]]
| [[File:Ohbclelevels.png|250px]]
|}

Molecule 2 was initially minimised using an MM2 calculation. The reactions of molecule A with an electrophile can be illustrated by taking a more advanced, quantum mechanical approach to modelling the molecule and its orbitals. This will also allow prediction of which C=C reacts with an electrophile.
Of the two alekenes, the endo is favoured rather than the exo because the cl-c sigma star orbital mixes with the exo alkene. This stabilises both orbitals, as shown by the frequency calculation having a higher value than the endo alkene, but reduces the pi bond character of the exo alkene. This is also shown by the comparative lengths of the alkene bonds - the exo is 1.3355A and the endo is 1.33190A. The cycloaddition of the carbene requires an alkene and so favours the endo alkene as it has a higher p character. The homo is also focused entirely on the endo side of the molecule, with the lumo focused mainly on the exo side. The Homo shows the high pi bond character of the endo alkene. The Homo-1 is mainly focused ont he exo alekene, so shows the pi bond character of the exo alekene. This is lower in energy and so is less likely to react with the carbene molecule.

====Glycosidation====

When the monosaccharide pyranose has an acetal in the 2 position, four different isomers can be formed, all of differing stability. These differing positions of the acetal group and its interactions with the neighbouring group means that it acts as a directing group to nucleophilic attack. With deprotonation to an oxenium cation being the initial step, the acetal group can then stabilise this to varying degrees depending on its position. Due to the Sn1 nature of the glycosidation nucleophilic attack occurring, the access of the nucleophile to the sigma* orbital of the carbon is crucial, and this depends on the Burgi-Dunitz angle of 107<ref> H. B. Bürgi, J. D. Dunitz, J. M. Lehn, G. Wipff (1974). "Stereochemistry of reaction paths at carbonyl centres". Tetrahedron 30 (12): 1563–1572. doi:10.1016/S0040-4020(01)90678-7</ref>.
Two sets of calculations were performed; initially using an MM2 forcefield, and then with using the MOPAC approach. While both approaches showed a similar trend, the benefit of the MOPAC, to make and break bond meant that the structures formed by this minimisation resembled the transition state a lot more closely than those formed by the MM2.
As shown by the table, below, all of the initial cations are at a lower energy than the intermediate forms, however the structures differ slightly depending on whether an MM2 or MOPAC minimisation was performed; the MOPAC structures much more closely resemble the transition states.
The differences in energy can be directly related to the amount of strain present within the molecule and the repulsion between the oxygen atoms. The large amount of strain present in the intermediates, particularly of molecule 2, mean that they have a lot higher energy. A notable differences is that the MM2 struggles to accurately deal with the oxenium cation, whereas the MOPAC produces a more lifelike picture in this area.
The glycosidation mainly produces the trans isomers, ie molecules going through the pathways of molecules 1 & 4. This is predicted well by the computational methods used, with both the initial molecules and the intermediates being lower in energy and having lower anomeric carbon-acetal oxygen distances.

=====Mechanisms=====

[[file:Ohbglymech.gif|800px]]

{|class="wikitable" border="2"
!rowspan="5" |Initial molecule
!colspan="2" | Conformation
|1
|2
|3
|4
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2amm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 11.5430
| 46.2672
| 35.5277
| 29.5144
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -90.51343
| -70.57703
| -72.56010
| -85.04737
|-
!rowspan="5" |Intermediate
!colspan="2" | Conformation
|chemdraw
|chemdraw
|chemdraw
|chemdraw
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2Bmm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 28.4913
| 43.2706
| 41.0918
| 31.8763
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -91.66112
| -66.72331
| -84.44899
| -88.08089

|-
|}

==Comparison of coumpational results to a molecule from literature.==

===Taxol intermediate===

Computational chemistry can be a powerful tool in the analysis and reproduction of spectra. in this exercise, literature values and spectra are compared to computed data and the effectiveness and accuracy of both methods is compared and contrasted.

A different intermediate in the synthesis of taxol was optimised using MM2 to produce the structure (right) with a total energy of 66.7072kcal<sup>-1</sup>
{|class="wikitable border="1"
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
This file was then optimised using Guassian and B3LYP 6-31G(d,p) basis set. The resulting file was then resubmitted to the SCAN cluster for computation of the nmr spectrum using these keywords # mpw1pw91/6-31G(d,p) NMR SCRF=(CPCM,Solvent=chloroform). These results were then compared to those found in the literature<ref>#L. Paquette, N. A. Pegg, D. Toops, G. D. Maynard, R. D. Rogers, ''J. Am. Chem. Soc.,'', '''1990''', ''112'', 277-283. {{DOI|10.1021/ja00157a043}}</ref>.
The results are below. As can be seen by this comparison chart, in general there is very good agreement between the predicted and measured shift values. With the only major discrepancy being at Carbon 16.

This however, can be resolved. The large distance is probably to do with this carbon being bonded to two sulphur atoms. The 6-31G(d,p) basis set is not very good at approximating, and hence optimising sulphur molecules. This is because Sulphur contains f type functions, of which there are 7. However there are 10<ref>SIMPLIFIED INTRODUCTION TO AB INITIO
BASIS SETS. TERMS AND NOTATION.
Jan K. Labanowski, Ohio Supercomputer Center,
1224 Kinnear Rd., Columbus, OH 43212-1163,</ref> possible Guassians, and so an element of contamination from the 4p orbitals is brought in. As the 6-31G(d,p) does not containg any f functions, it is not that good at predicting the behaviour of the sulphur molecule to the level required by the nmr calculation. Despite all of this, the shift values are still similar, and so the assignmnet of this molecule inth e literature can be deemed correct.
{|class="wikitable" border="2"
!Atom number !! Calculated ppm value !! Lit. ppm value
|-
| 1
| 27.5886
| 25.66
|-
| 2
| 31.6721
| 28.79
|-
| 3
| 52.6851
| 48.5
|-
| 4
| 146.8944
| 144.63
|-
| 5
| 51.4817
| 46.8
|-
| 6
| 20.6456
| 18.71
|-
| 7
| 27.0826
| 23.86
|-
| 8
| 125.7193
| 125.33
|-
| 9
| 50.5885
| 45.76
|-
| 10
| 218.6545
| 218.79
|-
| 11
| colspan="2" | Oxygen
|-
| 12
| 54.1882
| 52.52
|-
| 13
| 30.8219
| 28.29
|-
| 14
| 63.85
| 56.19
|-
| 15
| 29.5406
| 26.88
|-
| 16
| 89.99
| 72.88
|-
| 17
| 48.9728
| 39.8
|-
| 18
| 24.6905
| 20.96
|-
| 19
| 41.3115
| 32.66
|-
| 21
| 44.3139
| 35.85
|-
| 22
| 45.5337
| 38.81
|}

===Literature Molecule===

In the synthesis of molecule A (right), using Kobayashi aldol chemistry, two stereoisomers are produced. Initially, the syn isomer is formed, with a diasteromic ratio of 1:14, and via a similar synthetic route, the anti isomer is also produced, with a high dr of 1:>50. The high stereoselectivity of both of these reactions is an important step in the synthesis of enationmerically pure natural products.
Initiallyu the models were optimised using an MM2 optimisation within ChemBio 12.0. They were then further optimised using an RB3LYP-6-31G(d,p) method and basis set. After the optimisation, and checking to see that the the two molecules were still distinct, with one syn and one anti form, they were submitted for nmr analysis, to produce a predicted nmr. This was then compared with the reported nmr, with a view to see if the assignments and conclusions made in the literature were correct. There was a good correlations between the predicted and measured nmr peaks, with deviations, as show below, of less than 1ppm for the H nmr and less than 10ppm for the <sup>13</sup>C nmr.
[[File:Ohbccomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each carbon atom]]
[[File:Ohbhcomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each Hydrogen atom]]

This correlation helps confirm that the structures are correct; the different enantiomers are differentiated and assigned correctly. If they were not, and the calculated syn nmr is compared to the measured anti nmr, and vice versa, larger differences are noted. This is highlighted on the graph below. The blue and red graphs are the correctly assigned and matched nmrs, the green and purple nmrs are if they are assigned incorrectly. It can clearly be seen that the green and purple line are consistently higher than their counterparts.
[[file:Ohbcomparisonnmr.png|thumb|900px|none|left|Comparison of correct and incorrect assignment for the two conformers]]
Within the literature all of the hydrogens and carbons are assigned, with the exception of Hydrogen 48. This is because this is a labile proton and so does not show up on measured nmrs due to rapid exchange with the deuterium in the deuterated solvent. However the calculated spectra does not take this into account and so displays the shift value for this hydrogen.

The computed IR spectra are very similar for the two molecules. The OH stretch is increased by 30cm<sup>-1</sup> in the syn form of the molecule and the CH bend region between 1000-1500cm<sup>-1</sup> is also significantly different. This acsn be rationalised by the different atomic orbital overlaps that are occuring due to the different positioning of the methyl group.

As both molecules are chiral, they both rotate light in opposite directions. However due to the large size of this molecule and although it is relatively conformationally limited due to the double bond and ring, the calculation for the syn and anti variants did not converge after 48 a 48 hour run on the SCAN.

==References==
<references></references>

Rep:Mod:benton2

2013-02-08T14:38:28Z

Ohb09: /* Taxol intermediate */

=Module 1 - Intro=
In this experiment, MM2 is compared to the more advanced MOPAC minimisation technique. A minimised molecule is then analysed and compared to literature.
Molecular mechanics, used here in its MM2 form is a very good first order approximation. Using data from previous experiments and breaking down the overall energy into different categories, such as van der Waals interaction, dipole-dipole, and bending before summing them to provide an overall energy is a very useful and more importantly quick method to calculate a molecules energy. The energy of molecule can then be iteratively reduced by tweaking the position of the atoms and conformations, providing a low energy structure. However it does have its limitations. Firstly, because of the large approximations used, the method is liable to fall, and remain, in an initial, smaller, potential well at a higher energy than the minimum possible. This can be overcome by carefully arranging the molecule by the user of the program to avoid these early, high energy minima, but requires a lot of rearrangement and prioir knowledge of low energy arrangements. As MM2 uses previously aquired data, it is also not that useful in determining new structures, or functional groups for which it does not have the data for.
MOPAC uses a different approach for minimisation. It uses semi empirical quantum chemistry functions to determine the energy of a molecule. This allows more advanced effects to be included in the calculation and allows for analysis of the neighbouring group effect in sacchardie chemistry and regioselectivity effects, as studied here.
Computational chemistry can also predict spectra, and in the last part of the experiment predicted spectra are compared to literature and the results analysed.

==Week 1==

===Hydrogenation of the Cyclopentadiene Dimer===
The endo dimer is primarily produced when cyclopentadiene dimerises, in a ratio of 99.5% to 0.5% <ref>
Małgorzata E Jamróz, Sławomir Gałka, Jan Cz Dobrowolski,
On dicyclopentadiene isomers,
Journal of Molecular Structure: THEOCHEM,
Volume 634, Issues 1–3, 5 September 2003,
Pages 225-233, ISSN 0166-1280,
<DOI|10.1016/S0166-1280(03)00348-8>
</ref>(at least when thermally initiated; photo initiation produces a racemic mixture of the two isomers<ref>
The Photosensitited Dimerization of Cyclopentadiene
Nicholas J. Turro and George S. Hammond
Journal of the American Chemical Society 1962 84 (14), 2841-2842
<DOI|10.1021/ja00873a050>
</ref>)
{| class="wikitable" border="1"

! rowspan="2" | Molecule
|style="text-align: center;" |Exo
|style="text-align: center;" |Endo
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbexodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Total E (kcal/mol)
|33.9975
|31.8764
|-
|}
[[file:Endoexoohb.bmp|thumb|left|500px]]
The small energy difference calculated by the MM2 forcefield does not highlight why the endo for is favoured over the exo form as it shows the exo form is lower in energy. While the difference between the two energies is relatively trivial, the high enationmeric excess of the products suggest that this is only part of the story, and suggest that this reaction is under kinetic rather than thermodynamic control.<ref> W.C.Herndon, C.R.Grayson, J.M.Manion; "Retro-Diels-Alder reactions. III. Kinetics of the thermal decompositions of exo- and endo-dicyclopentadiene" J. Org. Chem.; 1967, 32 (3); 526-529.DOI:10.1021/jo01278a003</ref> Being under kinetic control would imply the activation energy, and hence transition state, for the endo species is lower than the exo form and so the endo enantiomer is formed faster. This can be rationalised by looking at the orbital interactions in the two transition states.

The endo transition state is stabilised by the secondary favourable overlap whereas in the exo form there is no such overlap to stabilised the molecule meaning that the transition state is a higher energy, and so is less favourable. This cannot be handled by the simple MM2 calculation however.

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" colspan="2" |Different hydrogenation sites
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh3.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh4.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|1.2489
|1.1303
|-
!Bend
|19.1608
|13.10259
|-
!Torsion
|11.0730
|12.4118
|-
!VDW
|5.7962
|4.4398
|-
!Dipole-Dipole
|0.1622
|0.1410
|-
!Total E (kcal/mol)
|34.9643
|29.2475
|-
|}

The site of initial hydrogenation of the endo dimer can also be determined by calculating the energies of the two possible isomers. From these calculations it is clear that the second molecule is favoured more, as it is ~5.5kcalmol<sup>-1</sup> more stable. The bending energy in both of these molecules is the major difference. This manifests itself in the amount that the atoms are ebent away from their ideal positions, which is 109.5 for an sp3 carbon and 120 for an sp2 carbon. Across all of the key bonds, the second isomer has bond angles that are closer to the ideal than the first isomer; in particular the C-C=C bond angles; in the first molecule they are 107.6 and in the second 112.8. This difference of five degrees is enough to significantly stabilise the second isomer, making hydrogenation at that site the more preferable.

===Atropisomerism in an Intermediate related to the synthesis of Taxol===
In the complete synthesis of Taxol, and important cancer fighting drug, proposed by Pacquette <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 10.1016/S0040-4039(00)92617-0</ref> a key intermediate is either "Precursor 9" or "Precursor 10".

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" |Precursor 10
|style="text-align: center;" |Precursor 9
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol9.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol10.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|2.4687
|2.7846
|-
!Bend
|10.5555
|16.5411
|-
!Torsion
|17.4240
|18.2518
|-
!VDW
|13.1930
|13.1096
|-
!Dipole-Dipole
| -1.8818
| -1.7248
|-
!Total E (kcal/mol)
|39.1215
|47.8395
|-
|}
Precursor 9 and 10 are synthesised using a reversible oxy-Cope rearrangement as demonstrated below. As this process is in equilibrium that, with precursor 10 being more stable, it is predicted that this isomer will be the one produced as all of the molecules attempt to reduce the energy. As analysis of the individual energy componenets shows, this arrangement is a lot less strained than Precursor nine, which requires a lot more bending energy.

The molecule was then optimised with an MMFF94. Rather than rely on a large set of experimentally determined parameters like MM2, MMFF94 minimises the potential of each atom iteratively, attempting to minimise the whole molecule. Although the values produced for these two methods cannot be directly compared, they both correctly identify the correct altropisomer as being lower in energy.
{|class="wikitable" border="1"
! colspan="3" | Comparison of MMFF94 and MM2 minimisations
|-
!Molecule
| Precursor 9
| Precursor 10
|-
!MM2 minimised Energy (kJmol<sup><-1</sup>)
|39.1215
|47.8395
|-
!MMFF94 minimised Energy (kcalmol<sup><-1</sup>)
|58.7513
|70.5377
|-
|}

===Regioselective Addition of Dichlorocarbene to a diene===
Molecule A was initially optimised using a molecular mechanics (MM2) calculation

{| style="wikitable" border="1"
|<jmol>
<jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
It was then further optimised with a MOPAC calculation, which takes into effect stereoelectronic effects. The two were then compared.

{| class="wikitable" border="1"
!colspan="3" | Comparison of two optimisation calculations
|-
! Overlay of two optimised molecules !! MM2 optimised molecule !! MOPAC Optimised Molecule
|-
|[[file:Ohboverlaydiene.png|300px]]
The MM2 optimised molecule is coloured yellow for clarity
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1mopac.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! rowspan="6" | Distances between
corresponding atoms

on the overlaid molecules (Å)
|style="text-align: center;" | C(34)-C(9)
|0.5247
|-
|style="text-align: center;" | C(26)-C(1)
|0.5246
|-
|style="text-align: center;" | H(47)-H(22)
|0.8526
|-
|style="text-align: center;" | H(38)-H(13)
|0.8524
|-
|style="text-align: center;" | Cl(37)-Cl(12)
|0.0689
|}

As can be seen by the comparison above, when using the stereoelectronic interactions, the cyclohexadiene ring on the side with the Cl atom is moved further away from the Cl using the MOPAC calculation than the MM2. This is because the electronic effects included in this calculation include the repulsion between the electron rich Chlorine atom and the electron rich double bond, whereas the MM2 calculation doesn't include this and so a symmetrical molecule is formed.

====MOs====

The MOs of the previously MOPAC optimised molecule where then calculated using Guassian (B3LYP 6-31G)
{| style="wikitable" border="1"
! Homo-1 !! colspan="2" | Homo
|-
|[[File:Ohbclhomo-1.jpg|250px]]
| <jmol>
<jmolApplet>
<title>Orbital</title><color>white</color><size>250</size>
<script>isosurface color orange purple "images/f/f2/Ohbdienemo48.cub.jvxl" translucent; </script>
<uploadedFileContents>Ohbdienemo48.cub.xyz</uploadedFileContents>
</jmolApplet>
</jmol>
|[[File:Ohbclhomo.jpg|250px]]
|-
!Lumo !! Lumo+1 !! Lumo+2
|-
|[[File:Ohbcllumo.jpg|250px]]
|[[File:Ohbcllumo+1.jpg|250px]]
|[[File:Ohbcllumo+2.jpg|250px]]
|-
|colspan="2" | [[File:Ohbclmep.jpg|300px rotate="90"]]
| [[File:Ohbclelevels.png|250px]]
|}

Molecule 2 was initially minimised using an MM2 calculation. The reactions of molecule A with an electrophile can be illustrated by taking a more advanced, quantum mechanical approach to modelling the molecule and its orbitals. This will also allow prediction of which C=C reacts with an electrophile.
Of the two alekenes, the endo is favoured rather than the exo because the cl-c sigma star orbital mixes with the exo alkene. This stabilises both orbitals, as shown by the frequency calculation having a higher value than the endo alkene, but reduces the pi bond character of the exo alkene. This is also shown by the comparative lengths of the alkene bonds - the exo is 1.3355A and the endo is 1.33190A. The cycloaddition of the carbene requires an alkene and so favours the endo alkene as it has a higher p character. The homo is also focused entirely on the endo side of the molecule, with the lumo focused mainly on the exo side. The Homo shows the high pi bond character of the endo alkene. The Homo-1 is mainly focused ont he exo alekene, so shows the pi bond character of the exo alekene. This is lower in energy and so is less likely to react with the carbene molecule.

====Glycosidation====

When the monosaccharide pyranose has an acetal in the 2 position, four different isomers can be formed, all of differing stability. These differing positions of the acetal group and its interactions with the neighbouring group means that it acts as a directing group to nucleophilic attack. With deprotonation to an oxenium cation being the initial step, the acetal group can then stabilise this to varying degrees depending on its position. Due to the Sn1 nature of the glycosidation nucleophilic attack occurring, the access of the nucleophile to the sigma* orbital of the carbon is crucial, and this depends on the Burgi-Dunitz angle of 107<ref> H. B. Bürgi, J. D. Dunitz, J. M. Lehn, G. Wipff (1974). "Stereochemistry of reaction paths at carbonyl centres". Tetrahedron 30 (12): 1563–1572. doi:10.1016/S0040-4020(01)90678-7</ref>.
Two sets of calculations were performed; initially using an MM2 forcefield, and then with using the MOPAC approach. While both approaches showed a similar trend, the benefit of the MOPAC, to make and break bond meant that the structures formed by this minimisation resembled the transition state a lot more closely than those formed by the MM2.
As shown by the table, below, all of the initial cations are at a lower energy than the intermediate forms, however the structures differ slightly depending on whether an MM2 or MOPAC minimisation was performed; the MOPAC structures much more closely resemble the transition states.
The differences in energy can be directly related to the amount of strain present within the molecule and the repulsion between the oxygen atoms. The large amount of strain present in the intermediates, particularly of molecule 2, mean that they have a lot higher energy. A notable differences is that the MM2 struggles to accurately deal with the oxenium cation, whereas the MOPAC produces a more lifelike picture in this area.
The glycosidation mainly produces the trans isomers, ie molecules going through the pathways of molecules 1 & 4. This is predicted well by the computational methods used, with both the initial molecules and the intermediates being lower in energy and having lower anomeric carbon-acetal oxygen distances.

=====Mechanisms=====

[[file:Ohbglymech.gif|800px]]

{|class="wikitable" border="2"
!rowspan="5" |Initial molecule
!colspan="2" | Conformation
|1
|2
|3
|4
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2amm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 11.5430
| 46.2672
| 35.5277
| 29.5144
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -90.51343
| -70.57703
| -72.56010
| -85.04737
|-
!rowspan="5" |Intermediate
!colspan="2" | Conformation
|chemdraw
|chemdraw
|chemdraw
|chemdraw
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2Bmm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 28.4913
| 43.2706
| 41.0918
| 31.8763
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -91.66112
| -66.72331
| -84.44899
| -88.08089

|-
|}

==Comparison of coumpational results to a molecule from literature.==

===Taxol intermediate===

Computational chemistry can be a powerful tool in the analysis and reproduction of spectra. in this exercise, literature values and spectra are compared to computed data and the effectiveness and accuracy of both methods is compared and contrasted.

A different intermediate in the synthesis of taxol was optimised using MM2 to produce the structure (right) with a total energy of 66.7072kcal<sup>-1</sup>
{|class="wikitable border="1"
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
This file was then optimised using Guassian and B3LYP 6-31G(d,p) basis set. The resulting file was then resubmitted to the SCAN cluster for computation of the nmr spectrum using these keywords # mpw1pw91/6-31G(d,p) NMR SCRF=(CPCM,Solvent=chloroform). These results were then compared to those found in the literature<ref>#L. Paquette, N. A. Pegg, D. Toops, G. D. Maynard, R. D. Rogers, ''J. Am. Chem. Soc.,'', '''1990''', ''112'', 277-283. {{DOI|10.1021/ja00157a043}}</ref>.
The results are below. As can be seen by this comparison chart, in general there is very good agreement between the predicted and measured shift values. With the only major discrepancy being at Carbon 16.

This however, can be resolved. The large distance is probably to do with this carbon being bonded to two sulphur atoms. The 6-31G(d,p) basis set is not very good at approximating, and hence optimising sulphur molecules. This is because Sulphur contains f type functions, of which there are 7. However there are 10<ref>SIMPLIFIED INTRODUCTION TO AB INITIO
BASIS SETS. TERMS AND NOTATION.
Jan K. Labanowski, Ohio Supercomputer Center,
1224 Kinnear Rd., Columbus, OH 43212-1163,</ref> possible Guassians, and so an element of contamination from the 4p orbitals is brought in. As the 6-31G(d,p) does not containg any f functions, it is not that good at predicting the behaviour of the sulphur molecule to the level required by the nmr calculation. Despite all of this, the shift values are still similar.
{|class="wikitable" border="2"
!Atom number !! Calculated ppm value !! Lit. ppm value
|-
| 1
| 27.5886
| 25.66
|-
| 2
| 31.6721
| 28.79
|-
| 3
| 52.6851
| 48.5
|-
| 4
| 146.8944
| 144.63
|-
| 5
| 51.4817
| 46.8
|-
| 6
| 20.6456
| 18.71
|-
| 7
| 27.0826
| 23.86
|-
| 8
| 125.7193
| 125.33
|-
| 9
| 50.5885
| 45.76
|-
| 10
| 218.6545
| 218.79
|-
| 11
| colspan="2" | Oxygen
|-
| 12
| 54.1882
| 52.52
|-
| 13
| 30.8219
| 28.29
|-
| 14
| 63.85
| 56.19
|-
| 15
| 29.5406
| 26.88
|-
| 16
| 89.99
| 72.88
|-
| 17
| 48.9728
| 39.8
|-
| 18
| 24.6905
| 20.96
|-
| 19
| 41.3115
| 32.66
|-
| 21
| 44.3139
| 35.85
|-
| 22
| 45.5337
| 38.81
|}

===Literature Molecule===

In the synthesis of molecule A (right), using Kobayashi aldol chemistry, two stereoisomers are produced. Initially, the syn isomer is formed, with a diasteromic ratio of 1:14, and via a similar synthetic route, the anti isomer is also produced, with a high dr of 1:>50. The high stereoselectivity of both of these reactions is an important step in the synthesis of enationmerically pure natural products.
Initiallyu the models were optimised using an MM2 optimisation within ChemBio 12.0. They were then further optimised using an RB3LYP-6-31G(d,p) method and basis set. After the optimisation, and checking to see that the the two molecules were still distinct, with one syn and one anti form, they were submitted for nmr analysis, to produce a predicted nmr. This was then compared with the reported nmr, with a view to see if the assignments and conclusions made in the literature were correct. There was a good correlations between the predicted and measured nmr peaks, with deviations, as show below, of less than 1ppm for the H nmr and less than 10ppm for the <sup>13</sup>C nmr.
[[File:Ohbccomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each carbon atom]]
[[File:Ohbhcomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each Hydrogen atom]]

This correlation helps confirm that the structures are correct; the different enantiomers are differentiated and assigned correctly. If they were not, and the calculated syn nmr is compared to the measured anti nmr, and vice versa, larger differences are noted. This is highlighted on the graph below. The blue and red graphs are the correctly assigned and matched nmrs, the green and purple nmrs are if they are assigned incorrectly. It can clearly be seen that the green and purple line are consistently higher than their counterparts.
[[file:Ohbcomparisonnmr.png|thumb|900px|none|left|Comparison of correct and incorrect assignment for the two conformers]]
Within the literature all of the hydrogens and carbons are assigned, with the exception of Hydrogen 48. This is because this is a labile proton and so does not show up on measured nmrs due to rapid exchange with the deuterium in the deuterated solvent. However the calculated spectra does not take this into account and so displays the shift value for this hydrogen.

The computed IR spectra are very similar for the two molecules. The OH stretch is increased by 30cm<sup>-1</sup> in the syn form of the molecule and the CH bend region between 1000-1500cm<sup>-1</sup> is also significantly different. This acsn be rationalised by the different atomic orbital overlaps that are occuring due to the different positioning of the methyl group.

As both molecules are chiral, they both rotate light in opposite directions. However due to the large size of this molecule and although it is relatively conformationally limited due to the double bond and ring, the calculation for the syn and anti variants did not converge after 48 a 48 hour run on the SCAN.

==References==
<references></references>

Rep:Mod:benton2

2013-02-08T14:37:23Z

Ohb09: /* Taxol intermediate */

=Module 1 - Intro=
In this experiment, MM2 is compared to the more advanced MOPAC minimisation technique. A minimised molecule is then analysed and compared to literature.
Molecular mechanics, used here in its MM2 form is a very good first order approximation. Using data from previous experiments and breaking down the overall energy into different categories, such as van der Waals interaction, dipole-dipole, and bending before summing them to provide an overall energy is a very useful and more importantly quick method to calculate a molecules energy. The energy of molecule can then be iteratively reduced by tweaking the position of the atoms and conformations, providing a low energy structure. However it does have its limitations. Firstly, because of the large approximations used, the method is liable to fall, and remain, in an initial, smaller, potential well at a higher energy than the minimum possible. This can be overcome by carefully arranging the molecule by the user of the program to avoid these early, high energy minima, but requires a lot of rearrangement and prioir knowledge of low energy arrangements. As MM2 uses previously aquired data, it is also not that useful in determining new structures, or functional groups for which it does not have the data for.
MOPAC uses a different approach for minimisation. It uses semi empirical quantum chemistry functions to determine the energy of a molecule. This allows more advanced effects to be included in the calculation and allows for analysis of the neighbouring group effect in sacchardie chemistry and regioselectivity effects, as studied here.
Computational chemistry can also predict spectra, and in the last part of the experiment predicted spectra are compared to literature and the results analysed.

==Week 1==

===Hydrogenation of the Cyclopentadiene Dimer===
The endo dimer is primarily produced when cyclopentadiene dimerises, in a ratio of 99.5% to 0.5% <ref>
Małgorzata E Jamróz, Sławomir Gałka, Jan Cz Dobrowolski,
On dicyclopentadiene isomers,
Journal of Molecular Structure: THEOCHEM,
Volume 634, Issues 1–3, 5 September 2003,
Pages 225-233, ISSN 0166-1280,
<DOI|10.1016/S0166-1280(03)00348-8>
</ref>(at least when thermally initiated; photo initiation produces a racemic mixture of the two isomers<ref>
The Photosensitited Dimerization of Cyclopentadiene
Nicholas J. Turro and George S. Hammond
Journal of the American Chemical Society 1962 84 (14), 2841-2842
<DOI|10.1021/ja00873a050>
</ref>)
{| class="wikitable" border="1"

! rowspan="2" | Molecule
|style="text-align: center;" |Exo
|style="text-align: center;" |Endo
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbexodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Total E (kcal/mol)
|33.9975
|31.8764
|-
|}
[[file:Endoexoohb.bmp|thumb|left|500px]]
The small energy difference calculated by the MM2 forcefield does not highlight why the endo for is favoured over the exo form as it shows the exo form is lower in energy. While the difference between the two energies is relatively trivial, the high enationmeric excess of the products suggest that this is only part of the story, and suggest that this reaction is under kinetic rather than thermodynamic control.<ref> W.C.Herndon, C.R.Grayson, J.M.Manion; "Retro-Diels-Alder reactions. III. Kinetics of the thermal decompositions of exo- and endo-dicyclopentadiene" J. Org. Chem.; 1967, 32 (3); 526-529.DOI:10.1021/jo01278a003</ref> Being under kinetic control would imply the activation energy, and hence transition state, for the endo species is lower than the exo form and so the endo enantiomer is formed faster. This can be rationalised by looking at the orbital interactions in the two transition states.

The endo transition state is stabilised by the secondary favourable overlap whereas in the exo form there is no such overlap to stabilised the molecule meaning that the transition state is a higher energy, and so is less favourable. This cannot be handled by the simple MM2 calculation however.

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" colspan="2" |Different hydrogenation sites
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh3.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh4.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|1.2489
|1.1303
|-
!Bend
|19.1608
|13.10259
|-
!Torsion
|11.0730
|12.4118
|-
!VDW
|5.7962
|4.4398
|-
!Dipole-Dipole
|0.1622
|0.1410
|-
!Total E (kcal/mol)
|34.9643
|29.2475
|-
|}

The site of initial hydrogenation of the endo dimer can also be determined by calculating the energies of the two possible isomers. From these calculations it is clear that the second molecule is favoured more, as it is ~5.5kcalmol<sup>-1</sup> more stable. The bending energy in both of these molecules is the major difference. This manifests itself in the amount that the atoms are ebent away from their ideal positions, which is 109.5 for an sp3 carbon and 120 for an sp2 carbon. Across all of the key bonds, the second isomer has bond angles that are closer to the ideal than the first isomer; in particular the C-C=C bond angles; in the first molecule they are 107.6 and in the second 112.8. This difference of five degrees is enough to significantly stabilise the second isomer, making hydrogenation at that site the more preferable.

===Atropisomerism in an Intermediate related to the synthesis of Taxol===
In the complete synthesis of Taxol, and important cancer fighting drug, proposed by Pacquette <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 10.1016/S0040-4039(00)92617-0</ref> a key intermediate is either "Precursor 9" or "Precursor 10".

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" |Precursor 10
|style="text-align: center;" |Precursor 9
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol9.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol10.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|2.4687
|2.7846
|-
!Bend
|10.5555
|16.5411
|-
!Torsion
|17.4240
|18.2518
|-
!VDW
|13.1930
|13.1096
|-
!Dipole-Dipole
| -1.8818
| -1.7248
|-
!Total E (kcal/mol)
|39.1215
|47.8395
|-
|}
Precursor 9 and 10 are synthesised using a reversible oxy-Cope rearrangement as demonstrated below. As this process is in equilibrium that, with precursor 10 being more stable, it is predicted that this isomer will be the one produced as all of the molecules attempt to reduce the energy. As analysis of the individual energy componenets shows, this arrangement is a lot less strained than Precursor nine, which requires a lot more bending energy.

The molecule was then optimised with an MMFF94. Rather than rely on a large set of experimentally determined parameters like MM2, MMFF94 minimises the potential of each atom iteratively, attempting to minimise the whole molecule. Although the values produced for these two methods cannot be directly compared, they both correctly identify the correct altropisomer as being lower in energy.
{|class="wikitable" border="1"
! colspan="3" | Comparison of MMFF94 and MM2 minimisations
|-
!Molecule
| Precursor 9
| Precursor 10
|-
!MM2 minimised Energy (kJmol<sup><-1</sup>)
|39.1215
|47.8395
|-
!MMFF94 minimised Energy (kcalmol<sup><-1</sup>)
|58.7513
|70.5377
|-
|}

===Regioselective Addition of Dichlorocarbene to a diene===
Molecule A was initially optimised using a molecular mechanics (MM2) calculation

{| style="wikitable" border="1"
|<jmol>
<jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
It was then further optimised with a MOPAC calculation, which takes into effect stereoelectronic effects. The two were then compared.

{| class="wikitable" border="1"
!colspan="3" | Comparison of two optimisation calculations
|-
! Overlay of two optimised molecules !! MM2 optimised molecule !! MOPAC Optimised Molecule
|-
|[[file:Ohboverlaydiene.png|300px]]
The MM2 optimised molecule is coloured yellow for clarity
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1mopac.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! rowspan="6" | Distances between
corresponding atoms

on the overlaid molecules (Å)
|style="text-align: center;" | C(34)-C(9)
|0.5247
|-
|style="text-align: center;" | C(26)-C(1)
|0.5246
|-
|style="text-align: center;" | H(47)-H(22)
|0.8526
|-
|style="text-align: center;" | H(38)-H(13)
|0.8524
|-
|style="text-align: center;" | Cl(37)-Cl(12)
|0.0689
|}

As can be seen by the comparison above, when using the stereoelectronic interactions, the cyclohexadiene ring on the side with the Cl atom is moved further away from the Cl using the MOPAC calculation than the MM2. This is because the electronic effects included in this calculation include the repulsion between the electron rich Chlorine atom and the electron rich double bond, whereas the MM2 calculation doesn't include this and so a symmetrical molecule is formed.

====MOs====

The MOs of the previously MOPAC optimised molecule where then calculated using Guassian (B3LYP 6-31G)
{| style="wikitable" border="1"
! Homo-1 !! colspan="2" | Homo
|-
|[[File:Ohbclhomo-1.jpg|250px]]
| <jmol>
<jmolApplet>
<title>Orbital</title><color>white</color><size>250</size>
<script>isosurface color orange purple "images/f/f2/Ohbdienemo48.cub.jvxl" translucent; </script>
<uploadedFileContents>Ohbdienemo48.cub.xyz</uploadedFileContents>
</jmolApplet>
</jmol>
|[[File:Ohbclhomo.jpg|250px]]
|-
!Lumo !! Lumo+1 !! Lumo+2
|-
|[[File:Ohbcllumo.jpg|250px]]
|[[File:Ohbcllumo+1.jpg|250px]]
|[[File:Ohbcllumo+2.jpg|250px]]
|-
|colspan="2" | [[File:Ohbclmep.jpg|300px rotate="90"]]
| [[File:Ohbclelevels.png|250px]]
|}

Molecule 2 was initially minimised using an MM2 calculation. The reactions of molecule A with an electrophile can be illustrated by taking a more advanced, quantum mechanical approach to modelling the molecule and its orbitals. This will also allow prediction of which C=C reacts with an electrophile.
Of the two alekenes, the endo is favoured rather than the exo because the cl-c sigma star orbital mixes with the exo alkene. This stabilises both orbitals, as shown by the frequency calculation having a higher value than the endo alkene, but reduces the pi bond character of the exo alkene. This is also shown by the comparative lengths of the alkene bonds - the exo is 1.3355A and the endo is 1.33190A. The cycloaddition of the carbene requires an alkene and so favours the endo alkene as it has a higher p character. The homo is also focused entirely on the endo side of the molecule, with the lumo focused mainly on the exo side. The Homo shows the high pi bond character of the endo alkene. The Homo-1 is mainly focused ont he exo alekene, so shows the pi bond character of the exo alekene. This is lower in energy and so is less likely to react with the carbene molecule.

====Glycosidation====

When the monosaccharide pyranose has an acetal in the 2 position, four different isomers can be formed, all of differing stability. These differing positions of the acetal group and its interactions with the neighbouring group means that it acts as a directing group to nucleophilic attack. With deprotonation to an oxenium cation being the initial step, the acetal group can then stabilise this to varying degrees depending on its position. Due to the Sn1 nature of the glycosidation nucleophilic attack occurring, the access of the nucleophile to the sigma* orbital of the carbon is crucial, and this depends on the Burgi-Dunitz angle of 107<ref> H. B. Bürgi, J. D. Dunitz, J. M. Lehn, G. Wipff (1974). "Stereochemistry of reaction paths at carbonyl centres". Tetrahedron 30 (12): 1563–1572. doi:10.1016/S0040-4020(01)90678-7</ref>.
Two sets of calculations were performed; initially using an MM2 forcefield, and then with using the MOPAC approach. While both approaches showed a similar trend, the benefit of the MOPAC, to make and break bond meant that the structures formed by this minimisation resembled the transition state a lot more closely than those formed by the MM2.
As shown by the table, below, all of the initial cations are at a lower energy than the intermediate forms, however the structures differ slightly depending on whether an MM2 or MOPAC minimisation was performed; the MOPAC structures much more closely resemble the transition states.
The differences in energy can be directly related to the amount of strain present within the molecule and the repulsion between the oxygen atoms. The large amount of strain present in the intermediates, particularly of molecule 2, mean that they have a lot higher energy. A notable differences is that the MM2 struggles to accurately deal with the oxenium cation, whereas the MOPAC produces a more lifelike picture in this area.
The glycosidation mainly produces the trans isomers, ie molecules going through the pathways of molecules 1 & 4. This is predicted well by the computational methods used, with both the initial molecules and the intermediates being lower in energy and having lower anomeric carbon-acetal oxygen distances.

=====Mechanisms=====

[[file:Ohbglymech.gif|800px]]

{|class="wikitable" border="2"
!rowspan="5" |Initial molecule
!colspan="2" | Conformation
|1
|2
|3
|4
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2amm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 11.5430
| 46.2672
| 35.5277
| 29.5144
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -90.51343
| -70.57703
| -72.56010
| -85.04737
|-
!rowspan="5" |Intermediate
!colspan="2" | Conformation
|chemdraw
|chemdraw
|chemdraw
|chemdraw
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2Bmm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 28.4913
| 43.2706
| 41.0918
| 31.8763
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -91.66112
| -66.72331
| -84.44899
| -88.08089

|-
|}

==Comparison of coumpational results to a molecule from literature.==

===Taxol intermediate===

Computational chemistry can be a powerful tool in the analysis and reproduction of spectra. in this exercise, literature values and spectra are compared to computed data and the effectiveness and accuracy of both methods is compared and contrasted.

A different intermediate in the synthesis of taxol was optimised using MM2 to produce the structure (right) with a total energy of 66.7072kcal<sup>-1</sup>
{|class="wikitable border="1"
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
This file was then optimised using Guassian and B3LYP 6-31G(d,p) basis set. The resulting file was then resubmitted to the SCAN cluster for computation of the nmr spectrum using these keywords # mpw1pw91/6-31G(d,p) NMR SCRF=(CPCM,Solvent=chloroform). These results were then compared to those found in the literature<ref>#L. Paquette, N. A. Pegg, D. Toops, G. D. Maynard, R. D. Rogers, ''J. Am. Chem. Soc.,'', '''1990''', ''112'', 277-283. {{DOI|10.1021/ja00157a043}}</ref>.
The results are below. As can be seen by this comparison chart, in general there is very good agreement between the predicted and measured shift values. With the only major discrepancy being at Carbon 16.

This however, can be resolved. The large distance is probably to do with this carbon being bonded to two sulphur atoms. The 6-31G(d,p) basis set is not very good at approximating, and hence optimising sulphur molecules. This is because Sulphur contains f type functions, of which there are 7. However there are 10<ref>SIMPLIFIED INTRODUCTION TO AB INITIO
BASIS SETS. TERMS AND NOTATION.
Jan K. Labanowski, Ohio Supercomputer Center,
1224 Kinnear Rd., Columbus, OH 43212-1163,</ref> possible Guassians, and so an element of contamination from the 4p orbitals is brought in. As the 6-31G(d,p) does not containg any f functions, it is not that good at predicting the behaviour of the sulphur molecule to the level required by the nmr calculation. Despite all of this, the shift values are still similar.
{|class="wikitable" border="2"
!Atom number !! Calculated ppm value !! Lit. ppm value
|-
| 1
| 27.5886
| 25.66
|-
| 2
| 31.6721
| 28.79
|-
| 3
| 52.6851
| 48.5
|-
| 4
| 146.8944
| 144.63
|-
| 5
| 51.4817
| 46.8
|-
| 6
| 20.6456
| 18.71|
|-
| 7
| 27.0826
| 23.86
|-
| 8
| 125.7193
| 125.33
|-
| 9
| 50.5885
| 45.76
|-
| 10
| 218.6545
| 218.79
|-
| colspan="3" | Oxygen
|-
| 12
| 54.1882
| 52.52
|-
| 13
| 30.8219
| 28.29
|-
| 14
| 63.85
| 56.19
|-
| 15
| 29.5406
| 26.88
|-
| 16
| 89.99
| 72.88
|-
| 17
| 48.9728
| 39.8
|-
| 18
| 24.6905
| 20.96
|-
| 19
| 41.3115
| 32.66
|-
| 21
| 44.3139
| 35.85
|-
| 22
| 45.5337
| 38.81
|}

===Literature Molecule===

In the synthesis of molecule A (right), using Kobayashi aldol chemistry, two stereoisomers are produced. Initially, the syn isomer is formed, with a diasteromic ratio of 1:14, and via a similar synthetic route, the anti isomer is also produced, with a high dr of 1:>50. The high stereoselectivity of both of these reactions is an important step in the synthesis of enationmerically pure natural products.
Initiallyu the models were optimised using an MM2 optimisation within ChemBio 12.0. They were then further optimised using an RB3LYP-6-31G(d,p) method and basis set. After the optimisation, and checking to see that the the two molecules were still distinct, with one syn and one anti form, they were submitted for nmr analysis, to produce a predicted nmr. This was then compared with the reported nmr, with a view to see if the assignments and conclusions made in the literature were correct. There was a good correlations between the predicted and measured nmr peaks, with deviations, as show below, of less than 1ppm for the H nmr and less than 10ppm for the <sup>13</sup>C nmr.
[[File:Ohbccomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each carbon atom]]
[[File:Ohbhcomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each Hydrogen atom]]

This correlation helps confirm that the structures are correct; the different enantiomers are differentiated and assigned correctly. If they were not, and the calculated syn nmr is compared to the measured anti nmr, and vice versa, larger differences are noted. This is highlighted on the graph below. The blue and red graphs are the correctly assigned and matched nmrs, the green and purple nmrs are if they are assigned incorrectly. It can clearly be seen that the green and purple line are consistently higher than their counterparts.
[[file:Ohbcomparisonnmr.png|thumb|900px|none|left|Comparison of correct and incorrect assignment for the two conformers]]
Within the literature all of the hydrogens and carbons are assigned, with the exception of Hydrogen 48. This is because this is a labile proton and so does not show up on measured nmrs due to rapid exchange with the deuterium in the deuterated solvent. However the calculated spectra does not take this into account and so displays the shift value for this hydrogen.

The computed IR spectra are very similar for the two molecules. The OH stretch is increased by 30cm<sup>-1</sup> in the syn form of the molecule and the CH bend region between 1000-1500cm<sup>-1</sup> is also significantly different. This acsn be rationalised by the different atomic orbital overlaps that are occuring due to the different positioning of the methyl group.

As both molecules are chiral, they both rotate light in opposite directions. However due to the large size of this molecule and although it is relatively conformationally limited due to the double bond and ring, the calculation for the syn and anti variants did not converge after 48 a 48 hour run on the SCAN.

==References==
<references></references>

Rep:Mod:benton2

2013-02-08T14:35:02Z

Ohb09:

=Module 1 - Intro=
In this experiment, MM2 is compared to the more advanced MOPAC minimisation technique. A minimised molecule is then analysed and compared to literature.
Molecular mechanics, used here in its MM2 form is a very good first order approximation. Using data from previous experiments and breaking down the overall energy into different categories, such as van der Waals interaction, dipole-dipole, and bending before summing them to provide an overall energy is a very useful and more importantly quick method to calculate a molecules energy. The energy of molecule can then be iteratively reduced by tweaking the position of the atoms and conformations, providing a low energy structure. However it does have its limitations. Firstly, because of the large approximations used, the method is liable to fall, and remain, in an initial, smaller, potential well at a higher energy than the minimum possible. This can be overcome by carefully arranging the molecule by the user of the program to avoid these early, high energy minima, but requires a lot of rearrangement and prioir knowledge of low energy arrangements. As MM2 uses previously aquired data, it is also not that useful in determining new structures, or functional groups for which it does not have the data for.
MOPAC uses a different approach for minimisation. It uses semi empirical quantum chemistry functions to determine the energy of a molecule. This allows more advanced effects to be included in the calculation and allows for analysis of the neighbouring group effect in sacchardie chemistry and regioselectivity effects, as studied here.
Computational chemistry can also predict spectra, and in the last part of the experiment predicted spectra are compared to literature and the results analysed.

==Week 1==

===Hydrogenation of the Cyclopentadiene Dimer===
The endo dimer is primarily produced when cyclopentadiene dimerises, in a ratio of 99.5% to 0.5% <ref>
Małgorzata E Jamróz, Sławomir Gałka, Jan Cz Dobrowolski,
On dicyclopentadiene isomers,
Journal of Molecular Structure: THEOCHEM,
Volume 634, Issues 1–3, 5 September 2003,
Pages 225-233, ISSN 0166-1280,
<DOI|10.1016/S0166-1280(03)00348-8>
</ref>(at least when thermally initiated; photo initiation produces a racemic mixture of the two isomers<ref>
The Photosensitited Dimerization of Cyclopentadiene
Nicholas J. Turro and George S. Hammond
Journal of the American Chemical Society 1962 84 (14), 2841-2842
<DOI|10.1021/ja00873a050>
</ref>)
{| class="wikitable" border="1"

! rowspan="2" | Molecule
|style="text-align: center;" |Exo
|style="text-align: center;" |Endo
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbexodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Total E (kcal/mol)
|33.9975
|31.8764
|-
|}
[[file:Endoexoohb.bmp|thumb|left|500px]]
The small energy difference calculated by the MM2 forcefield does not highlight why the endo for is favoured over the exo form as it shows the exo form is lower in energy. While the difference between the two energies is relatively trivial, the high enationmeric excess of the products suggest that this is only part of the story, and suggest that this reaction is under kinetic rather than thermodynamic control.<ref> W.C.Herndon, C.R.Grayson, J.M.Manion; "Retro-Diels-Alder reactions. III. Kinetics of the thermal decompositions of exo- and endo-dicyclopentadiene" J. Org. Chem.; 1967, 32 (3); 526-529.DOI:10.1021/jo01278a003</ref> Being under kinetic control would imply the activation energy, and hence transition state, for the endo species is lower than the exo form and so the endo enantiomer is formed faster. This can be rationalised by looking at the orbital interactions in the two transition states.

The endo transition state is stabilised by the secondary favourable overlap whereas in the exo form there is no such overlap to stabilised the molecule meaning that the transition state is a higher energy, and so is less favourable. This cannot be handled by the simple MM2 calculation however.

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" colspan="2" |Different hydrogenation sites
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh3.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh4.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|1.2489
|1.1303
|-
!Bend
|19.1608
|13.10259
|-
!Torsion
|11.0730
|12.4118
|-
!VDW
|5.7962
|4.4398
|-
!Dipole-Dipole
|0.1622
|0.1410
|-
!Total E (kcal/mol)
|34.9643
|29.2475
|-
|}

The site of initial hydrogenation of the endo dimer can also be determined by calculating the energies of the two possible isomers. From these calculations it is clear that the second molecule is favoured more, as it is ~5.5kcalmol<sup>-1</sup> more stable. The bending energy in both of these molecules is the major difference. This manifests itself in the amount that the atoms are ebent away from their ideal positions, which is 109.5 for an sp3 carbon and 120 for an sp2 carbon. Across all of the key bonds, the second isomer has bond angles that are closer to the ideal than the first isomer; in particular the C-C=C bond angles; in the first molecule they are 107.6 and in the second 112.8. This difference of five degrees is enough to significantly stabilise the second isomer, making hydrogenation at that site the more preferable.

===Atropisomerism in an Intermediate related to the synthesis of Taxol===
In the complete synthesis of Taxol, and important cancer fighting drug, proposed by Pacquette <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 10.1016/S0040-4039(00)92617-0</ref> a key intermediate is either "Precursor 9" or "Precursor 10".

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" |Precursor 10
|style="text-align: center;" |Precursor 9
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol9.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol10.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|2.4687
|2.7846
|-
!Bend
|10.5555
|16.5411
|-
!Torsion
|17.4240
|18.2518
|-
!VDW
|13.1930
|13.1096
|-
!Dipole-Dipole
| -1.8818
| -1.7248
|-
!Total E (kcal/mol)
|39.1215
|47.8395
|-
|}
Precursor 9 and 10 are synthesised using a reversible oxy-Cope rearrangement as demonstrated below. As this process is in equilibrium that, with precursor 10 being more stable, it is predicted that this isomer will be the one produced as all of the molecules attempt to reduce the energy. As analysis of the individual energy componenets shows, this arrangement is a lot less strained than Precursor nine, which requires a lot more bending energy.

The molecule was then optimised with an MMFF94. Rather than rely on a large set of experimentally determined parameters like MM2, MMFF94 minimises the potential of each atom iteratively, attempting to minimise the whole molecule. Although the values produced for these two methods cannot be directly compared, they both correctly identify the correct altropisomer as being lower in energy.
{|class="wikitable" border="1"
! colspan="3" | Comparison of MMFF94 and MM2 minimisations
|-
!Molecule
| Precursor 9
| Precursor 10
|-
!MM2 minimised Energy (kJmol<sup><-1</sup>)
|39.1215
|47.8395
|-
!MMFF94 minimised Energy (kcalmol<sup><-1</sup>)
|58.7513
|70.5377
|-
|}

===Regioselective Addition of Dichlorocarbene to a diene===
Molecule A was initially optimised using a molecular mechanics (MM2) calculation

{| style="wikitable" border="1"
|<jmol>
<jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
It was then further optimised with a MOPAC calculation, which takes into effect stereoelectronic effects. The two were then compared.

{| class="wikitable" border="1"
!colspan="3" | Comparison of two optimisation calculations
|-
! Overlay of two optimised molecules !! MM2 optimised molecule !! MOPAC Optimised Molecule
|-
|[[file:Ohboverlaydiene.png|300px]]
The MM2 optimised molecule is coloured yellow for clarity
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1mopac.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! rowspan="6" | Distances between
corresponding atoms

on the overlaid molecules (Å)
|style="text-align: center;" | C(34)-C(9)
|0.5247
|-
|style="text-align: center;" | C(26)-C(1)
|0.5246
|-
|style="text-align: center;" | H(47)-H(22)
|0.8526
|-
|style="text-align: center;" | H(38)-H(13)
|0.8524
|-
|style="text-align: center;" | Cl(37)-Cl(12)
|0.0689
|}

As can be seen by the comparison above, when using the stereoelectronic interactions, the cyclohexadiene ring on the side with the Cl atom is moved further away from the Cl using the MOPAC calculation than the MM2. This is because the electronic effects included in this calculation include the repulsion between the electron rich Chlorine atom and the electron rich double bond, whereas the MM2 calculation doesn't include this and so a symmetrical molecule is formed.

====MOs====

The MOs of the previously MOPAC optimised molecule where then calculated using Guassian (B3LYP 6-31G)
{| style="wikitable" border="1"
! Homo-1 !! colspan="2" | Homo
|-
|[[File:Ohbclhomo-1.jpg|250px]]
| <jmol>
<jmolApplet>
<title>Orbital</title><color>white</color><size>250</size>
<script>isosurface color orange purple "images/f/f2/Ohbdienemo48.cub.jvxl" translucent; </script>
<uploadedFileContents>Ohbdienemo48.cub.xyz</uploadedFileContents>
</jmolApplet>
</jmol>
|[[File:Ohbclhomo.jpg|250px]]
|-
!Lumo !! Lumo+1 !! Lumo+2
|-
|[[File:Ohbcllumo.jpg|250px]]
|[[File:Ohbcllumo+1.jpg|250px]]
|[[File:Ohbcllumo+2.jpg|250px]]
|-
|colspan="2" | [[File:Ohbclmep.jpg|300px rotate="90"]]
| [[File:Ohbclelevels.png|250px]]
|}

Molecule 2 was initially minimised using an MM2 calculation. The reactions of molecule A with an electrophile can be illustrated by taking a more advanced, quantum mechanical approach to modelling the molecule and its orbitals. This will also allow prediction of which C=C reacts with an electrophile.
Of the two alekenes, the endo is favoured rather than the exo because the cl-c sigma star orbital mixes with the exo alkene. This stabilises both orbitals, as shown by the frequency calculation having a higher value than the endo alkene, but reduces the pi bond character of the exo alkene. This is also shown by the comparative lengths of the alkene bonds - the exo is 1.3355A and the endo is 1.33190A. The cycloaddition of the carbene requires an alkene and so favours the endo alkene as it has a higher p character. The homo is also focused entirely on the endo side of the molecule, with the lumo focused mainly on the exo side. The Homo shows the high pi bond character of the endo alkene. The Homo-1 is mainly focused ont he exo alekene, so shows the pi bond character of the exo alekene. This is lower in energy and so is less likely to react with the carbene molecule.

====Glycosidation====

When the monosaccharide pyranose has an acetal in the 2 position, four different isomers can be formed, all of differing stability. These differing positions of the acetal group and its interactions with the neighbouring group means that it acts as a directing group to nucleophilic attack. With deprotonation to an oxenium cation being the initial step, the acetal group can then stabilise this to varying degrees depending on its position. Due to the Sn1 nature of the glycosidation nucleophilic attack occurring, the access of the nucleophile to the sigma* orbital of the carbon is crucial, and this depends on the Burgi-Dunitz angle of 107<ref> H. B. Bürgi, J. D. Dunitz, J. M. Lehn, G. Wipff (1974). "Stereochemistry of reaction paths at carbonyl centres". Tetrahedron 30 (12): 1563–1572. doi:10.1016/S0040-4020(01)90678-7</ref>.
Two sets of calculations were performed; initially using an MM2 forcefield, and then with using the MOPAC approach. While both approaches showed a similar trend, the benefit of the MOPAC, to make and break bond meant that the structures formed by this minimisation resembled the transition state a lot more closely than those formed by the MM2.
As shown by the table, below, all of the initial cations are at a lower energy than the intermediate forms, however the structures differ slightly depending on whether an MM2 or MOPAC minimisation was performed; the MOPAC structures much more closely resemble the transition states.
The differences in energy can be directly related to the amount of strain present within the molecule and the repulsion between the oxygen atoms. The large amount of strain present in the intermediates, particularly of molecule 2, mean that they have a lot higher energy. A notable differences is that the MM2 struggles to accurately deal with the oxenium cation, whereas the MOPAC produces a more lifelike picture in this area.
The glycosidation mainly produces the trans isomers, ie molecules going through the pathways of molecules 1 & 4. This is predicted well by the computational methods used, with both the initial molecules and the intermediates being lower in energy and having lower anomeric carbon-acetal oxygen distances.

=====Mechanisms=====

[[file:Ohbglymech.gif|800px]]

{|class="wikitable" border="2"
!rowspan="5" |Initial molecule
!colspan="2" | Conformation
|1
|2
|3
|4
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2amm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 11.5430
| 46.2672
| 35.5277
| 29.5144
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -90.51343
| -70.57703
| -72.56010
| -85.04737
|-
!rowspan="5" |Intermediate
!colspan="2" | Conformation
|chemdraw
|chemdraw
|chemdraw
|chemdraw
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2Bmm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 28.4913
| 43.2706
| 41.0918
| 31.8763
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -91.66112
| -66.72331
| -84.44899
| -88.08089

|-
|}

==Comparison of coumpational results to a molecule from literature.==

===Taxol intermediate===

Computational chemistry can be a powerful tool in the analysis and reproduction of spectra. in this exercise, literature values and spectra are compared to computed data and the effectiveness and accuracy of both methods is compared and contrasted.

A different intermediate in the synthesis of taxol was optimised using MM2 to produce the structure (right) with a total energy of 66.7072kcal<sup>-1</sup>
{|class="wikitable border="1"
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
This file was then optimised using Guassian and B3LYP 6-31G(d,p) basis set. The resulting file was then resubmitted to the SCAN cluster for computation of the nmr spectrum using these keywords # mpw1pw91/6-31G(d,p) NMR SCRF=(CPCM,Solvent=chloroform). These results were then compared to those found in the literature<ref>#L. Paquette, N. A. Pegg, D. Toops, G. D. Maynard, R. D. Rogers, ''J. Am. Chem. Soc.,'', '''1990''', ''112'', 277-283. {{DOI|10.1021/ja00157a043}}</ref>.
The results are below. As can be seen by this comparison chart, in general there is very good agreement between the predicted and measured shift values. With the only major discrepancy being at Carbon 16.

This however, can be resolved. The large distance is probably to do with this carbon being bonded to two sulphur atoms. The 6-31G(d,p) basis set is not very good at approximating, and hence optimising sulphur molecules. This is because Sulphur contains f type functions, of which there are 7. However there are 10<ref>SIMPLIFIED INTRODUCTION TO AB INITIO
BASIS SETS. TERMS AND NOTATION.
Jan K. Labanowski, Ohio Supercomputer Center,
1224 Kinnear Rd., Columbus, OH 43212-1163,</ref> possible Guassians, and so an element of contamination from the 4p orbitals is brought in. As the 6-31G(d,p) does not containg any f functions, it is not that good at predicting the behaviour of the sulphur molecule to the level required by the nmr calculation. Despite all of this, the shift values are still similar.
{|class="wikitable" border="2"
!Atom number !! Calculated ppm value !! Lit. ppm value
|-
| 1 | 27.5886 | 25.66
|-
| 2 | 31.6721 | 28.79
|-
| 3 | 52.6851 | 48.5
|-
| 4 | 146.8944 | 144.63
|-
| 5 | 51.4817 | 46.8
|-
| 6 | 20.6456 | 18.71|
|-
| 7 | 27.0826 | 23.86
|-
| 8 | 125.7193 | 125.33
|-
| 9 | 50.5885 | 45.76
|-
| 10 | 218.6545 | 218.79
|-
| colspan="3" | Oxygen
|-
| 12 | 54.1882 | 52.52
|-
| 13 | 30.8219 | 28.29
|-
| 14 | 63.85 | 56.19
|-
| 15 | 29.5406 | 26.88
|-
| 16 | 89.99 | 72.88
|-
| 17 | 48.9728 | 39.8
|-
| 18 | 24.6905 | 20.96
|-
| 19 | 41.3115 | 32.66
|-
| 21 | 44.3139 | 35.85
|-
| 22 | 45.5337 | 38.81
|}

===Literature Molecule===

In the synthesis of molecule A (right), using Kobayashi aldol chemistry, two stereoisomers are produced. Initially, the syn isomer is formed, with a diasteromic ratio of 1:14, and via a similar synthetic route, the anti isomer is also produced, with a high dr of 1:>50. The high stereoselectivity of both of these reactions is an important step in the synthesis of enationmerically pure natural products.
Initiallyu the models were optimised using an MM2 optimisation within ChemBio 12.0. They were then further optimised using an RB3LYP-6-31G(d,p) method and basis set. After the optimisation, and checking to see that the the two molecules were still distinct, with one syn and one anti form, they were submitted for nmr analysis, to produce a predicted nmr. This was then compared with the reported nmr, with a view to see if the assignments and conclusions made in the literature were correct. There was a good correlations between the predicted and measured nmr peaks, with deviations, as show below, of less than 1ppm for the H nmr and less than 10ppm for the <sup>13</sup>C nmr.
[[File:Ohbccomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each carbon atom]]
[[File:Ohbhcomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each Hydrogen atom]]

This correlation helps confirm that the structures are correct; the different enantiomers are differentiated and assigned correctly. If they were not, and the calculated syn nmr is compared to the measured anti nmr, and vice versa, larger differences are noted. This is highlighted on the graph below. The blue and red graphs are the correctly assigned and matched nmrs, the green and purple nmrs are if they are assigned incorrectly. It can clearly be seen that the green and purple line are consistently higher than their counterparts.
[[file:Ohbcomparisonnmr.png|thumb|900px|none|left|Comparison of correct and incorrect assignment for the two conformers]]
Within the literature all of the hydrogens and carbons are assigned, with the exception of Hydrogen 48. This is because this is a labile proton and so does not show up on measured nmrs due to rapid exchange with the deuterium in the deuterated solvent. However the calculated spectra does not take this into account and so displays the shift value for this hydrogen.

The computed IR spectra are very similar for the two molecules. The OH stretch is increased by 30cm<sup>-1</sup> in the syn form of the molecule and the CH bend region between 1000-1500cm<sup>-1</sup> is also significantly different. This acsn be rationalised by the different atomic orbital overlaps that are occuring due to the different positioning of the methyl group.

As both molecules are chiral, they both rotate light in opposite directions. However due to the large size of this molecule and although it is relatively conformationally limited due to the double bond and ring, the calculation for the syn and anti variants did not converge after 48 a 48 hour run on the SCAN.

==References==
<references></references>

Rep:Mod:benton2

2013-02-08T14:32:39Z

Ohb09: /* Taxol intermediate */

=Module 1 - Intro=
In this experiment, MM2 is compared to the more advanced MOPAC minimisation technique. A minimised molecule is then analysed and compared to literature.
Molecular mechanics, used here in its MM2 form is a very good first order approximation. Using data from previous experiments and breaking down the overall energy into different categories, such as van der Waals interaction, dipole-dipole, and bending before summing them to provide an overall energy is a very useful and more importantly quick method to calculate a molecules energy. The energy of molecule can then be iteratively reduced by tweaking the position of the atoms and conformations, providing a low energy structure. However it does have its limitations. Firstly, because of the large approximations used, the method is liable to fall, and remain, in an initial, smaller, potential well at a higher energy than the minimum possible. This can be overcome by carefully arranging the molecule by the user of the program to avoid these early, high energy minima, but requires a lot of rearrangement and prioir knowledge of low energy arrangements. As MM2 uses previously aquired data, it is also not that useful in determining new structures, or functional groups for which it does not have the data for.
MOPAC uses a different approach for minimisation. It uses semi empirical quantum chemistry functions to determine the energy of a molecule. This allows more advanced effects to be included in the calculation and allows for analysis of the neighbouring group effect in sacchardie chemistry and regioselectivity effects, as studied here.
Computational chemistry can also predict spectra, and in the last part of the experiment predicted spectra are compared to literature and the results analysed.

==Week 1==

===Hydrogenation of the Cyclopentadiene Dimer===
The endo dimer is primarily produced when cyclopentadiene dimerises, in a ratio of 99.5% to 0.5% <ref>
Małgorzata E Jamróz, Sławomir Gałka, Jan Cz Dobrowolski,
On dicyclopentadiene isomers,
Journal of Molecular Structure: THEOCHEM,
Volume 634, Issues 1–3, 5 September 2003,
Pages 225-233, ISSN 0166-1280,
<DOI|10.1016/S0166-1280(03)00348-8>
</ref>(at least when thermally initiated; photo initiation produces a racemic mixture of the two isomers<ref>
The Photosensitited Dimerization of Cyclopentadiene
Nicholas J. Turro and George S. Hammond
Journal of the American Chemical Society 1962 84 (14), 2841-2842
<DOI|10.1021/ja00873a050>
</ref>)
{| class="wikitable" border="1"

! rowspan="2" | Molecule
|style="text-align: center;" |Exo
|style="text-align: center;" |Endo
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbexodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Total E (kcal/mol)
|33.9975
|31.8764
|-
|}
[[file:Endoexoohb.bmp|thumb|left|500px]]
The small energy difference calculated by the MM2 forcefield does not highlight why the endo for is favoured over the exo form as it shows the exo form is lower in energy. While the difference between the two energies is relatively trivial, the high enationmeric excess of the products suggest that this is only part of the story, and suggest that this reaction is under kinetic rather than thermodynamic control.<ref> W.C.Herndon, C.R.Grayson, J.M.Manion; "Retro-Diels-Alder reactions. III. Kinetics of the thermal decompositions of exo- and endo-dicyclopentadiene" J. Org. Chem.; 1967, 32 (3); 526-529.DOI:10.1021/jo01278a003</ref> Being under kinetic control would imply the activation energy, and hence transition state, for the endo species is lower than the exo form and so the endo enantiomer is formed faster. This can be rationalised by looking at the orbital interactions in the two transition states.

The endo transition state is stabilised by the secondary favourable overlap whereas in the exo form there is no such overlap to stabilised the molecule meaning that the transition state is a higher energy, and so is less favourable. This cannot be handled by the simple MM2 calculation however.

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" colspan="2" |Different hydrogenation sites
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh3.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh4.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|1.2489
|1.1303
|-
!Bend
|19.1608
|13.10259
|-
!Torsion
|11.0730
|12.4118
|-
!VDW
|5.7962
|4.4398
|-
!Dipole-Dipole
|0.1622
|0.1410
|-
!Total E (kcal/mol)
|34.9643
|29.2475
|-
|}

The site of initial hydrogenation of the endo dimer can also be determined by calculating the energies of the two possible isomers. From these calculations it is clear that the second molecule is favoured more, as it is ~5.5kcalmol<sup>-1</sup> more stable. The bending energy in both of these molecules is the major difference. This manifests itself in the amount that the atoms are ebent away from their ideal positions, which is 109.5 for an sp3 carbon and 120 for an sp2 carbon. Across all of the key bonds, the second isomer has bond angles that are closer to the ideal than the first isomer; in particular the C-C=C bond angles; in the first molecule they are 107.6 and in the second 112.8. This difference of five degrees is enough to significantly stabilise the second isomer, making hydrogenation at that site the more preferable.

===Atropisomerism in an Intermediate related to the synthesis of Taxol===
In the complete synthesis of Taxol, and important cancer fighting drug, proposed by Pacquette <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 10.1016/S0040-4039(00)92617-0</ref> a key intermediate is either "Precursor 9" or "Precursor 10".

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" |Precursor 10
|style="text-align: center;" |Precursor 9
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol9.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol10.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|2.4687
|2.7846
|-
!Bend
|10.5555
|16.5411
|-
!Torsion
|17.4240
|18.2518
|-
!VDW
|13.1930
|13.1096
|-
!Dipole-Dipole
| -1.8818
| -1.7248
|-
!Total E (kcal/mol)
|39.1215
|47.8395
|-
|}
Precursor 9 and 10 are synthesised using a reversible oxy-Cope rearrangement as demonstrated below. As this process is in equilibrium that, with precursor 10 being more stable, it is predicted that this isomer will be the one produced as all of the molecules attempt to reduce the energy. As analysis of the individual energy componenets shows, this arrangement is a lot less strained than Precursor nine, which requires a lot more bending energy.

The molecule was then optimised with an MMFF94. Rather than rely on a large set of experimentally determined parameters like MM2, MMFF94 minimises the potential of each atom iteratively, attempting to minimise the whole molecule. Although the values produced for these two methods cannot be directly compared, they both correctly identify the correct altropisomer as being lower in energy.
{|class="wikitable" border="1"
! colspan="3" | Comparison of MMFF94 and MM2 minimisations
|-
!Molecule
| Precursor 9
| Precursor 10
|-
!MM2 minimised Energy (kJmol<sup><-1</sup>)
|39.1215
|47.8395
|-
!MMFF94 minimised Energy (kcalmol<sup><-1</sup>)
|58.7513
|70.5377
|-
|}

===Regioselective Addition of Dichlorocarbene to a diene===
Molecule A was initially optimised using a molecular mechanics (MM2) calculation

{| style="wikitable" border="1"
|<jmol>
<jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
It was then further optimised with a MOPAC calculation, which takes into effect stereoelectronic effects. The two were then compared.

{| class="wikitable" border="1"
!colspan="3" | Comparison of two optimisation calculations
|-
! Overlay of two optimised molecules !! MM2 optimised molecule !! MOPAC Optimised Molecule
|-
|[[file:Ohboverlaydiene.png|300px]]
The MM2 optimised molecule is coloured yellow for clarity
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1mopac.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! rowspan="6" | Distances between
corresponding atoms

on the overlaid molecules (Å)
|style="text-align: center;" | C(34)-C(9)
|0.5247
|-
|style="text-align: center;" | C(26)-C(1)
|0.5246
|-
|style="text-align: center;" | H(47)-H(22)
|0.8526
|-
|style="text-align: center;" | H(38)-H(13)
|0.8524
|-
|style="text-align: center;" | Cl(37)-Cl(12)
|0.0689
|}

As can be seen by the comparison above, when using the stereoelectronic interactions, the cyclohexadiene ring on the side with the Cl atom is moved further away from the Cl using the MOPAC calculation than the MM2. This is because the electronic effects included in this calculation include the repulsion between the electron rich Chlorine atom and the electron rich double bond, whereas the MM2 calculation doesn't include this and so a symmetrical molecule is formed.

====MOs====

The MOs of the previously MOPAC optimised molecule where then calculated using Guassian (B3LYP 6-31G)
{| style="wikitable" border="1"
! Homo-1 !! colspan="2" | Homo
|-
|[[File:Ohbclhomo-1.jpg|250px]]
| <jmol>
<jmolApplet>
<title>Orbital</title><color>white</color><size>250</size>
<script>isosurface color orange purple "images/f/f2/Ohbdienemo48.cub.jvxl" translucent; </script>
<uploadedFileContents>Ohbdienemo48.cub.xyz</uploadedFileContents>
</jmolApplet>
</jmol>
|[[File:Ohbclhomo.jpg|250px]]
|-
!Lumo !! Lumo+1 !! Lumo+2
|-
|[[File:Ohbcllumo.jpg|250px]]
|[[File:Ohbcllumo+1.jpg|250px]]
|[[File:Ohbcllumo+2.jpg|250px]]
|-
|colspan="2" | [[File:Ohbclmep.jpg|300px rotate="90"]]
| [[File:Ohbclelevels.png|250px]]
|}

Molecule 2 was initially minimised using an MM2 calculation. The reactions of molecule A with an electrophile can be illustrated by taking a more advanced, quantum mechanical approach to modelling the molecule and its orbitals. This will also allow prediction of which C=C reacts with an electrophile.
Of the two alekenes, the endo is favoured rather than the exo because the cl-c sigma star orbital mixes with the exo alkene. This stabilises both orbitals, as shown by the frequency calculation having a higher value than the endo alkene, but reduces the pi bond character of the exo alkene. This is also shown by the comparative lengths of the alkene bonds - the exo is 1.3355A and the endo is 1.33190A. The cycloaddition of the carbene requires an alkene and so favours the endo alkene as it has a higher p character. The homo is also focused entirely on the endo side of the molecule, with the lumo focused mainly on the exo side. The Homo shows the high pi bond character of the endo alkene. The Homo-1 is mainly focused ont he exo alekene, so shows the pi bond character of the exo alekene. This is lower in energy and so is less likely to react with the carbene molecule.

====Glycosidation====

When the monosaccharide pyranose has an acetal in the 2 position, four different isomers can be formed, all of differing stability. These differing positions of the acetal group and its interactions with the neighbouring group means that it acts as a directing group to nucleophilic attack. With deprotonation to an oxenium cation being the initial step, the acetal group can then stabilise this to varying degrees depending on its position. Due to the Sn1 nature of the glycosidation nucleophilic attack occurring, the access of the nucleophile to the sigma* orbital of the carbon is crucial, and this depends on the Burgi-Dunitz angle of 107<ref> H. B. Bürgi, J. D. Dunitz, J. M. Lehn, G. Wipff (1974). "Stereochemistry of reaction paths at carbonyl centres". Tetrahedron 30 (12): 1563–1572. doi:10.1016/S0040-4020(01)90678-7</ref>.
Two sets of calculations were performed; initially using an MM2 forcefield, and then with using the MOPAC approach. While both approaches showed a similar trend, the benefit of the MOPAC, to make and break bond meant that the structures formed by this minimisation resembled the transition state a lot more closely than those formed by the MM2.
As shown by the table, below, all of the initial cations are at a lower energy than the intermediate forms, however the structures differ slightly depending on whether an MM2 or MOPAC minimisation was performed; the MOPAC structures much more closely resemble the transition states.
The differences in energy can be directly related to the amount of strain present within the molecule and the repulsion between the oxygen atoms. The large amount of strain present in the intermediates, particularly of molecule 2, mean that they have a lot higher energy. A notable differences is that the MM2 struggles to accurately deal with the oxenium cation, whereas the MOPAC produces a more lifelike picture in this area.
The glycosidation mainly produces the trans isomers, ie molecules going through the pathways of molecules 1 & 4. This is predicted well by the computational methods used, with both the initial molecules and the intermediates being lower in energy and having lower anomeric carbon-acetal oxygen distances.

=====Mechanisms=====

[[file:Ohbglymech.gif|800px]]

{|class="wikitable" border="2"
!rowspan="5" |Initial molecule
!colspan="2" | Conformation
|1
|2
|3
|4
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2amm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 11.5430
| 46.2672
| 35.5277
| 29.5144
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -90.51343
| -70.57703
| -72.56010
| -85.04737
|-
!rowspan="5" |Intermediate
!colspan="2" | Conformation
|chemdraw
|chemdraw
|chemdraw
|chemdraw
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2Bmm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 28.4913
| 43.2706
| 41.0918
| 31.8763
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -91.66112
| -66.72331
| -84.44899
| -88.08089

|-
|}

==Comparison of coumpational results to a molecule from literature.==

===Taxol intermediate===

Computational chemistry can be a powerful tool in the analysis and reproduction of spectra. in this exercise, literature values and spectra are compared to computed data and the effectiveness and accuracy of both methods is compared and contrasted.

A different intermediate in the synthesis of taxol was optimised using MM2 to produce the structure (right) with a total energy of 66.7072kcal<sup>-1</sup>
{|class="wikitable border="1"
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
This file was then optimised using Guassian and B3LYP 6-31G(d,p) basis set. The resulting file was then resubmitted to the SCAN cluster for computation of the nmr spectrum using these keywords # mpw1pw91/6-31G(d,p) NMR SCRF=(CPCM,Solvent=chloroform). These results were then compared to those found in the literature<ref>#L. Paquette, N. A. Pegg, D. Toops, G. D. Maynard, R. D. Rogers, ''J. Am. Chem. Soc.,'', '''1990''', ''112'', 277-283. {{DOI|10.1021/ja00157a043}}</ref>.
The results are below. As can be seen by this comparison chart, in general there is very good agreement between the predicted and measured shift values. With the only major discrepancy being at Carbon 16.

This however, can be resolved. The large distance is probably to do with this carbon being bonded to two sulphur atoms. The 6-31G(d,p) basis set is not very good at approximating, and hence optimising sulphur molecules. This is because Sulphur contains f type functions, of which there are 7. However there are 10<ref>SIMPLIFIED INTRODUCTION TO AB INITIO
BASIS SETS. TERMS AND NOTATION.
Jan K. Labanowski, Ohio Supercomputer Center,
1224 Kinnear Rd., Columbus, OH 43212-1163,</ref> possible Guassians, and so an element of contamination from the 4p orbitals is brought in. As the 6-31G(d,p) does not containg any f functions, it is not that good at predicting the behaviour of the sulphur molecule to the level required by the nmr calculation. Despite all of this, the shift values are still similar.
{|class="wikitable border="2"
!Atom number !! Calculated ppm value !! Lit. ppm value
|-
|1 | 27.5886 | 25.66
|-
|2 | 31.6721 | 28.79
|-
|3 | 52.6851 | 48.5
|-
|4 | 146.8944 | 144.63
|-
|5 | 51.4817 | 46.8
|-
|6 | 20.6456 | 18.71|
|-
|7 | 27.0826 | 23.86
|-
|8 | 125.7193 | 125.33
|-
|9 | 50.5885 | 45.76
|-
|10 | 218.6545 | 218.79
|-
|colspan="3"|Oxygen
|-
|12 | 54.1882 | 52.52
|-
|13 | 30.8219 | 28.29
|-
|14 | 63.85 | 56.19
|-
|15 | 29.5406 | 26.88
|-
|16 | 89.99 | 72.88
|-
|17 | 48.9728 | 39.8
|-
|18 | 24.6905 | 20.96
|-
|19 | 41.3115 | 32.66
|-
|21 | 44.3139 | 35.85
|-
|22 | 45.5337 | 38.81
|}

===Literature Molecule===

In the synthesis of molecule A (right), using Kobayashi aldol chemistry, two stereoisomers are produced. Initially, the syn isomer is formed, with a diasteromic ratio of 1:14, and via a similar synthetic route, the anti isomer is also produced, with a high dr of 1:>50. The high stereoselectivity of both of these reactions is an important step in the synthesis of enationmerically pure natural products.
Initiallyu the models were optimised using an MM2 optimisation within ChemBio 12.0. They were then further optimised using an RB3LYP-6-31G(d,p) method and basis set. After the optimisation, and checking to see that the the two molecules were still distinct, with one syn and one anti form, they were submitted for nmr analysis, to produce a predicted nmr. This was then compared with the reported nmr, with a view to see if the assignments and conclusions made in the literature were correct. There was a good correlations between the predicted and measured nmr peaks, with deviations, as show below, of less than 1ppm for the H nmr and less than 10ppm for the <sup>13</sup>C nmr.
[[File:Ohbccomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each carbon atom]]
[[File:Ohbhcomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each Hydrogen atom]]

This correlation helps confirm that the structures are correct; the different enantiomers are differentiated and assigned correctly. If they were not, and the calculated syn nmr is compared to the measured anti nmr, and vice versa, larger differences are noted. This is highlighted on the graph below. The blue and red graphs are the correctly assigned and matched nmrs, the green and purple nmrs are if they are assigned incorrectly. It can clearly be seen that the green and purple line are consistently higher than their counterparts.
[[file:Ohbcomparisonnmr.png|thumb|900px|none|left|Comparison of correct and incorrect assignment for the two conformers]]
Within the literature all of the hydrogens and carbons are assigned, with the exception of Hydrogen 48. This is because this is a labile proton and so does not show up on measured nmrs due to rapid exchange with the deuterium in the deuterated solvent. However the calculated spectra does not take this into account and so displays the shift value for this hydrogen.

The computed IR spectra are very similar for the two molecules. The OH stretch is increased by 30cm<sup>-1</sup> in the syn form of the molecule and the CH bend region between 1000-1500cm<sup>-1</sup> is also significantly different. This acsn be rationalised by the different atomic orbital overlaps that are occuring due to the different positioning of the methyl group.

As both molecules are chiral, they both rotate light in opposite directions. However due to the large size of this molecule and although it is relatively conformationally limited due to the double bond and ring, the calculation for the syn and anti variants did not converge after 48 a 48 hour run on the SCAN.

==References==
<references></references>

Rep:Mod:benton2

2013-02-08T14:30:46Z

Ohb09:

=Module 1 - Intro=
In this experiment, MM2 is compared to the more advanced MOPAC minimisation technique. A minimised molecule is then analysed and compared to literature.
Molecular mechanics, used here in its MM2 form is a very good first order approximation. Using data from previous experiments and breaking down the overall energy into different categories, such as van der Waals interaction, dipole-dipole, and bending before summing them to provide an overall energy is a very useful and more importantly quick method to calculate a molecules energy. The energy of molecule can then be iteratively reduced by tweaking the position of the atoms and conformations, providing a low energy structure. However it does have its limitations. Firstly, because of the large approximations used, the method is liable to fall, and remain, in an initial, smaller, potential well at a higher energy than the minimum possible. This can be overcome by carefully arranging the molecule by the user of the program to avoid these early, high energy minima, but requires a lot of rearrangement and prioir knowledge of low energy arrangements. As MM2 uses previously aquired data, it is also not that useful in determining new structures, or functional groups for which it does not have the data for.
MOPAC uses a different approach for minimisation. It uses semi empirical quantum chemistry functions to determine the energy of a molecule. This allows more advanced effects to be included in the calculation and allows for analysis of the neighbouring group effect in sacchardie chemistry and regioselectivity effects, as studied here.
Computational chemistry can also predict spectra, and in the last part of the experiment predicted spectra are compared to literature and the results analysed.

==Week 1==

===Hydrogenation of the Cyclopentadiene Dimer===
The endo dimer is primarily produced when cyclopentadiene dimerises, in a ratio of 99.5% to 0.5% <ref>
Małgorzata E Jamróz, Sławomir Gałka, Jan Cz Dobrowolski,
On dicyclopentadiene isomers,
Journal of Molecular Structure: THEOCHEM,
Volume 634, Issues 1–3, 5 September 2003,
Pages 225-233, ISSN 0166-1280,
<DOI|10.1016/S0166-1280(03)00348-8>
</ref>(at least when thermally initiated; photo initiation produces a racemic mixture of the two isomers<ref>
The Photosensitited Dimerization of Cyclopentadiene
Nicholas J. Turro and George S. Hammond
Journal of the American Chemical Society 1962 84 (14), 2841-2842
<DOI|10.1021/ja00873a050>
</ref>)
{| class="wikitable" border="1"

! rowspan="2" | Molecule
|style="text-align: center;" |Exo
|style="text-align: center;" |Endo
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbexodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Total E (kcal/mol)
|33.9975
|31.8764
|-
|}
[[file:Endoexoohb.bmp|thumb|left|500px]]
The small energy difference calculated by the MM2 forcefield does not highlight why the endo for is favoured over the exo form as it shows the exo form is lower in energy. While the difference between the two energies is relatively trivial, the high enationmeric excess of the products suggest that this is only part of the story, and suggest that this reaction is under kinetic rather than thermodynamic control.<ref> W.C.Herndon, C.R.Grayson, J.M.Manion; "Retro-Diels-Alder reactions. III. Kinetics of the thermal decompositions of exo- and endo-dicyclopentadiene" J. Org. Chem.; 1967, 32 (3); 526-529.DOI:10.1021/jo01278a003</ref> Being under kinetic control would imply the activation energy, and hence transition state, for the endo species is lower than the exo form and so the endo enantiomer is formed faster. This can be rationalised by looking at the orbital interactions in the two transition states.

The endo transition state is stabilised by the secondary favourable overlap whereas in the exo form there is no such overlap to stabilised the molecule meaning that the transition state is a higher energy, and so is less favourable. This cannot be handled by the simple MM2 calculation however.

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" colspan="2" |Different hydrogenation sites
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh3.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh4.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|1.2489
|1.1303
|-
!Bend
|19.1608
|13.10259
|-
!Torsion
|11.0730
|12.4118
|-
!VDW
|5.7962
|4.4398
|-
!Dipole-Dipole
|0.1622
|0.1410
|-
!Total E (kcal/mol)
|34.9643
|29.2475
|-
|}

The site of initial hydrogenation of the endo dimer can also be determined by calculating the energies of the two possible isomers. From these calculations it is clear that the second molecule is favoured more, as it is ~5.5kcalmol<sup>-1</sup> more stable. The bending energy in both of these molecules is the major difference. This manifests itself in the amount that the atoms are ebent away from their ideal positions, which is 109.5 for an sp3 carbon and 120 for an sp2 carbon. Across all of the key bonds, the second isomer has bond angles that are closer to the ideal than the first isomer; in particular the C-C=C bond angles; in the first molecule they are 107.6 and in the second 112.8. This difference of five degrees is enough to significantly stabilise the second isomer, making hydrogenation at that site the more preferable.

===Atropisomerism in an Intermediate related to the synthesis of Taxol===
In the complete synthesis of Taxol, and important cancer fighting drug, proposed by Pacquette <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 10.1016/S0040-4039(00)92617-0</ref> a key intermediate is either "Precursor 9" or "Precursor 10".

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" |Precursor 10
|style="text-align: center;" |Precursor 9
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol9.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol10.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|2.4687
|2.7846
|-
!Bend
|10.5555
|16.5411
|-
!Torsion
|17.4240
|18.2518
|-
!VDW
|13.1930
|13.1096
|-
!Dipole-Dipole
| -1.8818
| -1.7248
|-
!Total E (kcal/mol)
|39.1215
|47.8395
|-
|}
Precursor 9 and 10 are synthesised using a reversible oxy-Cope rearrangement as demonstrated below. As this process is in equilibrium that, with precursor 10 being more stable, it is predicted that this isomer will be the one produced as all of the molecules attempt to reduce the energy. As analysis of the individual energy componenets shows, this arrangement is a lot less strained than Precursor nine, which requires a lot more bending energy.

The molecule was then optimised with an MMFF94. Rather than rely on a large set of experimentally determined parameters like MM2, MMFF94 minimises the potential of each atom iteratively, attempting to minimise the whole molecule. Although the values produced for these two methods cannot be directly compared, they both correctly identify the correct altropisomer as being lower in energy.
{|class="wikitable" border="1"
! colspan="3" | Comparison of MMFF94 and MM2 minimisations
|-
!Molecule
| Precursor 9
| Precursor 10
|-
!MM2 minimised Energy (kJmol<sup><-1</sup>)
|39.1215
|47.8395
|-
!MMFF94 minimised Energy (kcalmol<sup><-1</sup>)
|58.7513
|70.5377
|-
|}

===Regioselective Addition of Dichlorocarbene to a diene===
Molecule A was initially optimised using a molecular mechanics (MM2) calculation

{| style="wikitable" border="1"
|<jmol>
<jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
It was then further optimised with a MOPAC calculation, which takes into effect stereoelectronic effects. The two were then compared.

{| class="wikitable" border="1"
!colspan="3" | Comparison of two optimisation calculations
|-
! Overlay of two optimised molecules !! MM2 optimised molecule !! MOPAC Optimised Molecule
|-
|[[file:Ohboverlaydiene.png|300px]]
The MM2 optimised molecule is coloured yellow for clarity
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1mopac.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! rowspan="6" | Distances between
corresponding atoms

on the overlaid molecules (Å)
|style="text-align: center;" | C(34)-C(9)
|0.5247
|-
|style="text-align: center;" | C(26)-C(1)
|0.5246
|-
|style="text-align: center;" | H(47)-H(22)
|0.8526
|-
|style="text-align: center;" | H(38)-H(13)
|0.8524
|-
|style="text-align: center;" | Cl(37)-Cl(12)
|0.0689
|}

As can be seen by the comparison above, when using the stereoelectronic interactions, the cyclohexadiene ring on the side with the Cl atom is moved further away from the Cl using the MOPAC calculation than the MM2. This is because the electronic effects included in this calculation include the repulsion between the electron rich Chlorine atom and the electron rich double bond, whereas the MM2 calculation doesn't include this and so a symmetrical molecule is formed.

====MOs====

The MOs of the previously MOPAC optimised molecule where then calculated using Guassian (B3LYP 6-31G)
{| style="wikitable" border="1"
! Homo-1 !! colspan="2" | Homo
|-
|[[File:Ohbclhomo-1.jpg|250px]]
| <jmol>
<jmolApplet>
<title>Orbital</title><color>white</color><size>250</size>
<script>isosurface color orange purple "images/f/f2/Ohbdienemo48.cub.jvxl" translucent; </script>
<uploadedFileContents>Ohbdienemo48.cub.xyz</uploadedFileContents>
</jmolApplet>
</jmol>
|[[File:Ohbclhomo.jpg|250px]]
|-
!Lumo !! Lumo+1 !! Lumo+2
|-
|[[File:Ohbcllumo.jpg|250px]]
|[[File:Ohbcllumo+1.jpg|250px]]
|[[File:Ohbcllumo+2.jpg|250px]]
|-
|colspan="2" | [[File:Ohbclmep.jpg|300px rotate="90"]]
| [[File:Ohbclelevels.png|250px]]
|}

Molecule 2 was initially minimised using an MM2 calculation. The reactions of molecule A with an electrophile can be illustrated by taking a more advanced, quantum mechanical approach to modelling the molecule and its orbitals. This will also allow prediction of which C=C reacts with an electrophile.
Of the two alekenes, the endo is favoured rather than the exo because the cl-c sigma star orbital mixes with the exo alkene. This stabilises both orbitals, as shown by the frequency calculation having a higher value than the endo alkene, but reduces the pi bond character of the exo alkene. This is also shown by the comparative lengths of the alkene bonds - the exo is 1.3355A and the endo is 1.33190A. The cycloaddition of the carbene requires an alkene and so favours the endo alkene as it has a higher p character. The homo is also focused entirely on the endo side of the molecule, with the lumo focused mainly on the exo side. The Homo shows the high pi bond character of the endo alkene. The Homo-1 is mainly focused ont he exo alekene, so shows the pi bond character of the exo alekene. This is lower in energy and so is less likely to react with the carbene molecule.

====Glycosidation====

When the monosaccharide pyranose has an acetal in the 2 position, four different isomers can be formed, all of differing stability. These differing positions of the acetal group and its interactions with the neighbouring group means that it acts as a directing group to nucleophilic attack. With deprotonation to an oxenium cation being the initial step, the acetal group can then stabilise this to varying degrees depending on its position. Due to the Sn1 nature of the glycosidation nucleophilic attack occurring, the access of the nucleophile to the sigma* orbital of the carbon is crucial, and this depends on the Burgi-Dunitz angle of 107<ref> H. B. Bürgi, J. D. Dunitz, J. M. Lehn, G. Wipff (1974). "Stereochemistry of reaction paths at carbonyl centres". Tetrahedron 30 (12): 1563–1572. doi:10.1016/S0040-4020(01)90678-7</ref>.
Two sets of calculations were performed; initially using an MM2 forcefield, and then with using the MOPAC approach. While both approaches showed a similar trend, the benefit of the MOPAC, to make and break bond meant that the structures formed by this minimisation resembled the transition state a lot more closely than those formed by the MM2.
As shown by the table, below, all of the initial cations are at a lower energy than the intermediate forms, however the structures differ slightly depending on whether an MM2 or MOPAC minimisation was performed; the MOPAC structures much more closely resemble the transition states.
The differences in energy can be directly related to the amount of strain present within the molecule and the repulsion between the oxygen atoms. The large amount of strain present in the intermediates, particularly of molecule 2, mean that they have a lot higher energy. A notable differences is that the MM2 struggles to accurately deal with the oxenium cation, whereas the MOPAC produces a more lifelike picture in this area.
The glycosidation mainly produces the trans isomers, ie molecules going through the pathways of molecules 1 & 4. This is predicted well by the computational methods used, with both the initial molecules and the intermediates being lower in energy and having lower anomeric carbon-acetal oxygen distances.

=====Mechanisms=====

[[file:Ohbglymech.gif|800px]]

{|class="wikitable" border="2"
!rowspan="5" |Initial molecule
!colspan="2" | Conformation
|1
|2
|3
|4
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2amm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 11.5430
| 46.2672
| 35.5277
| 29.5144
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -90.51343
| -70.57703
| -72.56010
| -85.04737
|-
!rowspan="5" |Intermediate
!colspan="2" | Conformation
|chemdraw
|chemdraw
|chemdraw
|chemdraw
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2Bmm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 28.4913
| 43.2706
| 41.0918
| 31.8763
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -91.66112
| -66.72331
| -84.44899
| -88.08089

|-
|}

==Comparison of coumpational results to a molecule from literature.==

===Taxol intermediate===

Computational chemistry can be a powerful tool in the analysis and reproduction of spectra. in this exercise, literature values and spectra are compared to computed data and the effectiveness and accuracy of both methods is compared and contrasted.

A different intermediate in the synthesis of taxol was optimised using MM2 to produce the structure (right) with a total energy of 66.7072kcal<sup>-1</sup>
{|class="wikitable border="2"
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
This file was then optimised using Guassian and B3LYP 6-31G(d,p) basis set. The resulting file was then resubmitted to the SCAN cluster for computation of the nmr spectrum using these keywords # mpw1pw91/6-31G(d,p) NMR SCRF=(CPCM,Solvent=chloroform). These results were then compared to those found in the literature<ref>#L. Paquette, N. A. Pegg, D. Toops, G. D. Maynard, R. D. Rogers, ''J. Am. Chem. Soc.,'', '''1990''', ''112'', 277-283. {{DOI|10.1021/ja00157a043}}</ref>.
The results are below. As can be seen by this comparison chart, in general there is very good agreement between the predicted and measured shift values. With the only major discrepancy being at Carbon 16.

This however, can be resolved. The large distance is probably to do with this carbon being bonded to two sulphur atoms. The 6-31G(d,p) basis set is not very good at approximating, and hence optimising sulphur molecules. This is because Sulphur contains f type functions, of which there are 7. However there are 10<ref>SIMPLIFIED INTRODUCTION TO AB INITIO
BASIS SETS. TERMS AND NOTATION.
Jan K. Labanowski, Ohio Supercomputer Center,
1224 Kinnear Rd., Columbus, OH 43212-1163,</ref> possible Guassians, and so an element of contamination from the 4p orbitals is brought in. As the 6-31G(d,p) does not containg any f functions, it is not that good at predicting the behaviour of the sulphur molecule to the level required by the nmr calculation. Despite all of this, the shift values are still similar.
{|class="wikitable border="1"
!Atom number !! Calculated ppm value !! Lit. ppm value
|-
|1 |27.5886 | 25.66
|-
|2|31.6721|28.79
|-
|3|52.6851|48.5
|-
|4|146.8944|144.63
|-
|5|51.4817|46.8
|-
|6|20.6456|18.71|
|-
|7|27.0826|23.86
|-
|8|125.7193|125.33
|-
|9|50.5885|45.76
|-
|10|218.6545|218.79
|-
|colspan="3"|Oxygen
|-
|12|54.1882|52.52
|-
|13|30.8219|28.29
|-
|14|63.85|56.19
|-
|15|29.5406|26.88
|-
|16|89.99|72.88
|-
|17|48.9728|39.8
|-
|18|24.6905|20.96
|-
|19|41.3115|32.66
|-
|21|44.3139|35.85
|-
|22|45.5337|38.81
|}

===Literature Molecule===

In the synthesis of molecule A (right), using Kobayashi aldol chemistry, two stereoisomers are produced. Initially, the syn isomer is formed, with a diasteromic ratio of 1:14, and via a similar synthetic route, the anti isomer is also produced, with a high dr of 1:>50. The high stereoselectivity of both of these reactions is an important step in the synthesis of enationmerically pure natural products.
Initiallyu the models were optimised using an MM2 optimisation within ChemBio 12.0. They were then further optimised using an RB3LYP-6-31G(d,p) method and basis set. After the optimisation, and checking to see that the the two molecules were still distinct, with one syn and one anti form, they were submitted for nmr analysis, to produce a predicted nmr. This was then compared with the reported nmr, with a view to see if the assignments and conclusions made in the literature were correct. There was a good correlations between the predicted and measured nmr peaks, with deviations, as show below, of less than 1ppm for the H nmr and less than 10ppm for the <sup>13</sup>C nmr.
[[File:Ohbccomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each carbon atom]]
[[File:Ohbhcomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each Hydrogen atom]]

This correlation helps confirm that the structures are correct; the different enantiomers are differentiated and assigned correctly. If they were not, and the calculated syn nmr is compared to the measured anti nmr, and vice versa, larger differences are noted. This is highlighted on the graph below. The blue and red graphs are the correctly assigned and matched nmrs, the green and purple nmrs are if they are assigned incorrectly. It can clearly be seen that the green and purple line are consistently higher than their counterparts.
[[file:Ohbcomparisonnmr.png|thumb|900px|none|left|Comparison of correct and incorrect assignment for the two conformers]]
Within the literature all of the hydrogens and carbons are assigned, with the exception of Hydrogen 48. This is because this is a labile proton and so does not show up on measured nmrs due to rapid exchange with the deuterium in the deuterated solvent. However the calculated spectra does not take this into account and so displays the shift value for this hydrogen.

The computed IR spectra are very similar for the two molecules. The OH stretch is increased by 30cm<sup>-1</sup> in the syn form of the molecule and the CH bend region between 1000-1500cm<sup>-1</sup> is also significantly different. This acsn be rationalised by the different atomic orbital overlaps that are occuring due to the different positioning of the methyl group.

As both molecules are chiral, they both rotate light in opposite directions. However due to the large size of this molecule and although it is relatively conformationally limited due to the double bond and ring, the calculation for the syn and anti variants did not converge after 48 a 48 hour run on the SCAN.

==References==
<references></references>

Rep:Mod:benton2

2013-02-08T14:23:12Z

Ohb09: /* Taxol intermediate */

=Module 1 - Intro=
In this experiment, MM2 is compared to the more advanced MOPAC minimisation technique. A minimised molecule is then analysed and compared to literature.
Molecular mechanics, used here in its MM2 form is a very good first order approximation. Using data from previous experiments and breaking down the overall energy into different categories, such as van der Waals interaction, dipole-dipole, and bending before summing them to provide an overall energy is a very useful and more importantly quick method to calculate a molecules energy. The energy of molecule can then be iteratively reduced by tweaking the position of the atoms and conformations, providing a low energy structure. However it does have its limitations. Firstly, because of the large approximations used, the method is liable to fall, and remain, in an initial, smaller, potential well at a higher energy than the minimum possible. This can be overcome by carefully arranging the molecule by the user of the program to avoid these early, high energy minima, but requires a lot of rearrangement and prioir knowledge of low energy arrangements. As MM2 uses previously aquired data, it is also not that useful in determining new structures, or functional groups for which it does not have the data for.
MOPAC uses a different approach for minimisation. It uses semi empirical quantum chemistry functions to determine the energy of a molecule. This allows more advanced effects to be included in the calculation and allows for analysis of the neighbouring group effect in sacchardie chemistry and regioselectivity effects, as studied here.
Computational chemistry can also predict spectra, and in the last part of the experiment predicted spectra are compared to literature and the results analysed.

==Week 1==

===Hydrogenation of the Cyclopentadiene Dimer===
The endo dimer is primarily produced when cyclopentadiene dimerises, in a ratio of 99.5% to 0.5% <ref>
Małgorzata E Jamróz, Sławomir Gałka, Jan Cz Dobrowolski,
On dicyclopentadiene isomers,
Journal of Molecular Structure: THEOCHEM,
Volume 634, Issues 1–3, 5 September 2003,
Pages 225-233, ISSN 0166-1280,
<DOI|10.1016/S0166-1280(03)00348-8>
</ref>(at least when thermally initiated; photo initiation produces a racemic mixture of the two isomers<ref>
The Photosensitited Dimerization of Cyclopentadiene
Nicholas J. Turro and George S. Hammond
Journal of the American Chemical Society 1962 84 (14), 2841-2842
<DOI|10.1021/ja00873a050>
</ref>)
{| class="wikitable" border="1"

! rowspan="2" | Molecule
|style="text-align: center;" |Exo
|style="text-align: center;" |Endo
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbexodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Total E (kcal/mol)
|33.9975
|31.8764
|-
|}
[[file:Endoexoohb.bmp|thumb|left|500px]]
The small energy difference calculated by the MM2 forcefield does not highlight why the endo for is favoured over the exo form as it shows the exo form is lower in energy. While the difference between the two energies is relatively trivial, the high enationmeric excess of the products suggest that this is only part of the story, and suggest that this reaction is under kinetic rather than thermodynamic control.<ref> W.C.Herndon, C.R.Grayson, J.M.Manion; "Retro-Diels-Alder reactions. III. Kinetics of the thermal decompositions of exo- and endo-dicyclopentadiene" J. Org. Chem.; 1967, 32 (3); 526-529.DOI:10.1021/jo01278a003</ref> Being under kinetic control would imply the activation energy, and hence transition state, for the endo species is lower than the exo form and so the endo enantiomer is formed faster. This can be rationalised by looking at the orbital interactions in the two transition states.

The endo transition state is stabilised by the secondary favourable overlap whereas in the exo form there is no such overlap to stabilised the molecule meaning that the transition state is a higher energy, and so is less favourable. This cannot be handled by the simple MM2 calculation however.

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" colspan="2" |Different hydrogenation sites
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh3.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh4.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|1.2489
|1.1303
|-
!Bend
|19.1608
|13.10259
|-
!Torsion
|11.0730
|12.4118
|-
!VDW
|5.7962
|4.4398
|-
!Dipole-Dipole
|0.1622
|0.1410
|-
!Total E (kcal/mol)
|34.9643
|29.2475
|-
|}

The site of initial hydrogenation of the endo dimer can also be determined by calculating the energies of the two possible isomers. From these calculations it is clear that the second molecule is favoured more, as it is ~5.5kcalmol<sup>-1</sup> more stable. The bending energy in both of these molecules is the major difference. This manifests itself in the amount that the atoms are ebent away from their ideal positions, which is 109.5 for an sp3 carbon and 120 for an sp2 carbon. Across all of the key bonds, the second isomer has bond angles that are closer to the ideal than the first isomer; in particular the C-C=C bond angles; in the first molecule they are 107.6 and in the second 112.8. This difference of five degrees is enough to significantly stabilise the second isomer, making hydrogenation at that site the more preferable.

===Atropisomerism in an Intermediate related to the synthesis of Taxol===
In the complete synthesis of Taxol, and important cancer fighting drug, proposed by Pacquette <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 10.1016/S0040-4039(00)92617-0</ref> a key intermediate is either "Precursor 9" or "Precursor 10".

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" |Precursor 10
|style="text-align: center;" |Precursor 9
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol9.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol10.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|2.4687
|2.7846
|-
!Bend
|10.5555
|16.5411
|-
!Torsion
|17.4240
|18.2518
|-
!VDW
|13.1930
|13.1096
|-
!Dipole-Dipole
| -1.8818
| -1.7248
|-
!Total E (kcal/mol)
|39.1215
|47.8395
|-
|}
Precursor 9 and 10 are synthesised using a reversible oxy-Cope rearrangement as demonstrated below. As this process is in equilibrium that, with precursor 10 being more stable, it is predicted that this isomer will be the one produced as all of the molecules attempt to reduce the energy. As analysis of the individual energy componenets shows, this arrangement is a lot less strained than Precursor nine, which requires a lot more bending energy.

The molecule was then optimised with an MMFF94. Rather than rely on a large set of experimentally determined parameters like MM2, MMFF94 minimises the potential of each atom iteratively, attempting to minimise the whole molecule. Although the values produced for these two methods cannot be directly compared, they both correctly identify the correct altropisomer as being lower in energy.
{|class="wikitable" border="1"
! colspan="3" | Comparison of MMFF94 and MM2 minimisations
|-
!Molecule
| Precursor 9
| Precursor 10
|-
!MM2 minimised Energy (kJmol<sup><-1</sup>)
|39.1215
|47.8395
|-
!MMFF94 minimised Energy (kcalmol<sup><-1</sup>)
|58.7513
|70.5377
|-
|}

===Regioselective Addition of Dichlorocarbene to a diene===
Molecule A was initially optimised using a molecular mechanics (MM2) calculation

{| style="wikitable" border="1"
|<jmol>
<jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
It was then further optimised with a MOPAC calculation, which takes into effect stereoelectronic effects. The two were then compared.

{| class="wikitable" border="1"
!colspan="3" | Comparison of two optimisation calculations
|-
! Overlay of two optimised molecules !! MM2 optimised molecule !! MOPAC Optimised Molecule
|-
|[[file:Ohboverlaydiene.png|300px]]
The MM2 optimised molecule is coloured yellow for clarity
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1mopac.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! rowspan="6" | Distances between
corresponding atoms

on the overlaid molecules (Å)
|style="text-align: center;" | C(34)-C(9)
|0.5247
|-
|style="text-align: center;" | C(26)-C(1)
|0.5246
|-
|style="text-align: center;" | H(47)-H(22)
|0.8526
|-
|style="text-align: center;" | H(38)-H(13)
|0.8524
|-
|style="text-align: center;" | Cl(37)-Cl(12)
|0.0689
|}

As can be seen by the comparison above, when using the stereoelectronic interactions, the cyclohexadiene ring on the side with the Cl atom is moved further away from the Cl using the MOPAC calculation than the MM2. This is because the electronic effects included in this calculation include the repulsion between the electron rich Chlorine atom and the electron rich double bond, whereas the MM2 calculation doesn't include this and so a symmetrical molecule is formed.

====MOs====

The MOs of the previously MOPAC optimised molecule where then calculated using Guassian (B3LYP 6-31G)
{| style="wikitable" border="1"
! Homo-1 !! colspan="2" | Homo
|-
|[[File:Ohbclhomo-1.jpg|250px]]
| <jmol>
<jmolApplet>
<title>Orbital</title><color>white</color><size>250</size>
<script>isosurface color orange purple "images/f/f2/Ohbdienemo48.cub.jvxl" translucent; </script>
<uploadedFileContents>Ohbdienemo48.cub.xyz</uploadedFileContents>
</jmolApplet>
</jmol>
|[[File:Ohbclhomo.jpg|250px]]
|-
!Lumo !! Lumo+1 !! Lumo+2
|-
|[[File:Ohbcllumo.jpg|250px]]
|[[File:Ohbcllumo+1.jpg|250px]]
|[[File:Ohbcllumo+2.jpg|250px]]
|-
|colspan="2" | [[File:Ohbclmep.jpg|300px rotate="90"]]
| [[File:Ohbclelevels.png|250px]]
|}

Molecule 2 was initially minimised using an MM2 calculation. The reactions of molecule A with an electrophile can be illustrated by taking a more advanced, quantum mechanical approach to modelling the molecule and its orbitals. This will also allow prediction of which C=C reacts with an electrophile.
Of the two alekenes, the endo is favoured rather than the exo because the cl-c sigma star orbital mixes with the exo alkene. This stabilises both orbitals, as shown by the frequency calculation having a higher value than the endo alkene, but reduces the pi bond character of the exo alkene. This is also shown by the comparative lengths of the alkene bonds - the exo is 1.3355A and the endo is 1.33190A. The cycloaddition of the carbene requires an alkene and so favours the endo alkene as it has a higher p character. The homo is also focused entirely on the endo side of the molecule, with the lumo focused mainly on the exo side. The Homo shows the high pi bond character of the endo alkene. The Homo-1 is mainly focused ont he exo alekene, so shows the pi bond character of the exo alekene. This is lower in energy and so is less likely to react with the carbene molecule.

====Glycosidation====

When the monosaccharide pyranose has an acetal in the 2 position, four different isomers can be formed, all of differing stability. These differing positions of the acetal group and its interactions with the neighbouring group means that it acts as a directing group to nucleophilic attack. With deprotonation to an oxenium cation being the initial step, the acetal group can then stabilise this to varying degrees depending on its position. Due to the Sn1 nature of the glycosidation nucleophilic attack occurring, the access of the nucleophile to the sigma* orbital of the carbon is crucial, and this depends on the Burgi-Dunitz angle of 107<ref> H. B. Bürgi, J. D. Dunitz, J. M. Lehn, G. Wipff (1974). "Stereochemistry of reaction paths at carbonyl centres". Tetrahedron 30 (12): 1563–1572. doi:10.1016/S0040-4020(01)90678-7</ref>.
Two sets of calculations were performed; initially using an MM2 forcefield, and then with using the MOPAC approach. While both approaches showed a similar trend, the benefit of the MOPAC, to make and break bond meant that the structures formed by this minimisation resembled the transition state a lot more closely than those formed by the MM2.
As shown by the table, below, all of the initial cations are at a lower energy than the intermediate forms, however the structures differ slightly depending on whether an MM2 or MOPAC minimisation was performed; the MOPAC structures much more closely resemble the transition states.
The differences in energy can be directly related to the amount of strain present within the molecule and the repulsion between the oxygen atoms. The large amount of strain present in the intermediates, particularly of molecule 2, mean that they have a lot higher energy. A notable differences is that the MM2 struggles to accurately deal with the oxenium cation, whereas the MOPAC produces a more lifelike picture in this area.
The glycosidation mainly produces the trans isomers, ie molecules going through the pathways of molecules 1 & 4. This is predicted well by the computational methods used, with both the initial molecules and the intermediates being lower in energy and having lower anomeric carbon-acetal oxygen distances.

=====Mechanisms=====

[[file:Ohbglymech.gif|800px]]

{|class="wikitable" border="2"
!rowspan="5" |Initial molecule
!colspan="2" | Conformation
|1
|2
|3
|4
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2amm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 11.5430
| 46.2672
| 35.5277
| 29.5144
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -90.51343
| -70.57703
| -72.56010
| -85.04737
|-
!rowspan="5" |Intermediate
!colspan="2" | Conformation
|chemdraw
|chemdraw
|chemdraw
|chemdraw
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2Bmm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 28.4913
| 43.2706
| 41.0918
| 31.8763
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -91.66112
| -66.72331
| -84.44899
| -88.08089

|-
|}

==Comparison of coumpational results to a molecule from literature.==

===Taxol intermediate===

Computational chemistry can be a powerful tool in the analysis and reproduction of spectra. in this exercise, literature values and spectra are compared to computed data and the effectiveness and accuracy of both methods is compared and contrasted.

A different intermediate in the synthesis of taxol was optimised using MM2 to produce the structure (right) with a total energy of 66.7072kcal<sup>-1</sup>
{|class="wikitable border="2"
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
This file was then optimised using Guassian and B3LYP 6-31G(d,p) basis set. The resulting file was then resubmitted to the SCAN cluster for computation of the nmr spectrum using these keywords # mpw1pw91/6-31G(d,p) NMR SCRF=(CPCM,Solvent=chloroform). These results were then compared to those found in the literature<ref>#L. Paquette, N. A. Pegg, D. Toops, G. D. Maynard, R. D. Rogers, ''J. Am. Chem. Soc.,'', '''1990''', ''112'', 277-283. {{DOI|10.1021/ja00157a043}}</ref>.
The results are below. As can be seen by this comparison chart, in general there is very good agreement between the predicted and measured shift values. With the only major discrepancy being at Carbon 16.

This however, can be resolved. The large distance is probably to do with this carbon being bonded to two sulphur atoms. The 6-31G(d,p) basis set is not very good at approximating, and hence optimising sulphur molecules. This is because Sulphur contains f type functions, of which there are 7. However there are 10<ref>SIMPLIFIED INTRODUCTION TO AB INITIO
BASIS SETS. TERMS AND NOTATION.
Jan K. Labanowski, Ohio Supercomputer Center,
1224 Kinnear Rd., Columbus, OH 43212-1163,<\ref> possible Guassians, and so an element of contamination from the 4p orbitals is brought in. As the 6-31G(d,p) does not containg any f functions, it is not that good at predicting the behaviour of the sulphur molecule to the level required by the nmr calculation. Despite all of this, the shift values are still similar.

===Literature Molecule===

In the synthesis of molecule A (right), using Kobayashi aldol chemistry, two stereoisomers are produced. Initially, the syn isomer is formed, with a diasteromic ratio of 1:14, and via a similar synthetic route, the anti isomer is also produced, with a high dr of 1:>50. The high stereoselectivity of both of these reactions is an important step in the synthesis of enationmerically pure natural products.
Initiallyu the models were optimised using an MM2 optimisation within ChemBio 12.0. They were then further optimised using an RB3LYP-6-31G(d,p) method and basis set. After the optimisation, and checking to see that the the two molecules were still distinct, with one syn and one anti form, they were submitted for nmr analysis, to produce a predicted nmr. This was then compared with the reported nmr, with a view to see if the assignments and conclusions made in the literature were correct. There was a good correlations between the predicted and measured nmr peaks, with deviations, as show below, of less than 1ppm for the H nmr and less than 10ppm for the <sup>13</sup>C nmr.
[[File:Ohbccomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each carbon atom]]
[[File:Ohbhcomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each Hydrogen atom]]

This correlation helps confirm that the structures are correct; the different enantiomers are differentiated and assigned correctly. If they were not, and the calculated syn nmr is compared to the measured anti nmr, and vice versa, larger differences are noted. This is highlighted on the graph below. The blue and red graphs are the correctly assigned and matched nmrs, the green and purple nmrs are if they are assigned incorrectly. It can clearly be seen that the green and purple line are consistently higher than their counterparts.
[[file:Ohbcomparisonnmr.png|thumb|900px|none|left|Comparison of correct and incorrect assignment for the two conformers]]
Within the literature all of the hydrogens and carbons are assigned, with the exception of Hydrogen 48. This is because this is a labile proton and so does not show up on measured nmrs due to rapid exchange with the deuterium in the deuterated solvent. However the calculated spectra does not take this into account and so displays the shift value for this hydrogen.

The computed IR spectra are very similar for the two molecules. The OH stretch is increased by 30cm<sup>-1</sup> in the syn form of the molecule and the CH bend region between 1000-1500cm<sup>-1</sup> is also significantly different. This acsn be rationalised by the different atomic orbital overlaps that are occuring due to the different positioning of the methyl group.

As both molecules are chiral, they both rotate light in opposite directions. However due to the large size of this molecule and although it is relatively conformationally limited due to the double bond and ring, the calculation for the syn and anti variants did not converge after 48 a 48 hour run on the SCAN.

==References==
<references></references>

File:Taxolchart.png

2013-02-08T14:05:34Z

Ohb09: uploaded a new version of "File:Taxolchart.png"

File:Taxolchart.png

2013-02-08T13:58:55Z

Ohb09:

Rep:Mod:benton2

2013-02-08T13:52:15Z

Ohb09:

=Module 1 - Intro=
In this experiment, MM2 is compared to the more advanced MOPAC minimisation technique. A minimised molecule is then analysed and compared to literature.
Molecular mechanics, used here in its MM2 form is a very good first order approximation. Using data from previous experiments and breaking down the overall energy into different categories, such as van der Waals interaction, dipole-dipole, and bending before summing them to provide an overall energy is a very useful and more importantly quick method to calculate a molecules energy. The energy of molecule can then be iteratively reduced by tweaking the position of the atoms and conformations, providing a low energy structure. However it does have its limitations. Firstly, because of the large approximations used, the method is liable to fall, and remain, in an initial, smaller, potential well at a higher energy than the minimum possible. This can be overcome by carefully arranging the molecule by the user of the program to avoid these early, high energy minima, but requires a lot of rearrangement and prioir knowledge of low energy arrangements. As MM2 uses previously aquired data, it is also not that useful in determining new structures, or functional groups for which it does not have the data for.
MOPAC uses a different approach for minimisation. It uses semi empirical quantum chemistry functions to determine the energy of a molecule. This allows more advanced effects to be included in the calculation and allows for analysis of the neighbouring group effect in sacchardie chemistry and regioselectivity effects, as studied here.
Computational chemistry can also predict spectra, and in the last part of the experiment predicted spectra are compared to literature and the results analysed.

==Week 1==

===Hydrogenation of the Cyclopentadiene Dimer===
The endo dimer is primarily produced when cyclopentadiene dimerises, in a ratio of 99.5% to 0.5% <ref>
Małgorzata E Jamróz, Sławomir Gałka, Jan Cz Dobrowolski,
On dicyclopentadiene isomers,
Journal of Molecular Structure: THEOCHEM,
Volume 634, Issues 1–3, 5 September 2003,
Pages 225-233, ISSN 0166-1280,
<DOI|10.1016/S0166-1280(03)00348-8>
</ref>(at least when thermally initiated; photo initiation produces a racemic mixture of the two isomers<ref>
The Photosensitited Dimerization of Cyclopentadiene
Nicholas J. Turro and George S. Hammond
Journal of the American Chemical Society 1962 84 (14), 2841-2842
<DOI|10.1021/ja00873a050>
</ref>)
{| class="wikitable" border="1"

! rowspan="2" | Molecule
|style="text-align: center;" |Exo
|style="text-align: center;" |Endo
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbexodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Total E (kcal/mol)
|33.9975
|31.8764
|-
|}
[[file:Endoexoohb.bmp|thumb|left|500px]]
The small energy difference calculated by the MM2 forcefield does not highlight why the endo for is favoured over the exo form as it shows the exo form is lower in energy. While the difference between the two energies is relatively trivial, the high enationmeric excess of the products suggest that this is only part of the story, and suggest that this reaction is under kinetic rather than thermodynamic control.<ref> W.C.Herndon, C.R.Grayson, J.M.Manion; "Retro-Diels-Alder reactions. III. Kinetics of the thermal decompositions of exo- and endo-dicyclopentadiene" J. Org. Chem.; 1967, 32 (3); 526-529.DOI:10.1021/jo01278a003</ref> Being under kinetic control would imply the activation energy, and hence transition state, for the endo species is lower than the exo form and so the endo enantiomer is formed faster. This can be rationalised by looking at the orbital interactions in the two transition states.

The endo transition state is stabilised by the secondary favourable overlap whereas in the exo form there is no such overlap to stabilised the molecule meaning that the transition state is a higher energy, and so is less favourable. This cannot be handled by the simple MM2 calculation however.

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" colspan="2" |Different hydrogenation sites
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh3.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh4.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|1.2489
|1.1303
|-
!Bend
|19.1608
|13.10259
|-
!Torsion
|11.0730
|12.4118
|-
!VDW
|5.7962
|4.4398
|-
!Dipole-Dipole
|0.1622
|0.1410
|-
!Total E (kcal/mol)
|34.9643
|29.2475
|-
|}

The site of initial hydrogenation of the endo dimer can also be determined by calculating the energies of the two possible isomers. From these calculations it is clear that the second molecule is favoured more, as it is ~5.5kcalmol<sup>-1</sup> more stable. The bending energy in both of these molecules is the major difference. This manifests itself in the amount that the atoms are ebent away from their ideal positions, which is 109.5 for an sp3 carbon and 120 for an sp2 carbon. Across all of the key bonds, the second isomer has bond angles that are closer to the ideal than the first isomer; in particular the C-C=C bond angles; in the first molecule they are 107.6 and in the second 112.8. This difference of five degrees is enough to significantly stabilise the second isomer, making hydrogenation at that site the more preferable.

===Atropisomerism in an Intermediate related to the synthesis of Taxol===
In the complete synthesis of Taxol, and important cancer fighting drug, proposed by Pacquette <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 10.1016/S0040-4039(00)92617-0</ref> a key intermediate is either "Precursor 9" or "Precursor 10".

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" |Precursor 10
|style="text-align: center;" |Precursor 9
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol9.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol10.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|2.4687
|2.7846
|-
!Bend
|10.5555
|16.5411
|-
!Torsion
|17.4240
|18.2518
|-
!VDW
|13.1930
|13.1096
|-
!Dipole-Dipole
| -1.8818
| -1.7248
|-
!Total E (kcal/mol)
|39.1215
|47.8395
|-
|}
Precursor 9 and 10 are synthesised using a reversible oxy-Cope rearrangement as demonstrated below. As this process is in equilibrium that, with precursor 10 being more stable, it is predicted that this isomer will be the one produced as all of the molecules attempt to reduce the energy. As analysis of the individual energy componenets shows, this arrangement is a lot less strained than Precursor nine, which requires a lot more bending energy.

The molecule was then optimised with an MMFF94. Rather than rely on a large set of experimentally determined parameters like MM2, MMFF94 minimises the potential of each atom iteratively, attempting to minimise the whole molecule. Although the values produced for these two methods cannot be directly compared, they both correctly identify the correct altropisomer as being lower in energy.
{|class="wikitable" border="1"
! colspan="3" | Comparison of MMFF94 and MM2 minimisations
|-
!Molecule
| Precursor 9
| Precursor 10
|-
!MM2 minimised Energy (kJmol<sup><-1</sup>)
|39.1215
|47.8395
|-
!MMFF94 minimised Energy (kcalmol<sup><-1</sup>)
|58.7513
|70.5377
|-
|}

===Regioselective Addition of Dichlorocarbene to a diene===
Molecule A was initially optimised using a molecular mechanics (MM2) calculation

{| style="wikitable" border="1"
|<jmol>
<jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
It was then further optimised with a MOPAC calculation, which takes into effect stereoelectronic effects. The two were then compared.

{| class="wikitable" border="1"
!colspan="3" | Comparison of two optimisation calculations
|-
! Overlay of two optimised molecules !! MM2 optimised molecule !! MOPAC Optimised Molecule
|-
|[[file:Ohboverlaydiene.png|300px]]
The MM2 optimised molecule is coloured yellow for clarity
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1mopac.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! rowspan="6" | Distances between
corresponding atoms

on the overlaid molecules (Å)
|style="text-align: center;" | C(34)-C(9)
|0.5247
|-
|style="text-align: center;" | C(26)-C(1)
|0.5246
|-
|style="text-align: center;" | H(47)-H(22)
|0.8526
|-
|style="text-align: center;" | H(38)-H(13)
|0.8524
|-
|style="text-align: center;" | Cl(37)-Cl(12)
|0.0689
|}

As can be seen by the comparison above, when using the stereoelectronic interactions, the cyclohexadiene ring on the side with the Cl atom is moved further away from the Cl using the MOPAC calculation than the MM2. This is because the electronic effects included in this calculation include the repulsion between the electron rich Chlorine atom and the electron rich double bond, whereas the MM2 calculation doesn't include this and so a symmetrical molecule is formed.

====MOs====

The MOs of the previously MOPAC optimised molecule where then calculated using Guassian (B3LYP 6-31G)
{| style="wikitable" border="1"
! Homo-1 !! colspan="2" | Homo
|-
|[[File:Ohbclhomo-1.jpg|250px]]
| <jmol>
<jmolApplet>
<title>Orbital</title><color>white</color><size>250</size>
<script>isosurface color orange purple "images/f/f2/Ohbdienemo48.cub.jvxl" translucent; </script>
<uploadedFileContents>Ohbdienemo48.cub.xyz</uploadedFileContents>
</jmolApplet>
</jmol>
|[[File:Ohbclhomo.jpg|250px]]
|-
!Lumo !! Lumo+1 !! Lumo+2
|-
|[[File:Ohbcllumo.jpg|250px]]
|[[File:Ohbcllumo+1.jpg|250px]]
|[[File:Ohbcllumo+2.jpg|250px]]
|-
|colspan="2" | [[File:Ohbclmep.jpg|300px rotate="90"]]
| [[File:Ohbclelevels.png|250px]]
|}

Molecule 2 was initially minimised using an MM2 calculation. The reactions of molecule A with an electrophile can be illustrated by taking a more advanced, quantum mechanical approach to modelling the molecule and its orbitals. This will also allow prediction of which C=C reacts with an electrophile.
Of the two alekenes, the endo is favoured rather than the exo because the cl-c sigma star orbital mixes with the exo alkene. This stabilises both orbitals, as shown by the frequency calculation having a higher value than the endo alkene, but reduces the pi bond character of the exo alkene. This is also shown by the comparative lengths of the alkene bonds - the exo is 1.3355A and the endo is 1.33190A. The cycloaddition of the carbene requires an alkene and so favours the endo alkene as it has a higher p character. The homo is also focused entirely on the endo side of the molecule, with the lumo focused mainly on the exo side. The Homo shows the high pi bond character of the endo alkene. The Homo-1 is mainly focused ont he exo alekene, so shows the pi bond character of the exo alekene. This is lower in energy and so is less likely to react with the carbene molecule.

====Glycosidation====

When the monosaccharide pyranose has an acetal in the 2 position, four different isomers can be formed, all of differing stability. These differing positions of the acetal group and its interactions with the neighbouring group means that it acts as a directing group to nucleophilic attack. With deprotonation to an oxenium cation being the initial step, the acetal group can then stabilise this to varying degrees depending on its position. Due to the Sn1 nature of the glycosidation nucleophilic attack occurring, the access of the nucleophile to the sigma* orbital of the carbon is crucial, and this depends on the Burgi-Dunitz angle of 107<ref> H. B. Bürgi, J. D. Dunitz, J. M. Lehn, G. Wipff (1974). "Stereochemistry of reaction paths at carbonyl centres". Tetrahedron 30 (12): 1563–1572. doi:10.1016/S0040-4020(01)90678-7</ref>.
Two sets of calculations were performed; initially using an MM2 forcefield, and then with using the MOPAC approach. While both approaches showed a similar trend, the benefit of the MOPAC, to make and break bond meant that the structures formed by this minimisation resembled the transition state a lot more closely than those formed by the MM2.
As shown by the table, below, all of the initial cations are at a lower energy than the intermediate forms, however the structures differ slightly depending on whether an MM2 or MOPAC minimisation was performed; the MOPAC structures much more closely resemble the transition states.
The differences in energy can be directly related to the amount of strain present within the molecule and the repulsion between the oxygen atoms. The large amount of strain present in the intermediates, particularly of molecule 2, mean that they have a lot higher energy. A notable differences is that the MM2 struggles to accurately deal with the oxenium cation, whereas the MOPAC produces a more lifelike picture in this area.
The glycosidation mainly produces the trans isomers, ie molecules going through the pathways of molecules 1 & 4. This is predicted well by the computational methods used, with both the initial molecules and the intermediates being lower in energy and having lower anomeric carbon-acetal oxygen distances.

=====Mechanisms=====

[[file:Ohbglymech.gif|800px]]

{|class="wikitable" border="2"
!rowspan="5" |Initial molecule
!colspan="2" | Conformation
|1
|2
|3
|4
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2amm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 11.5430
| 46.2672
| 35.5277
| 29.5144
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -90.51343
| -70.57703
| -72.56010
| -85.04737
|-
!rowspan="5" |Intermediate
!colspan="2" | Conformation
|chemdraw
|chemdraw
|chemdraw
|chemdraw
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2Bmm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 28.4913
| 43.2706
| 41.0918
| 31.8763
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -91.66112
| -66.72331
| -84.44899
| -88.08089

|-
|}

==Comparison of coumpational results to a molecule from literature.==

===Taxol intermediate===

Computational chemistry can be a powerful tool in the analysis and reproduction of spectra. in this exercise, literature values and spectra are compared to computed data and the effectiveness and accuracy of both methods is compared and contrasted.

A different intermediate int he synthesis of taxol was optimised using MM2 and MOPAC, to produce the structure (right)
{class="wikitable border="2"
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}

===Literature Molecule===

In the synthesis of molecule A (right), using Kobayashi aldol chemistry, two stereoisomers are produced. Initially, the syn isomer is formed, with a diasteromic ratio of 1:14, and via a similar synthetic route, the anti isomer is also produced, with a high dr of 1:>50. The high stereoselectivity of both of these reactions is an important step in the synthesis of enationmerically pure natural products.
Initiallyu the models were optimised using an MM2 optimisation within ChemBio 12.0. They were then further optimised using an RB3LYP-6-31G(d,p) method and basis set. After the optimisation, and checking to see that the the two molecules were still distinct, with one syn and one anti form, they were submitted for nmr analysis, to produce a predicted nmr. This was then compared with the reported nmr, with a view to see if the assignments and conclusions made in the literature were correct. There was a good correlations between the predicted and measured nmr peaks, with deviations, as show below, of less than 1ppm for the H nmr and less than 10ppm for the <sup>13</sup>C nmr.
[[File:Ohbccomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each carbon atom]]
[[File:Ohbhcomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each Hydrogen atom]]

This correlation helps confirm that the structures are correct; the different enantiomers are differentiated and assigned correctly. If they were not, and the calculated syn nmr is compared to the measured anti nmr, and vice versa, larger differences are noted. This is highlighted on the graph below. The blue and red graphs are the correctly assigned and matched nmrs, the green and purple nmrs are if they are assigned incorrectly. It can clearly be seen that the green and purple line are consistently higher than their counterparts.
[[file:Ohbcomparisonnmr.png|thumb|900px|none|left|Comparison of correct and incorrect assignment for the two conformers]]
Within the literature all of the hydrogens and carbons are assigned, with the exception of Hydrogen 48. This is because this is a labile proton and so does not show up on measured nmrs due to rapid exchange with the deuterium in the deuterated solvent. However the calculated spectra does not take this into account and so displays the shift value for this hydrogen.

The computed IR spectra are very similar for the two molecules. The OH stretch is increased by 30cm<sup>-1</sup> in the syn form of the molecule and the CH bend region between 1000-1500cm<sup>-1</sup> is also significantly different. This acsn be rationalised by the different atomic orbital overlaps that are occuring due to the different positioning of the methyl group.

As both molecules are chiral, they both rotate light in opposite directions. However due to the large size of this molecule and although it is relatively conformationally limited due to the double bond and ring, the calculation for the syn and anti variants did not converge after 48 a 48 hour run on the SCAN.

==References==
<references></references>

Rep:Mod:benton2

2013-02-08T13:51:10Z

Ohb09: /* Comparison of coumpational results to a molecule from literature. */

=Module 1 - Intro=
In this experiment, MM2 is compared to the more advanced MOPAC minimisation technique. A minimised molecule is then analysed and compared to literature.
Molecular mechanics, used here in its MM2 form is a very good first order approximation. Using data from previous experiments and breaking down the overall energy into different categories, such as van der Waals interaction, dipole-dipole, and bending before summing them to provide an overall energy is a very useful and more importantly quick method to calculate a molecules energy. The energy of molecule can then be iteratively reduced by tweaking the position of the atoms and conformations, providing a low energy structure. However it does have its limitations. Firstly, because of the large approximations used, the method is liable to fall, and remain, in an initial, smaller, potential well at a higher energy than the minimum possible. This can be overcome by carefully arranging the molecule by the user of the program to avoid these early, high energy minima, but requires a lot of rearrangement and prioir knowledge of low energy arrangements. As MM2 uses previously aquired data, it is also not that useful in determining new structures, or functional groups for which it does not have the data for.
MOPAC uses a different approach for minimisation. It uses semi empirical quantum chemistry functions to determine the energy of a molecule. This allows more advanced effects to be included in the calculation and allows for analysis of the neighbouring group effect in sacchardie chemistry and regioselectivity effects, as studied here.
Computational chemistry can also predict spectra, and in the last part of the experiment predicted spectra are compared to literature and the results analysed.

==Week 1==

===Hydrogenation of the Cyclopentadiene Dimer===
The endo dimer is primarily produced when cyclopentadiene dimerises, in a ratio of 99.5% to 0.5% <ref>
Małgorzata E Jamróz, Sławomir Gałka, Jan Cz Dobrowolski,
On dicyclopentadiene isomers,
Journal of Molecular Structure: THEOCHEM,
Volume 634, Issues 1–3, 5 September 2003,
Pages 225-233, ISSN 0166-1280,
<DOI|10.1016/S0166-1280(03)00348-8>
</ref>(at least when thermally initiated; photo initiation produces a racemic mixture of the two isomers<ref>
The Photosensitited Dimerization of Cyclopentadiene
Nicholas J. Turro and George S. Hammond
Journal of the American Chemical Society 1962 84 (14), 2841-2842
<DOI|10.1021/ja00873a050>
</ref>)
{| class="wikitable" border="1"

! rowspan="2" | Molecule
|style="text-align: center;" |Exo
|style="text-align: center;" |Endo
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbexodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Total E (kcal/mol)
|33.9975
|31.8764
|-
|}
[[file:Endoexoohb.bmp|thumb|left|500px]]
The small energy difference calculated by the MM2 forcefield does not highlight why the endo for is favoured over the exo form as it shows the exo form is lower in energy. While the difference between the two energies is relatively trivial, the high enationmeric excess of the products suggest that this is only part of the story, and suggest that this reaction is under kinetic rather than thermodynamic control.<ref> W.C.Herndon, C.R.Grayson, J.M.Manion; "Retro-Diels-Alder reactions. III. Kinetics of the thermal decompositions of exo- and endo-dicyclopentadiene" J. Org. Chem.; 1967, 32 (3); 526-529.DOI:10.1021/jo01278a003</ref> Being under kinetic control would imply the activation energy, and hence transition state, for the endo species is lower than the exo form and so the endo enantiomer is formed faster. This can be rationalised by looking at the orbital interactions in the two transition states.

The endo transition state is stabilised by the secondary favourable overlap whereas in the exo form there is no such overlap to stabilised the molecule meaning that the transition state is a higher energy, and so is less favourable. This cannot be handled by the simple MM2 calculation however.

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" colspan="2" |Different hydrogenation sites
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh3.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh4.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|1.2489
|1.1303
|-
!Bend
|19.1608
|13.10259
|-
!Torsion
|11.0730
|12.4118
|-
!VDW
|5.7962
|4.4398
|-
!Dipole-Dipole
|0.1622
|0.1410
|-
!Total E (kcal/mol)
|34.9643
|29.2475
|-
|}

The site of initial hydrogenation of the endo dimer can also be determined by calculating the energies of the two possible isomers. From these calculations it is clear that the second molecule is favoured more, as it is ~5.5kcalmol<sup>-1</sup> more stable. The bending energy in both of these molecules is the major difference. This manifests itself in the amount that the atoms are ebent away from their ideal positions, which is 109.5 for an sp3 carbon and 120 for an sp2 carbon. Across all of the key bonds, the second isomer has bond angles that are closer to the ideal than the first isomer; in particular the C-C=C bond angles; in the first molecule they are 107.6 and in the second 112.8. This difference of five degrees is enough to significantly stabilise the second isomer, making hydrogenation at that site the more preferable.

===Atropisomerism in an Intermediate related to the synthesis of Taxol===
In the complete synthesis of Taxol, and important cancer fighting drug, proposed by Pacquette <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 10.1016/S0040-4039(00)92617-0</ref> a key intermediate is either "Precursor 9" or "Precursor 10".

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" |Precursor 10
|style="text-align: center;" |Precursor 9
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol9.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol10.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|2.4687
|2.7846
|-
!Bend
|10.5555
|16.5411
|-
!Torsion
|17.4240
|18.2518
|-
!VDW
|13.1930
|13.1096
|-
!Dipole-Dipole
| -1.8818
| -1.7248
|-
!Total E (kcal/mol)
|39.1215
|47.8395
|-
|}
Precursor 9 and 10 are synthesised using a reversible oxy-Cope rearrangement as demonstrated below. As this process is in equilibrium that, with precursor 10 being more stable, it is predicted that this isomer will be the one produced as all of the molecules attempt to reduce the energy. As analysis of the individual energy componenets shows, this arrangement is a lot less strained than Precursor nine, which requires a lot more bending energy.

The molecule was then optimised with an MMFF94. Rather than rely on a large set of experimentally determined parameters like MM2, MMFF94 minimises the potential of each atom iteratively, attempting to minimise the whole molecule. Although the values produced for these two methods cannot be directly compared, they both correctly identify the correct altropisomer as being lower in energy.
{|class="wikitable" border="1"
! colspan="3" | Comparison of MMFF94 and MM2 minimisations
|-
!Molecule
| Precursor 9
| Precursor 10
|-
!MM2 minimised Energy (kJmol<sup><-1</sup>)
|39.1215
|47.8395
|-
!MMFF94 minimised Energy (kcalmol<sup><-1</sup>)
|58.7513
|70.5377
|-
|}

===Regioselective Addition of Dichlorocarbene to a diene===
Molecule A was initially optimised using a molecular mechanics (MM2) calculation

{| style="wikitable" border="1"
|<jmol>
<jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
It was then further optimised with a MOPAC calculation, which takes into effect stereoelectronic effects. The two were then compared.

{| class="wikitable" border="1"
!colspan="3" | Comparison of two optimisation calculations
|-
! Overlay of two optimised molecules !! MM2 optimised molecule !! MOPAC Optimised Molecule
|-
|[[file:Ohboverlaydiene.png|300px]]
The MM2 optimised molecule is coloured yellow for clarity
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1mopac.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! rowspan="6" | Distances between
corresponding atoms

on the overlaid molecules (Å)
|style="text-align: center;" | C(34)-C(9)
|0.5247
|-
|style="text-align: center;" | C(26)-C(1)
|0.5246
|-
|style="text-align: center;" | H(47)-H(22)
|0.8526
|-
|style="text-align: center;" | H(38)-H(13)
|0.8524
|-
|style="text-align: center;" | Cl(37)-Cl(12)
|0.0689
|}

As can be seen by the comparison above, when using the stereoelectronic interactions, the cyclohexadiene ring on the side with the Cl atom is moved further away from the Cl using the MOPAC calculation than the MM2. This is because the electronic effects included in this calculation include the repulsion between the electron rich Chlorine atom and the electron rich double bond, whereas the MM2 calculation doesn't include this and so a symmetrical molecule is formed.

====MOs====

The MOs of the previously MOPAC optimised molecule where then calculated using Guassian (B3LYP 6-31G)
{| style="wikitable" border="1"
! Homo-1 !! colspan="2" | Homo
|-
|[[File:Ohbclhomo-1.jpg|250px]]
| <jmol>
<jmolApplet>
<title>Orbital</title><color>white</color><size>250</size>
<script>isosurface color orange purple "images/f/f2/Ohbdienemo48.cub.jvxl" translucent; </script>
<uploadedFileContents>Ohbdienemo48.cub.xyz</uploadedFileContents>
</jmolApplet>
</jmol>
|[[File:Ohbclhomo.jpg|250px]]
|-
!Lumo !! Lumo+1 !! Lumo+2
|-
|[[File:Ohbcllumo.jpg|250px]]
|[[File:Ohbcllumo+1.jpg|250px]]
|[[File:Ohbcllumo+2.jpg|250px]]
|-
|colspan="2" | [[File:Ohbclmep.jpg|300px rotate="90"]]
| [[File:Ohbclelevels.png|250px]]
|}

Molecule 2 was initially minimised using an MM2 calculation. The reactions of molecule A with an electrophile can be illustrated by taking a more advanced, quantum mechanical approach to modelling the molecule and its orbitals. This will also allow prediction of which C=C reacts with an electrophile.
Of the two alekenes, the endo is favoured rather than the exo because the cl-c sigma star orbital mixes with the exo alkene. This stabilises both orbitals, as shown by the frequency calculation having a higher value than the endo alkene, but reduces the pi bond character of the exo alkene. This is also shown by the comparative lengths of the alkene bonds - the exo is 1.3355A and the endo is 1.33190A. The cycloaddition of the carbene requires an alkene and so favours the endo alkene as it has a higher p character. The homo is also focused entirely on the endo side of the molecule, with the lumo focused mainly on the exo side. The Homo shows the high pi bond character of the endo alkene. The Homo-1 is mainly focused ont he exo alekene, so shows the pi bond character of the exo alekene. This is lower in energy and so is less likely to react with the carbene molecule.

====Glycosidation====

When the monosaccharide pyranose has an acetal in the 2 position, four different isomers can be formed, all of differing stability. These differing positions of the acetal group and its interactions with the neighbouring group means that it acts as a directing group to nucleophilic attack. With deprotonation to an oxenium cation being the initial step, the acetal group can then stabilise this to varying degrees depending on its position. Due to the Sn1 nature of the glycosidation nucleophilic attack occurring, the access of the nucleophile to the sigma* orbital of the carbon is crucial, and this depends on the Burgi-Dunitz angle of 107<ref> H. B. Bürgi, J. D. Dunitz, J. M. Lehn, G. Wipff (1974). "Stereochemistry of reaction paths at carbonyl centres". Tetrahedron 30 (12): 1563–1572. doi:10.1016/S0040-4020(01)90678-7</ref>.
Two sets of calculations were performed; initially using an MM2 forcefield, and then with using the MOPAC approach. While both approaches showed a similar trend, the benefit of the MOPAC, to make and break bond meant that the structures formed by this minimisation resembled the transition state a lot more closely than those formed by the MM2.
As shown by the table, below, all of the initial cations are at a lower energy than the intermediate forms, however the structures differ slightly depending on whether an MM2 or MOPAC minimisation was performed; the MOPAC structures much more closely resemble the transition states.
The differences in energy can be directly related to the amount of strain present within the molecule and the repulsion between the oxygen atoms. The large amount of strain present in the intermediates, particularly of molecule 2, mean that they have a lot higher energy. A notable differences is that the MM2 struggles to accurately deal with the oxenium cation, whereas the MOPAC produces a more lifelike picture in this area.
The glycosidation mainly produces the trans isomers, ie molecules going through the pathways of molecules 1 & 4. This is predicted well by the computational methods used, with both the initial molecules and the intermediates being lower in energy and having lower anomeric carbon-acetal oxygen distances.

=====Mechanisms=====

[[file:Ohbglymech.gif|800px]]

{|class="wikitable" border="2"
!rowspan="5" |Initial molecule
!colspan="2" | Conformation
|1
|2
|3
|4
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2amm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 11.5430
| 46.2672
| 35.5277
| 29.5144
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -90.51343
| -70.57703
| -72.56010
| -85.04737
|-
!rowspan="5" |Intermediate
!colspan="2" | Conformation
|chemdraw
|chemdraw
|chemdraw
|chemdraw
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2Bmm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 28.4913
| 43.2706
| 41.0918
| 31.8763
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -91.66112
| -66.72331
| -84.44899
| -88.08089

|-
|}

==Comparison of coumpational results to a molecule from literature.==

===Taxol intermediate===

Computational chemistry can be a powerful tool in the analysis and reproduction of spectra. in this exercise, literature values and spectra are compared to computed data and the effectiveness and accuracy of both methods is compared and contrasted.

A different intermediate int he synthesis of taxol was optimised using MM2 and MOPAC, to produce the structure (right)

===Literature Molecule===

In the synthesis of molecule A (right), using Kobayashi aldol chemistry, two stereoisomers are produced. Initially, the syn isomer is formed, with a diasteromic ratio of 1:14, and via a similar synthetic route, the anti isomer is also produced, with a high dr of 1:>50. The high stereoselectivity of both of these reactions is an important step in the synthesis of enationmerically pure natural products.
Initiallyu the models were optimised using an MM2 optimisation within ChemBio 12.0. They were then further optimised using an RB3LYP-6-31G(d,p) method and basis set. After the optimisation, and checking to see that the the two molecules were still distinct, with one syn and one anti form, they were submitted for nmr analysis, to produce a predicted nmr. This was then compared with the reported nmr, with a view to see if the assignments and conclusions made in the literature were correct. There was a good correlations between the predicted and measured nmr peaks, with deviations, as show below, of less than 1ppm for the H nmr and less than 10ppm for the <sup>13</sup>C nmr.
[[File:Ohbccomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each carbon atom]]
[[File:Ohbhcomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each Hydrogen atom]]

This correlation helps confirm that the structures are correct; the different enantiomers are differentiated and assigned correctly. If they were not, and the calculated syn nmr is compared to the measured anti nmr, and vice versa, larger differences are noted. This is highlighted on the graph below. The blue and red graphs are the correctly assigned and matched nmrs, the green and purple nmrs are if they are assigned incorrectly. It can clearly be seen that the green and purple line are consistently higher than their counterparts.
[[file:Ohbcomparisonnmr.png|thumb|900px|none|left|Comparison of correct and incorrect assignment for the two conformers]]
Within the literature all of the hydrogens and carbons are assigned, with the exception of Hydrogen 48. This is because this is a labile proton and so does not show up on measured nmrs due to rapid exchange with the deuterium in the deuterated solvent. However the calculated spectra does not take this into account and so displays the shift value for this hydrogen.

The computed IR spectra are very similar for the two molecules. The OH stretch is increased by 30cm<sup>-1</sup> in the syn form of the molecule and the CH bend region between 1000-1500cm<sup>-1</sup> is also significantly different. This acsn be rationalised by the different atomic orbital overlaps that are occuring due to the different positioning of the methyl group.

As both molecules are chiral, they both rotate light in opposite directions. However due to the large size of this molecule and although it is relatively conformationally limited due to the double bond and ring, the calculation for the syn and anti variants did not converge after 48 a 48 hour run on the SCAN.

==References==
<references></references>

File:Ohbtaxol1.mol

2013-02-08T13:50:58Z

Ohb09:

Rep:Mod:benton2

2013-02-08T13:37:25Z

Ohb09: /* Mechanisms */

=Module 1 - Intro=
In this experiment, MM2 is compared to the more advanced MOPAC minimisation technique. A minimised molecule is then analysed and compared to literature.
Molecular mechanics, used here in its MM2 form is a very good first order approximation. Using data from previous experiments and breaking down the overall energy into different categories, such as van der Waals interaction, dipole-dipole, and bending before summing them to provide an overall energy is a very useful and more importantly quick method to calculate a molecules energy. The energy of molecule can then be iteratively reduced by tweaking the position of the atoms and conformations, providing a low energy structure. However it does have its limitations. Firstly, because of the large approximations used, the method is liable to fall, and remain, in an initial, smaller, potential well at a higher energy than the minimum possible. This can be overcome by carefully arranging the molecule by the user of the program to avoid these early, high energy minima, but requires a lot of rearrangement and prioir knowledge of low energy arrangements. As MM2 uses previously aquired data, it is also not that useful in determining new structures, or functional groups for which it does not have the data for.
MOPAC uses a different approach for minimisation. It uses semi empirical quantum chemistry functions to determine the energy of a molecule. This allows more advanced effects to be included in the calculation and allows for analysis of the neighbouring group effect in sacchardie chemistry and regioselectivity effects, as studied here.
Computational chemistry can also predict spectra, and in the last part of the experiment predicted spectra are compared to literature and the results analysed.

==Week 1==

===Hydrogenation of the Cyclopentadiene Dimer===
The endo dimer is primarily produced when cyclopentadiene dimerises, in a ratio of 99.5% to 0.5% <ref>
Małgorzata E Jamróz, Sławomir Gałka, Jan Cz Dobrowolski,
On dicyclopentadiene isomers,
Journal of Molecular Structure: THEOCHEM,
Volume 634, Issues 1–3, 5 September 2003,
Pages 225-233, ISSN 0166-1280,
<DOI|10.1016/S0166-1280(03)00348-8>
</ref>(at least when thermally initiated; photo initiation produces a racemic mixture of the two isomers<ref>
The Photosensitited Dimerization of Cyclopentadiene
Nicholas J. Turro and George S. Hammond
Journal of the American Chemical Society 1962 84 (14), 2841-2842
<DOI|10.1021/ja00873a050>
</ref>)
{| class="wikitable" border="1"

! rowspan="2" | Molecule
|style="text-align: center;" |Exo
|style="text-align: center;" |Endo
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbexodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Total E (kcal/mol)
|33.9975
|31.8764
|-
|}
[[file:Endoexoohb.bmp|thumb|left|500px]]
The small energy difference calculated by the MM2 forcefield does not highlight why the endo for is favoured over the exo form as it shows the exo form is lower in energy. While the difference between the two energies is relatively trivial, the high enationmeric excess of the products suggest that this is only part of the story, and suggest that this reaction is under kinetic rather than thermodynamic control.<ref> W.C.Herndon, C.R.Grayson, J.M.Manion; "Retro-Diels-Alder reactions. III. Kinetics of the thermal decompositions of exo- and endo-dicyclopentadiene" J. Org. Chem.; 1967, 32 (3); 526-529.DOI:10.1021/jo01278a003</ref> Being under kinetic control would imply the activation energy, and hence transition state, for the endo species is lower than the exo form and so the endo enantiomer is formed faster. This can be rationalised by looking at the orbital interactions in the two transition states.

The endo transition state is stabilised by the secondary favourable overlap whereas in the exo form there is no such overlap to stabilised the molecule meaning that the transition state is a higher energy, and so is less favourable. This cannot be handled by the simple MM2 calculation however.

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" colspan="2" |Different hydrogenation sites
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh3.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh4.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|1.2489
|1.1303
|-
!Bend
|19.1608
|13.10259
|-
!Torsion
|11.0730
|12.4118
|-
!VDW
|5.7962
|4.4398
|-
!Dipole-Dipole
|0.1622
|0.1410
|-
!Total E (kcal/mol)
|34.9643
|29.2475
|-
|}

The site of initial hydrogenation of the endo dimer can also be determined by calculating the energies of the two possible isomers. From these calculations it is clear that the second molecule is favoured more, as it is ~5.5kcalmol<sup>-1</sup> more stable. The bending energy in both of these molecules is the major difference. This manifests itself in the amount that the atoms are ebent away from their ideal positions, which is 109.5 for an sp3 carbon and 120 for an sp2 carbon. Across all of the key bonds, the second isomer has bond angles that are closer to the ideal than the first isomer; in particular the C-C=C bond angles; in the first molecule they are 107.6 and in the second 112.8. This difference of five degrees is enough to significantly stabilise the second isomer, making hydrogenation at that site the more preferable.

===Atropisomerism in an Intermediate related to the synthesis of Taxol===
In the complete synthesis of Taxol, and important cancer fighting drug, proposed by Pacquette <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 10.1016/S0040-4039(00)92617-0</ref> a key intermediate is either "Precursor 9" or "Precursor 10".

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" |Precursor 10
|style="text-align: center;" |Precursor 9
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol9.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol10.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|2.4687
|2.7846
|-
!Bend
|10.5555
|16.5411
|-
!Torsion
|17.4240
|18.2518
|-
!VDW
|13.1930
|13.1096
|-
!Dipole-Dipole
| -1.8818
| -1.7248
|-
!Total E (kcal/mol)
|39.1215
|47.8395
|-
|}
Precursor 9 and 10 are synthesised using a reversible oxy-Cope rearrangement as demonstrated below. As this process is in equilibrium that, with precursor 10 being more stable, it is predicted that this isomer will be the one produced as all of the molecules attempt to reduce the energy. As analysis of the individual energy componenets shows, this arrangement is a lot less strained than Precursor nine, which requires a lot more bending energy.

The molecule was then optimised with an MMFF94. Rather than rely on a large set of experimentally determined parameters like MM2, MMFF94 minimises the potential of each atom iteratively, attempting to minimise the whole molecule. Although the values produced for these two methods cannot be directly compared, they both correctly identify the correct altropisomer as being lower in energy.
{|class="wikitable" border="1"
! colspan="3" | Comparison of MMFF94 and MM2 minimisations
|-
!Molecule
| Precursor 9
| Precursor 10
|-
!MM2 minimised Energy (kJmol<sup><-1</sup>)
|39.1215
|47.8395
|-
!MMFF94 minimised Energy (kcalmol<sup><-1</sup>)
|58.7513
|70.5377
|-
|}

===Regioselective Addition of Dichlorocarbene to a diene===
Molecule A was initially optimised using a molecular mechanics (MM2) calculation

{| style="wikitable" border="1"
|<jmol>
<jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
It was then further optimised with a MOPAC calculation, which takes into effect stereoelectronic effects. The two were then compared.

{| class="wikitable" border="1"
!colspan="3" | Comparison of two optimisation calculations
|-
! Overlay of two optimised molecules !! MM2 optimised molecule !! MOPAC Optimised Molecule
|-
|[[file:Ohboverlaydiene.png|300px]]
The MM2 optimised molecule is coloured yellow for clarity
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1mopac.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! rowspan="6" | Distances between
corresponding atoms

on the overlaid molecules (Å)
|style="text-align: center;" | C(34)-C(9)
|0.5247
|-
|style="text-align: center;" | C(26)-C(1)
|0.5246
|-
|style="text-align: center;" | H(47)-H(22)
|0.8526
|-
|style="text-align: center;" | H(38)-H(13)
|0.8524
|-
|style="text-align: center;" | Cl(37)-Cl(12)
|0.0689
|}

As can be seen by the comparison above, when using the stereoelectronic interactions, the cyclohexadiene ring on the side with the Cl atom is moved further away from the Cl using the MOPAC calculation than the MM2. This is because the electronic effects included in this calculation include the repulsion between the electron rich Chlorine atom and the electron rich double bond, whereas the MM2 calculation doesn't include this and so a symmetrical molecule is formed.

====MOs====

The MOs of the previously MOPAC optimised molecule where then calculated using Guassian (B3LYP 6-31G)
{| style="wikitable" border="1"
! Homo-1 !! colspan="2" | Homo
|-
|[[File:Ohbclhomo-1.jpg|250px]]
| <jmol>
<jmolApplet>
<title>Orbital</title><color>white</color><size>250</size>
<script>isosurface color orange purple "images/f/f2/Ohbdienemo48.cub.jvxl" translucent; </script>
<uploadedFileContents>Ohbdienemo48.cub.xyz</uploadedFileContents>
</jmolApplet>
</jmol>
|[[File:Ohbclhomo.jpg|250px]]
|-
!Lumo !! Lumo+1 !! Lumo+2
|-
|[[File:Ohbcllumo.jpg|250px]]
|[[File:Ohbcllumo+1.jpg|250px]]
|[[File:Ohbcllumo+2.jpg|250px]]
|-
|colspan="2" | [[File:Ohbclmep.jpg|300px rotate="90"]]
| [[File:Ohbclelevels.png|250px]]
|}

Molecule 2 was initially minimised using an MM2 calculation. The reactions of molecule A with an electrophile can be illustrated by taking a more advanced, quantum mechanical approach to modelling the molecule and its orbitals. This will also allow prediction of which C=C reacts with an electrophile.
Of the two alekenes, the endo is favoured rather than the exo because the cl-c sigma star orbital mixes with the exo alkene. This stabilises both orbitals, as shown by the frequency calculation having a higher value than the endo alkene, but reduces the pi bond character of the exo alkene. This is also shown by the comparative lengths of the alkene bonds - the exo is 1.3355A and the endo is 1.33190A. The cycloaddition of the carbene requires an alkene and so favours the endo alkene as it has a higher p character. The homo is also focused entirely on the endo side of the molecule, with the lumo focused mainly on the exo side. The Homo shows the high pi bond character of the endo alkene. The Homo-1 is mainly focused ont he exo alekene, so shows the pi bond character of the exo alekene. This is lower in energy and so is less likely to react with the carbene molecule.

====Glycosidation====

When the monosaccharide pyranose has an acetal in the 2 position, four different isomers can be formed, all of differing stability. These differing positions of the acetal group and its interactions with the neighbouring group means that it acts as a directing group to nucleophilic attack. With deprotonation to an oxenium cation being the initial step, the acetal group can then stabilise this to varying degrees depending on its position. Due to the Sn1 nature of the glycosidation nucleophilic attack occurring, the access of the nucleophile to the sigma* orbital of the carbon is crucial, and this depends on the Burgi-Dunitz angle of 107<ref> H. B. Bürgi, J. D. Dunitz, J. M. Lehn, G. Wipff (1974). "Stereochemistry of reaction paths at carbonyl centres". Tetrahedron 30 (12): 1563–1572. doi:10.1016/S0040-4020(01)90678-7</ref>.
Two sets of calculations were performed; initially using an MM2 forcefield, and then with using the MOPAC approach. While both approaches showed a similar trend, the benefit of the MOPAC, to make and break bond meant that the structures formed by this minimisation resembled the transition state a lot more closely than those formed by the MM2.
As shown by the table, below, all of the initial cations are at a lower energy than the intermediate forms, however the structures differ slightly depending on whether an MM2 or MOPAC minimisation was performed; the MOPAC structures much more closely resemble the transition states.
The differences in energy can be directly related to the amount of strain present within the molecule and the repulsion between the oxygen atoms. The large amount of strain present in the intermediates, particularly of molecule 2, mean that they have a lot higher energy. A notable differences is that the MM2 struggles to accurately deal with the oxenium cation, whereas the MOPAC produces a more lifelike picture in this area.
The glycosidation mainly produces the trans isomers, ie molecules going through the pathways of molecules 1 & 4. This is predicted well by the computational methods used, with both the initial molecules and the intermediates being lower in energy and having lower anomeric carbon-acetal oxygen distances.

=====Mechanisms=====

[[file:Ohbglymech.gif|800px]]

{|class="wikitable" border="2"
!rowspan="5" |Initial molecule
!colspan="2" | Conformation
|1
|2
|3
|4
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2amm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 11.5430
| 46.2672
| 35.5277
| 29.5144
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -90.51343
| -70.57703
| -72.56010
| -85.04737
|-
!rowspan="5" |Intermediate
!colspan="2" | Conformation
|chemdraw
|chemdraw
|chemdraw
|chemdraw
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2Bmm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 28.4913
| 43.2706
| 41.0918
| 31.8763
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -91.66112
| -66.72331
| -84.44899
| -88.08089

|-
|}

==Comparison of coumpational results to a molecule from literature.==

Computational chemistry can be a powerful tool in the analysis and reproduction of spectra. in this exercise, literature values and spectra are compared to computed data and the effectiveness and accuracy of both methods is compared and contrasted.
In the synthesis of molecule A (right), using Kobayashi aldol chemistry, two stereoisomers are produced. Initially, the syn isomer is formed, with a diasteromic ratio of 1:14, and via a similar synthetic route, the anti isomer is also produced, with a high dr of 1:>50. The high stereoselectivity of both of these reactions is an important step in the synthesis of enationmerically pure natural products.
Initiallyu the models were optimised using an MM2 optimisation within ChemBio 12.0. They were then further optimised using an RB3LYP-6-31G(d,p) method and basis set. After the optimisation, and checking to see that the the two molecules were still distinct, with one syn and one anti form, they were submitted for nmr analysis, to produce a predicted nmr. This was then compared with the reported nmr, with a view to see if the assignments and conclusions made in the literature were correct. There was a good correlations between the predicted and measured nmr peaks, with deviations, as show below, of less than 1ppm for the H nmr and less than 10ppm for the <sup>13</sup>C nmr.
[[File:Ohbccomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each carbon atom]]
[[File:Ohbhcomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each Hydrogen atom]]

This correlation helps confirm that the structures are correct; the different enantiomers are differentiated and assigned correctly. If they were not, and the calculated syn nmr is compared to the measured anti nmr, and vice versa, larger differences are noted. This is highlighted on the graph below. The blue and red graphs are the correctly assigned and matched nmrs, the green and purple nmrs are if they are assigned incorrectly. It can clearly be seen that the green and purple line are consistently higher than their counterparts.
[[file:Ohbcomparisonnmr.png|thumb|900px|none|left|Comparison of correct and incorrect assignment for the two conformers]]
Within the literature all of the hydrogens and carbons are assigned, with the exception of Hydrogen 48. This is because this is a labile proton and so does not show up on measured nmrs due to rapid exchange with the deuterium in the deuterated solvent. However the calculated spectra does not take this into account and so displays the shift value for this hydrogen.

The computed IR spectra are very similar for the two molecules. The OH stretch is increased by 30cm<sup>-1</sup> in the syn form of the molecule and the CH bend region between 1000-1500cm<sup>-1</sup> is also significantly different. This acsn be rationalised by the different atomic orbital overlaps that are occuring due to the different positioning of the methyl group.

As both molecules are chiral, they both rotate light in opposite directions. However due to the large size of this molecule and although it is relatively conformationally limited due to the double bond and ring, the calculation for the syn and anti variants did not converge after 48 a 48 hour run on the SCAN.

==References==
<references></references>

Rep:Mod:benton2

2013-02-08T13:21:25Z

Ohb09: /* Mechanisms */

=Module 1 - Intro=
In this experiment, MM2 is compared to the more advanced MOPAC minimisation technique. A minimised molecule is then analysed and compared to literature.
Molecular mechanics, used here in its MM2 form is a very good first order approximation. Using data from previous experiments and breaking down the overall energy into different categories, such as van der Waals interaction, dipole-dipole, and bending before summing them to provide an overall energy is a very useful and more importantly quick method to calculate a molecules energy. The energy of molecule can then be iteratively reduced by tweaking the position of the atoms and conformations, providing a low energy structure. However it does have its limitations. Firstly, because of the large approximations used, the method is liable to fall, and remain, in an initial, smaller, potential well at a higher energy than the minimum possible. This can be overcome by carefully arranging the molecule by the user of the program to avoid these early, high energy minima, but requires a lot of rearrangement and prioir knowledge of low energy arrangements. As MM2 uses previously aquired data, it is also not that useful in determining new structures, or functional groups for which it does not have the data for.
MOPAC uses a different approach for minimisation. It uses semi empirical quantum chemistry functions to determine the energy of a molecule. This allows more advanced effects to be included in the calculation and allows for analysis of the neighbouring group effect in sacchardie chemistry and regioselectivity effects, as studied here.
Computational chemistry can also predict spectra, and in the last part of the experiment predicted spectra are compared to literature and the results analysed.

==Week 1==

===Hydrogenation of the Cyclopentadiene Dimer===
The endo dimer is primarily produced when cyclopentadiene dimerises, in a ratio of 99.5% to 0.5% <ref>
Małgorzata E Jamróz, Sławomir Gałka, Jan Cz Dobrowolski,
On dicyclopentadiene isomers,
Journal of Molecular Structure: THEOCHEM,
Volume 634, Issues 1–3, 5 September 2003,
Pages 225-233, ISSN 0166-1280,
<DOI|10.1016/S0166-1280(03)00348-8>
</ref>(at least when thermally initiated; photo initiation produces a racemic mixture of the two isomers<ref>
The Photosensitited Dimerization of Cyclopentadiene
Nicholas J. Turro and George S. Hammond
Journal of the American Chemical Society 1962 84 (14), 2841-2842
<DOI|10.1021/ja00873a050>
</ref>)
{| class="wikitable" border="1"

! rowspan="2" | Molecule
|style="text-align: center;" |Exo
|style="text-align: center;" |Endo
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbexodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Total E (kcal/mol)
|33.9975
|31.8764
|-
|}
[[file:Endoexoohb.bmp|thumb|left|500px]]
The small energy difference calculated by the MM2 forcefield does not highlight why the endo for is favoured over the exo form as it shows the exo form is lower in energy. While the difference between the two energies is relatively trivial, the high enationmeric excess of the products suggest that this is only part of the story, and suggest that this reaction is under kinetic rather than thermodynamic control.<ref> W.C.Herndon, C.R.Grayson, J.M.Manion; "Retro-Diels-Alder reactions. III. Kinetics of the thermal decompositions of exo- and endo-dicyclopentadiene" J. Org. Chem.; 1967, 32 (3); 526-529.DOI:10.1021/jo01278a003</ref> Being under kinetic control would imply the activation energy, and hence transition state, for the endo species is lower than the exo form and so the endo enantiomer is formed faster. This can be rationalised by looking at the orbital interactions in the two transition states.

The endo transition state is stabilised by the secondary favourable overlap whereas in the exo form there is no such overlap to stabilised the molecule meaning that the transition state is a higher energy, and so is less favourable. This cannot be handled by the simple MM2 calculation however.

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" colspan="2" |Different hydrogenation sites
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh3.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh4.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|1.2489
|1.1303
|-
!Bend
|19.1608
|13.10259
|-
!Torsion
|11.0730
|12.4118
|-
!VDW
|5.7962
|4.4398
|-
!Dipole-Dipole
|0.1622
|0.1410
|-
!Total E (kcal/mol)
|34.9643
|29.2475
|-
|}

The site of initial hydrogenation of the endo dimer can also be determined by calculating the energies of the two possible isomers. From these calculations it is clear that the second molecule is favoured more, as it is ~5.5kcalmol<sup>-1</sup> more stable. The bending energy in both of these molecules is the major difference. This manifests itself in the amount that the atoms are ebent away from their ideal positions, which is 109.5 for an sp3 carbon and 120 for an sp2 carbon. Across all of the key bonds, the second isomer has bond angles that are closer to the ideal than the first isomer; in particular the C-C=C bond angles; in the first molecule they are 107.6 and in the second 112.8. This difference of five degrees is enough to significantly stabilise the second isomer, making hydrogenation at that site the more preferable.

===Atropisomerism in an Intermediate related to the synthesis of Taxol===
In the complete synthesis of Taxol, and important cancer fighting drug, proposed by Pacquette <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 10.1016/S0040-4039(00)92617-0</ref> a key intermediate is either "Precursor 9" or "Precursor 10".

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" |Precursor 10
|style="text-align: center;" |Precursor 9
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol9.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol10.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|2.4687
|2.7846
|-
!Bend
|10.5555
|16.5411
|-
!Torsion
|17.4240
|18.2518
|-
!VDW
|13.1930
|13.1096
|-
!Dipole-Dipole
| -1.8818
| -1.7248
|-
!Total E (kcal/mol)
|39.1215
|47.8395
|-
|}
Precursor 9 and 10 are synthesised using a reversible oxy-Cope rearrangement as demonstrated below. As this process is in equilibrium that, with precursor 10 being more stable, it is predicted that this isomer will be the one produced as all of the molecules attempt to reduce the energy. As analysis of the individual energy componenets shows, this arrangement is a lot less strained than Precursor nine, which requires a lot more bending energy.

The molecule was then optimised with an MMFF94. Rather than rely on a large set of experimentally determined parameters like MM2, MMFF94 minimises the potential of each atom iteratively, attempting to minimise the whole molecule. Although the values produced for these two methods cannot be directly compared, they both correctly identify the correct altropisomer as being lower in energy.
{|class="wikitable" border="1"
! colspan="3" | Comparison of MMFF94 and MM2 minimisations
|-
!Molecule
| Precursor 9
| Precursor 10
|-
!MM2 minimised Energy (kJmol<sup><-1</sup>)
|39.1215
|47.8395
|-
!MMFF94 minimised Energy (kcalmol<sup><-1</sup>)
|58.7513
|70.5377
|-
|}

===Regioselective Addition of Dichlorocarbene to a diene===
Molecule A was initially optimised using a molecular mechanics (MM2) calculation

{| style="wikitable" border="1"
|<jmol>
<jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
It was then further optimised with a MOPAC calculation, which takes into effect stereoelectronic effects. The two were then compared.

{| class="wikitable" border="1"
!colspan="3" | Comparison of two optimisation calculations
|-
! Overlay of two optimised molecules !! MM2 optimised molecule !! MOPAC Optimised Molecule
|-
|[[file:Ohboverlaydiene.png|300px]]
The MM2 optimised molecule is coloured yellow for clarity
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1mopac.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! rowspan="6" | Distances between
corresponding atoms

on the overlaid molecules (Å)
|style="text-align: center;" | C(34)-C(9)
|0.5247
|-
|style="text-align: center;" | C(26)-C(1)
|0.5246
|-
|style="text-align: center;" | H(47)-H(22)
|0.8526
|-
|style="text-align: center;" | H(38)-H(13)
|0.8524
|-
|style="text-align: center;" | Cl(37)-Cl(12)
|0.0689
|}

As can be seen by the comparison above, when using the stereoelectronic interactions, the cyclohexadiene ring on the side with the Cl atom is moved further away from the Cl using the MOPAC calculation than the MM2. This is because the electronic effects included in this calculation include the repulsion between the electron rich Chlorine atom and the electron rich double bond, whereas the MM2 calculation doesn't include this and so a symmetrical molecule is formed.

====MOs====

The MOs of the previously MOPAC optimised molecule where then calculated using Guassian (B3LYP 6-31G)
{| style="wikitable" border="1"
! Homo-1 !! colspan="2" | Homo
|-
|[[File:Ohbclhomo-1.jpg|250px]]
| <jmol>
<jmolApplet>
<title>Orbital</title><color>white</color><size>250</size>
<script>isosurface color orange purple "images/f/f2/Ohbdienemo48.cub.jvxl" translucent; </script>
<uploadedFileContents>Ohbdienemo48.cub.xyz</uploadedFileContents>
</jmolApplet>
</jmol>
|[[File:Ohbclhomo.jpg|250px]]
|-
!Lumo !! Lumo+1 !! Lumo+2
|-
|[[File:Ohbcllumo.jpg|250px]]
|[[File:Ohbcllumo+1.jpg|250px]]
|[[File:Ohbcllumo+2.jpg|250px]]
|-
|colspan="2" | [[File:Ohbclmep.jpg|300px rotate="90"]]
| [[File:Ohbclelevels.png|250px]]
|}

Molecule 2 was initially minimised using an MM2 calculation. The reactions of molecule A with an electrophile can be illustrated by taking a more advanced, quantum mechanical approach to modelling the molecule and its orbitals. This will also allow prediction of which C=C reacts with an electrophile.
Of the two alekenes, the endo is favoured rather than the exo because the cl-c sigma star orbital mixes with the exo alkene. This stabilises both orbitals, as shown by the frequency calculation having a higher value than the endo alkene, but reduces the pi bond character of the exo alkene. This is also shown by the comparative lengths of the alkene bonds - the exo is 1.3355A and the endo is 1.33190A. The cycloaddition of the carbene requires an alkene and so favours the endo alkene as it has a higher p character. The homo is also focused entirely on the endo side of the molecule, with the lumo focused mainly on the exo side. The Homo shows the high pi bond character of the endo alkene. The Homo-1 is mainly focused ont he exo alekene, so shows the pi bond character of the exo alekene. This is lower in energy and so is less likely to react with the carbene molecule.

====Glycosidation====

=====Mechanisms=====

[[file:Ohbglymech.gif|800px]]

{|class="wikitable" border="2"
!rowspan="5" |Initial molecule
!colspan="2" | Conformation
|1
|2
|3
|4
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2amm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 11.5430
| 46.2672
| 35.5277
| 29.5144
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -90.51343
| -70.57703
| -72.56010
| -85.04737
|-
!rowspan="5" |Intermediate
!colspan="2" | Conformation
|chemdraw
|chemdraw
|chemdraw
|chemdraw
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2Bmm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 28.4913
| 43.2706
| 41.0918
| 31.8763
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -91.66112
| -66.72331
| -84.44899
| -88.08089

|-
|}

==Comparison of coumpational results to a molecule from literature.==

Computational chemistry can be a powerful tool in the analysis and reproduction of spectra. in this exercise, literature values and spectra are compared to computed data and the effectiveness and accuracy of both methods is compared and contrasted.
In the synthesis of molecule A (right), using Kobayashi aldol chemistry, two stereoisomers are produced. Initially, the syn isomer is formed, with a diasteromic ratio of 1:14, and via a similar synthetic route, the anti isomer is also produced, with a high dr of 1:>50. The high stereoselectivity of both of these reactions is an important step in the synthesis of enationmerically pure natural products.
Initiallyu the models were optimised using an MM2 optimisation within ChemBio 12.0. They were then further optimised using an RB3LYP-6-31G(d,p) method and basis set. After the optimisation, and checking to see that the the two molecules were still distinct, with one syn and one anti form, they were submitted for nmr analysis, to produce a predicted nmr. This was then compared with the reported nmr, with a view to see if the assignments and conclusions made in the literature were correct. There was a good correlations between the predicted and measured nmr peaks, with deviations, as show below, of less than 1ppm for the H nmr and less than 10ppm for the <sup>13</sup>C nmr.
[[File:Ohbccomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each carbon atom]]
[[File:Ohbhcomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each Hydrogen atom]]

This correlation helps confirm that the structures are correct; the different enantiomers are differentiated and assigned correctly. If they were not, and the calculated syn nmr is compared to the measured anti nmr, and vice versa, larger differences are noted. This is highlighted on the graph below. The blue and red graphs are the correctly assigned and matched nmrs, the green and purple nmrs are if they are assigned incorrectly. It can clearly be seen that the green and purple line are consistently higher than their counterparts.
[[file:Ohbcomparisonnmr.png|thumb|900px|none|left|Comparison of correct and incorrect assignment for the two conformers]]
Within the literature all of the hydrogens and carbons are assigned, with the exception of Hydrogen 48. This is because this is a labile proton and so does not show up on measured nmrs due to rapid exchange with the deuterium in the deuterated solvent. However the calculated spectra does not take this into account and so displays the shift value for this hydrogen.

The computed IR spectra are very similar for the two molecules. The OH stretch is increased by 30cm<sup>-1</sup> in the syn form of the molecule and the CH bend region between 1000-1500cm<sup>-1</sup> is also significantly different. This acsn be rationalised by the different atomic orbital overlaps that are occuring due to the different positioning of the methyl group.

As both molecules are chiral, they both rotate light in opposite directions. However due to the large size of this molecule and although it is relatively conformationally limited due to the double bond and ring, the calculation for the syn and anti variants did not converge after 48 a 48 hour run on the SCAN.

==References==
<references></references>

Rep:Mod:benton2

2013-02-08T13:08:27Z

Ohb09: /* Mechanisms */

=Module 1 - Intro=
In this experiment, MM2 is compared to the more advanced MOPAC minimisation technique. A minimised molecule is then analysed and compared to literature.
Molecular mechanics, used here in its MM2 form is a very good first order approximation. Using data from previous experiments and breaking down the overall energy into different categories, such as van der Waals interaction, dipole-dipole, and bending before summing them to provide an overall energy is a very useful and more importantly quick method to calculate a molecules energy. The energy of molecule can then be iteratively reduced by tweaking the position of the atoms and conformations, providing a low energy structure. However it does have its limitations. Firstly, because of the large approximations used, the method is liable to fall, and remain, in an initial, smaller, potential well at a higher energy than the minimum possible. This can be overcome by carefully arranging the molecule by the user of the program to avoid these early, high energy minima, but requires a lot of rearrangement and prioir knowledge of low energy arrangements. As MM2 uses previously aquired data, it is also not that useful in determining new structures, or functional groups for which it does not have the data for.
MOPAC uses a different approach for minimisation. It uses semi empirical quantum chemistry functions to determine the energy of a molecule. This allows more advanced effects to be included in the calculation and allows for analysis of the neighbouring group effect in sacchardie chemistry and regioselectivity effects, as studied here.
Computational chemistry can also predict spectra, and in the last part of the experiment predicted spectra are compared to literature and the results analysed.

==Week 1==

===Hydrogenation of the Cyclopentadiene Dimer===
The endo dimer is primarily produced when cyclopentadiene dimerises, in a ratio of 99.5% to 0.5% <ref>
Małgorzata E Jamróz, Sławomir Gałka, Jan Cz Dobrowolski,
On dicyclopentadiene isomers,
Journal of Molecular Structure: THEOCHEM,
Volume 634, Issues 1–3, 5 September 2003,
Pages 225-233, ISSN 0166-1280,
<DOI|10.1016/S0166-1280(03)00348-8>
</ref>(at least when thermally initiated; photo initiation produces a racemic mixture of the two isomers<ref>
The Photosensitited Dimerization of Cyclopentadiene
Nicholas J. Turro and George S. Hammond
Journal of the American Chemical Society 1962 84 (14), 2841-2842
<DOI|10.1021/ja00873a050>
</ref>)
{| class="wikitable" border="1"

! rowspan="2" | Molecule
|style="text-align: center;" |Exo
|style="text-align: center;" |Endo
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbexodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Total E (kcal/mol)
|33.9975
|31.8764
|-
|}
[[file:Endoexoohb.bmp|thumb|left|500px]]
The small energy difference calculated by the MM2 forcefield does not highlight why the endo for is favoured over the exo form as it shows the exo form is lower in energy. While the difference between the two energies is relatively trivial, the high enationmeric excess of the products suggest that this is only part of the story, and suggest that this reaction is under kinetic rather than thermodynamic control.<ref> W.C.Herndon, C.R.Grayson, J.M.Manion; "Retro-Diels-Alder reactions. III. Kinetics of the thermal decompositions of exo- and endo-dicyclopentadiene" J. Org. Chem.; 1967, 32 (3); 526-529.DOI:10.1021/jo01278a003</ref> Being under kinetic control would imply the activation energy, and hence transition state, for the endo species is lower than the exo form and so the endo enantiomer is formed faster. This can be rationalised by looking at the orbital interactions in the two transition states.

The endo transition state is stabilised by the secondary favourable overlap whereas in the exo form there is no such overlap to stabilised the molecule meaning that the transition state is a higher energy, and so is less favourable. This cannot be handled by the simple MM2 calculation however.

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" colspan="2" |Different hydrogenation sites
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh3.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh4.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|1.2489
|1.1303
|-
!Bend
|19.1608
|13.10259
|-
!Torsion
|11.0730
|12.4118
|-
!VDW
|5.7962
|4.4398
|-
!Dipole-Dipole
|0.1622
|0.1410
|-
!Total E (kcal/mol)
|34.9643
|29.2475
|-
|}

The site of initial hydrogenation of the endo dimer can also be determined by calculating the energies of the two possible isomers. From these calculations it is clear that the second molecule is favoured more, as it is ~5.5kcalmol<sup>-1</sup> more stable. The bending energy in both of these molecules is the major difference. This manifests itself in the amount that the atoms are ebent away from their ideal positions, which is 109.5 for an sp3 carbon and 120 for an sp2 carbon. Across all of the key bonds, the second isomer has bond angles that are closer to the ideal than the first isomer; in particular the C-C=C bond angles; in the first molecule they are 107.6 and in the second 112.8. This difference of five degrees is enough to significantly stabilise the second isomer, making hydrogenation at that site the more preferable.

===Atropisomerism in an Intermediate related to the synthesis of Taxol===
In the complete synthesis of Taxol, and important cancer fighting drug, proposed by Pacquette <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 10.1016/S0040-4039(00)92617-0</ref> a key intermediate is either "Precursor 9" or "Precursor 10".

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" |Precursor 10
|style="text-align: center;" |Precursor 9
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol9.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol10.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|2.4687
|2.7846
|-
!Bend
|10.5555
|16.5411
|-
!Torsion
|17.4240
|18.2518
|-
!VDW
|13.1930
|13.1096
|-
!Dipole-Dipole
| -1.8818
| -1.7248
|-
!Total E (kcal/mol)
|39.1215
|47.8395
|-
|}
Precursor 9 and 10 are synthesised using a reversible oxy-Cope rearrangement as demonstrated below. As this process is in equilibrium that, with precursor 10 being more stable, it is predicted that this isomer will be the one produced as all of the molecules attempt to reduce the energy. As analysis of the individual energy componenets shows, this arrangement is a lot less strained than Precursor nine, which requires a lot more bending energy.

The molecule was then optimised with an MMFF94. Rather than rely on a large set of experimentally determined parameters like MM2, MMFF94 minimises the potential of each atom iteratively, attempting to minimise the whole molecule. Although the values produced for these two methods cannot be directly compared, they both correctly identify the correct altropisomer as being lower in energy.
{|class="wikitable" border="1"
! colspan="3" | Comparison of MMFF94 and MM2 minimisations
|-
!Molecule
| Precursor 9
| Precursor 10
|-
!MM2 minimised Energy (kJmol<sup><-1</sup>)
|39.1215
|47.8395
|-
!MMFF94 minimised Energy (kcalmol<sup><-1</sup>)
|58.7513
|70.5377
|-
|}

===Regioselective Addition of Dichlorocarbene to a diene===
Molecule A was initially optimised using a molecular mechanics (MM2) calculation

{| style="wikitable" border="1"
|<jmol>
<jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
It was then further optimised with a MOPAC calculation, which takes into effect stereoelectronic effects. The two were then compared.

{| class="wikitable" border="1"
!colspan="3" | Comparison of two optimisation calculations
|-
! Overlay of two optimised molecules !! MM2 optimised molecule !! MOPAC Optimised Molecule
|-
|[[file:Ohboverlaydiene.png|300px]]
The MM2 optimised molecule is coloured yellow for clarity
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1mopac.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! rowspan="6" | Distances between
corresponding atoms

on the overlaid molecules (Å)
|style="text-align: center;" | C(34)-C(9)
|0.5247
|-
|style="text-align: center;" | C(26)-C(1)
|0.5246
|-
|style="text-align: center;" | H(47)-H(22)
|0.8526
|-
|style="text-align: center;" | H(38)-H(13)
|0.8524
|-
|style="text-align: center;" | Cl(37)-Cl(12)
|0.0689
|}

As can be seen by the comparison above, when using the stereoelectronic interactions, the cyclohexadiene ring on the side with the Cl atom is moved further away from the Cl using the MOPAC calculation than the MM2. This is because the electronic effects included in this calculation include the repulsion between the electron rich Chlorine atom and the electron rich double bond, whereas the MM2 calculation doesn't include this and so a symmetrical molecule is formed.

====MOs====

The MOs of the previously MOPAC optimised molecule where then calculated using Guassian (B3LYP 6-31G)
{| style="wikitable" border="1"
! Homo-1 !! colspan="2" | Homo
|-
|[[File:Ohbclhomo-1.jpg|250px]]
| <jmol>
<jmolApplet>
<title>Orbital</title><color>white</color><size>250</size>
<script>isosurface color orange purple "images/f/f2/Ohbdienemo48.cub.jvxl" translucent; </script>
<uploadedFileContents>Ohbdienemo48.cub.xyz</uploadedFileContents>
</jmolApplet>
</jmol>
|[[File:Ohbclhomo.jpg|250px]]
|-
!Lumo !! Lumo+1 !! Lumo+2
|-
|[[File:Ohbcllumo.jpg|250px]]
|[[File:Ohbcllumo+1.jpg|250px]]
|[[File:Ohbcllumo+2.jpg|250px]]
|-
|colspan="2" | [[File:Ohbclmep.jpg|300px rotate="90"]]
| [[File:Ohbclelevels.png|250px]]
|}

Molecule 2 was initially minimised using an MM2 calculation. The reactions of molecule A with an electrophile can be illustrated by taking a more advanced, quantum mechanical approach to modelling the molecule and its orbitals. This will also allow prediction of which C=C reacts with an electrophile.
Of the two alekenes, the endo is favoured rather than the exo because the cl-c sigma star orbital mixes with the exo alkene. This stabilises both orbitals, as shown by the frequency calculation having a higher value than the endo alkene, but reduces the pi bond character of the exo alkene. This is also shown by the comparative lengths of the alkene bonds - the exo is 1.3355A and the endo is 1.33190A. The cycloaddition of the carbene requires an alkene and so favours the endo alkene as it has a higher p character. The homo is also focused entirely on the endo side of the molecule, with the lumo focused mainly on the exo side. The Homo shows the high pi bond character of the endo alkene. The Homo-1 is mainly focused ont he exo alekene, so shows the pi bond character of the exo alekene. This is lower in energy and so is less likely to react with the carbene molecule.

====Glycosidation====

=====Mechanisms=====

[[file:Ohbglymech.gif|800px]]

{|class="wikitable" border="2"
!rowspan="5" |Initial molecule
!colspan="2" | Conformation
|1
|2
|3
|4
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2amm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 11.5430
| 46.2672
| 35.5277
| 29.5144
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -90.51343
| -70.57703
| -72.56010
| -85.04737
|-
!rowspan="5" |Intermediate
!colspan="2" | Conformation
|chemdraw
|chemdraw
|chemdraw
|chemdraw
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2Bmm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 28.4913
| 43.2706
| 41.0918
| 31.8763
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -91.66112
| -66.72331
| -84.44899
| -88.08089

|-
|}

==Comparison of coumpational results to a molecule from literature.==

Computational chemistry can be a powerful tool in the analysis and reproduction of spectra. in this exercise, literature values and spectra are compared to computed data and the effectiveness and accuracy of both methods is compared and contrasted.
In the synthesis of molecule A (right), using Kobayashi aldol chemistry, two stereoisomers are produced. Initially, the syn isomer is formed, with a diasteromic ratio of 1:14, and via a similar synthetic route, the anti isomer is also produced, with a high dr of 1:>50. The high stereoselectivity of both of these reactions is an important step in the synthesis of enationmerically pure natural products.
Initiallyu the models were optimised using an MM2 optimisation within ChemBio 12.0. They were then further optimised using an RB3LYP-6-31G(d,p) method and basis set. After the optimisation, and checking to see that the the two molecules were still distinct, with one syn and one anti form, they were submitted for nmr analysis, to produce a predicted nmr. This was then compared with the reported nmr, with a view to see if the assignments and conclusions made in the literature were correct. There was a good correlations between the predicted and measured nmr peaks, with deviations, as show below, of less than 1ppm for the H nmr and less than 10ppm for the <sup>13</sup>C nmr.
[[File:Ohbccomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each carbon atom]]
[[File:Ohbhcomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each Hydrogen atom]]

This correlation helps confirm that the structures are correct; the different enantiomers are differentiated and assigned correctly. If they were not, and the calculated syn nmr is compared to the measured anti nmr, and vice versa, larger differences are noted. This is highlighted on the graph below. The blue and red graphs are the correctly assigned and matched nmrs, the green and purple nmrs are if they are assigned incorrectly. It can clearly be seen that the green and purple line are consistently higher than their counterparts.
[[file:Ohbcomparisonnmr.png|thumb|900px|none|left|Comparison of correct and incorrect assignment for the two conformers]]
Within the literature all of the hydrogens and carbons are assigned, with the exception of Hydrogen 48. This is because this is a labile proton and so does not show up on measured nmrs due to rapid exchange with the deuterium in the deuterated solvent. However the calculated spectra does not take this into account and so displays the shift value for this hydrogen.

The computed IR spectra are very similar for the two molecules. The OH stretch is increased by 30cm<sup>-1</sup> in the syn form of the molecule and the CH bend region between 1000-1500cm<sup>-1</sup> is also significantly different. This acsn be rationalised by the different atomic orbital overlaps that are occuring due to the different positioning of the methyl group.

As both molecules are chiral, they both rotate light in opposite directions. However due to the large size of this molecule and although it is relatively conformationally limited due to the double bond and ring, the calculation for the syn and anti variants did not converge after 48 a 48 hour run on the SCAN.

==References==
<references></references>

Rep:Mod:benton2

2013-02-08T13:03:24Z

Ohb09: /* MOs */

=Module 1 - Intro=
In this experiment, MM2 is compared to the more advanced MOPAC minimisation technique. A minimised molecule is then analysed and compared to literature.
Molecular mechanics, used here in its MM2 form is a very good first order approximation. Using data from previous experiments and breaking down the overall energy into different categories, such as van der Waals interaction, dipole-dipole, and bending before summing them to provide an overall energy is a very useful and more importantly quick method to calculate a molecules energy. The energy of molecule can then be iteratively reduced by tweaking the position of the atoms and conformations, providing a low energy structure. However it does have its limitations. Firstly, because of the large approximations used, the method is liable to fall, and remain, in an initial, smaller, potential well at a higher energy than the minimum possible. This can be overcome by carefully arranging the molecule by the user of the program to avoid these early, high energy minima, but requires a lot of rearrangement and prioir knowledge of low energy arrangements. As MM2 uses previously aquired data, it is also not that useful in determining new structures, or functional groups for which it does not have the data for.
MOPAC uses a different approach for minimisation. It uses semi empirical quantum chemistry functions to determine the energy of a molecule. This allows more advanced effects to be included in the calculation and allows for analysis of the neighbouring group effect in sacchardie chemistry and regioselectivity effects, as studied here.
Computational chemistry can also predict spectra, and in the last part of the experiment predicted spectra are compared to literature and the results analysed.

==Week 1==

===Hydrogenation of the Cyclopentadiene Dimer===
The endo dimer is primarily produced when cyclopentadiene dimerises, in a ratio of 99.5% to 0.5% <ref>
Małgorzata E Jamróz, Sławomir Gałka, Jan Cz Dobrowolski,
On dicyclopentadiene isomers,
Journal of Molecular Structure: THEOCHEM,
Volume 634, Issues 1–3, 5 September 2003,
Pages 225-233, ISSN 0166-1280,
<DOI|10.1016/S0166-1280(03)00348-8>
</ref>(at least when thermally initiated; photo initiation produces a racemic mixture of the two isomers<ref>
The Photosensitited Dimerization of Cyclopentadiene
Nicholas J. Turro and George S. Hammond
Journal of the American Chemical Society 1962 84 (14), 2841-2842
<DOI|10.1021/ja00873a050>
</ref>)
{| class="wikitable" border="1"

! rowspan="2" | Molecule
|style="text-align: center;" |Exo
|style="text-align: center;" |Endo
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbexodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Total E (kcal/mol)
|33.9975
|31.8764
|-
|}
[[file:Endoexoohb.bmp|thumb|left|500px]]
The small energy difference calculated by the MM2 forcefield does not highlight why the endo for is favoured over the exo form as it shows the exo form is lower in energy. While the difference between the two energies is relatively trivial, the high enationmeric excess of the products suggest that this is only part of the story, and suggest that this reaction is under kinetic rather than thermodynamic control.<ref> W.C.Herndon, C.R.Grayson, J.M.Manion; "Retro-Diels-Alder reactions. III. Kinetics of the thermal decompositions of exo- and endo-dicyclopentadiene" J. Org. Chem.; 1967, 32 (3); 526-529.DOI:10.1021/jo01278a003</ref> Being under kinetic control would imply the activation energy, and hence transition state, for the endo species is lower than the exo form and so the endo enantiomer is formed faster. This can be rationalised by looking at the orbital interactions in the two transition states.

The endo transition state is stabilised by the secondary favourable overlap whereas in the exo form there is no such overlap to stabilised the molecule meaning that the transition state is a higher energy, and so is less favourable. This cannot be handled by the simple MM2 calculation however.

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" colspan="2" |Different hydrogenation sites
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh3.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh4.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|1.2489
|1.1303
|-
!Bend
|19.1608
|13.10259
|-
!Torsion
|11.0730
|12.4118
|-
!VDW
|5.7962
|4.4398
|-
!Dipole-Dipole
|0.1622
|0.1410
|-
!Total E (kcal/mol)
|34.9643
|29.2475
|-
|}

The site of initial hydrogenation of the endo dimer can also be determined by calculating the energies of the two possible isomers. From these calculations it is clear that the second molecule is favoured more, as it is ~5.5kcalmol<sup>-1</sup> more stable. The bending energy in both of these molecules is the major difference. This manifests itself in the amount that the atoms are ebent away from their ideal positions, which is 109.5 for an sp3 carbon and 120 for an sp2 carbon. Across all of the key bonds, the second isomer has bond angles that are closer to the ideal than the first isomer; in particular the C-C=C bond angles; in the first molecule they are 107.6 and in the second 112.8. This difference of five degrees is enough to significantly stabilise the second isomer, making hydrogenation at that site the more preferable.

===Atropisomerism in an Intermediate related to the synthesis of Taxol===
In the complete synthesis of Taxol, and important cancer fighting drug, proposed by Pacquette <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 10.1016/S0040-4039(00)92617-0</ref> a key intermediate is either "Precursor 9" or "Precursor 10".

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" |Precursor 10
|style="text-align: center;" |Precursor 9
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol9.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol10.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|2.4687
|2.7846
|-
!Bend
|10.5555
|16.5411
|-
!Torsion
|17.4240
|18.2518
|-
!VDW
|13.1930
|13.1096
|-
!Dipole-Dipole
| -1.8818
| -1.7248
|-
!Total E (kcal/mol)
|39.1215
|47.8395
|-
|}
Precursor 9 and 10 are synthesised using a reversible oxy-Cope rearrangement as demonstrated below. As this process is in equilibrium that, with precursor 10 being more stable, it is predicted that this isomer will be the one produced as all of the molecules attempt to reduce the energy. As analysis of the individual energy componenets shows, this arrangement is a lot less strained than Precursor nine, which requires a lot more bending energy.

The molecule was then optimised with an MMFF94. Rather than rely on a large set of experimentally determined parameters like MM2, MMFF94 minimises the potential of each atom iteratively, attempting to minimise the whole molecule. Although the values produced for these two methods cannot be directly compared, they both correctly identify the correct altropisomer as being lower in energy.
{|class="wikitable" border="1"
! colspan="3" | Comparison of MMFF94 and MM2 minimisations
|-
!Molecule
| Precursor 9
| Precursor 10
|-
!MM2 minimised Energy (kJmol<sup><-1</sup>)
|39.1215
|47.8395
|-
!MMFF94 minimised Energy (kcalmol<sup><-1</sup>)
|58.7513
|70.5377
|-
|}

===Regioselective Addition of Dichlorocarbene to a diene===
Molecule A was initially optimised using a molecular mechanics (MM2) calculation

{| style="wikitable" border="1"
|<jmol>
<jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
It was then further optimised with a MOPAC calculation, which takes into effect stereoelectronic effects. The two were then compared.

{| class="wikitable" border="1"
!colspan="3" | Comparison of two optimisation calculations
|-
! Overlay of two optimised molecules !! MM2 optimised molecule !! MOPAC Optimised Molecule
|-
|[[file:Ohboverlaydiene.png|300px]]
The MM2 optimised molecule is coloured yellow for clarity
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1mopac.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! rowspan="6" | Distances between
corresponding atoms

on the overlaid molecules (Å)
|style="text-align: center;" | C(34)-C(9)
|0.5247
|-
|style="text-align: center;" | C(26)-C(1)
|0.5246
|-
|style="text-align: center;" | H(47)-H(22)
|0.8526
|-
|style="text-align: center;" | H(38)-H(13)
|0.8524
|-
|style="text-align: center;" | Cl(37)-Cl(12)
|0.0689
|}

As can be seen by the comparison above, when using the stereoelectronic interactions, the cyclohexadiene ring on the side with the Cl atom is moved further away from the Cl using the MOPAC calculation than the MM2. This is because the electronic effects included in this calculation include the repulsion between the electron rich Chlorine atom and the electron rich double bond, whereas the MM2 calculation doesn't include this and so a symmetrical molecule is formed.

====MOs====

The MOs of the previously MOPAC optimised molecule where then calculated using Guassian (B3LYP 6-31G)
{| style="wikitable" border="1"
! Homo-1 !! colspan="2" | Homo
|-
|[[File:Ohbclhomo-1.jpg|250px]]
| <jmol>
<jmolApplet>
<title>Orbital</title><color>white</color><size>250</size>
<script>isosurface color orange purple "images/f/f2/Ohbdienemo48.cub.jvxl" translucent; </script>
<uploadedFileContents>Ohbdienemo48.cub.xyz</uploadedFileContents>
</jmolApplet>
</jmol>
|[[File:Ohbclhomo.jpg|250px]]
|-
!Lumo !! Lumo+1 !! Lumo+2
|-
|[[File:Ohbcllumo.jpg|250px]]
|[[File:Ohbcllumo+1.jpg|250px]]
|[[File:Ohbcllumo+2.jpg|250px]]
|-
|colspan="2" | [[File:Ohbclmep.jpg|300px rotate="90"]]
| [[File:Ohbclelevels.png|250px]]
|}

Molecule 2 was initially minimised using an MM2 calculation. The reactions of molecule A with an electrophile can be illustrated by taking a more advanced, quantum mechanical approach to modelling the molecule and its orbitals. This will also allow prediction of which C=C reacts with an electrophile.
Of the two alekenes, the endo is favoured rather than the exo because the cl-c sigma star orbital mixes with the exo alkene. This stabilises both orbitals, as shown by the frequency calculation having a higher value than the endo alkene, but reduces the pi bond character of the exo alkene. This is also shown by the comparative lengths of the alkene bonds - the exo is 1.3355A and the endo is 1.33190A. The cycloaddition of the carbene requires an alkene and so favours the endo alkene as it has a higher p character. The homo is also focused entirely on the endo side of the molecule, with the lumo focused mainly on the exo side. The Homo shows the high pi bond character of the endo alkene. The Homo-1 is mainly focused ont he exo alekene, so shows the pi bond character of the exo alekene. This is lower in energy and so is less likely to react with the carbene molecule.

====Glycosidation====

=====Mechanisms=====

[[file:Ohbglymech.gif|800px]]

{|class="wikitable" border="2"
!rowspan="5" |Initial molecule
!colspan="2" | Conformation
|1
|2
|3
|4
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2amm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 11.5430
| 35.5277
| 29.5144
| 46.2672
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -90.51343
| -72.56010
| -85.04737
| -70.57703
|-
!rowspan="5" |Intermediate
!colspan="2" | Conformation
|chemdraw
|chemdraw
|chemdraw
|chemdraw
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2Bmm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 28.4913
| 43.2706
| 41.0918
| 31.8763
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -91.66112
| -66.72331
| -88.08089
| -84.44899

|-
|}

==Comparison of coumpational results to a molecule from literature.==

Computational chemistry can be a powerful tool in the analysis and reproduction of spectra. in this exercise, literature values and spectra are compared to computed data and the effectiveness and accuracy of both methods is compared and contrasted.
In the synthesis of molecule A (right), using Kobayashi aldol chemistry, two stereoisomers are produced. Initially, the syn isomer is formed, with a diasteromic ratio of 1:14, and via a similar synthetic route, the anti isomer is also produced, with a high dr of 1:>50. The high stereoselectivity of both of these reactions is an important step in the synthesis of enationmerically pure natural products.
Initiallyu the models were optimised using an MM2 optimisation within ChemBio 12.0. They were then further optimised using an RB3LYP-6-31G(d,p) method and basis set. After the optimisation, and checking to see that the the two molecules were still distinct, with one syn and one anti form, they were submitted for nmr analysis, to produce a predicted nmr. This was then compared with the reported nmr, with a view to see if the assignments and conclusions made in the literature were correct. There was a good correlations between the predicted and measured nmr peaks, with deviations, as show below, of less than 1ppm for the H nmr and less than 10ppm for the <sup>13</sup>C nmr.
[[File:Ohbccomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each carbon atom]]
[[File:Ohbhcomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each Hydrogen atom]]

This correlation helps confirm that the structures are correct; the different enantiomers are differentiated and assigned correctly. If they were not, and the calculated syn nmr is compared to the measured anti nmr, and vice versa, larger differences are noted. This is highlighted on the graph below. The blue and red graphs are the correctly assigned and matched nmrs, the green and purple nmrs are if they are assigned incorrectly. It can clearly be seen that the green and purple line are consistently higher than their counterparts.
[[file:Ohbcomparisonnmr.png|thumb|900px|none|left|Comparison of correct and incorrect assignment for the two conformers]]
Within the literature all of the hydrogens and carbons are assigned, with the exception of Hydrogen 48. This is because this is a labile proton and so does not show up on measured nmrs due to rapid exchange with the deuterium in the deuterated solvent. However the calculated spectra does not take this into account and so displays the shift value for this hydrogen.

The computed IR spectra are very similar for the two molecules. The OH stretch is increased by 30cm<sup>-1</sup> in the syn form of the molecule and the CH bend region between 1000-1500cm<sup>-1</sup> is also significantly different. This acsn be rationalised by the different atomic orbital overlaps that are occuring due to the different positioning of the methyl group.

As both molecules are chiral, they both rotate light in opposite directions. However due to the large size of this molecule and although it is relatively conformationally limited due to the double bond and ring, the calculation for the syn and anti variants did not converge after 48 a 48 hour run on the SCAN.

==References==
<references></references>

Rep:Mod:benton2

2013-02-08T12:54:14Z

Ohb09: /* Regioselective Addition of Dichlorocarbene to a diene */

=Module 1 - Intro=
In this experiment, MM2 is compared to the more advanced MOPAC minimisation technique. A minimised molecule is then analysed and compared to literature.
Molecular mechanics, used here in its MM2 form is a very good first order approximation. Using data from previous experiments and breaking down the overall energy into different categories, such as van der Waals interaction, dipole-dipole, and bending before summing them to provide an overall energy is a very useful and more importantly quick method to calculate a molecules energy. The energy of molecule can then be iteratively reduced by tweaking the position of the atoms and conformations, providing a low energy structure. However it does have its limitations. Firstly, because of the large approximations used, the method is liable to fall, and remain, in an initial, smaller, potential well at a higher energy than the minimum possible. This can be overcome by carefully arranging the molecule by the user of the program to avoid these early, high energy minima, but requires a lot of rearrangement and prioir knowledge of low energy arrangements. As MM2 uses previously aquired data, it is also not that useful in determining new structures, or functional groups for which it does not have the data for.
MOPAC uses a different approach for minimisation. It uses semi empirical quantum chemistry functions to determine the energy of a molecule. This allows more advanced effects to be included in the calculation and allows for analysis of the neighbouring group effect in sacchardie chemistry and regioselectivity effects, as studied here.
Computational chemistry can also predict spectra, and in the last part of the experiment predicted spectra are compared to literature and the results analysed.

==Week 1==

===Hydrogenation of the Cyclopentadiene Dimer===
The endo dimer is primarily produced when cyclopentadiene dimerises, in a ratio of 99.5% to 0.5% <ref>
Małgorzata E Jamróz, Sławomir Gałka, Jan Cz Dobrowolski,
On dicyclopentadiene isomers,
Journal of Molecular Structure: THEOCHEM,
Volume 634, Issues 1–3, 5 September 2003,
Pages 225-233, ISSN 0166-1280,
<DOI|10.1016/S0166-1280(03)00348-8>
</ref>(at least when thermally initiated; photo initiation produces a racemic mixture of the two isomers<ref>
The Photosensitited Dimerization of Cyclopentadiene
Nicholas J. Turro and George S. Hammond
Journal of the American Chemical Society 1962 84 (14), 2841-2842
<DOI|10.1021/ja00873a050>
</ref>)
{| class="wikitable" border="1"

! rowspan="2" | Molecule
|style="text-align: center;" |Exo
|style="text-align: center;" |Endo
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbexodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Total E (kcal/mol)
|33.9975
|31.8764
|-
|}
[[file:Endoexoohb.bmp|thumb|left|500px]]
The small energy difference calculated by the MM2 forcefield does not highlight why the endo for is favoured over the exo form as it shows the exo form is lower in energy. While the difference between the two energies is relatively trivial, the high enationmeric excess of the products suggest that this is only part of the story, and suggest that this reaction is under kinetic rather than thermodynamic control.<ref> W.C.Herndon, C.R.Grayson, J.M.Manion; "Retro-Diels-Alder reactions. III. Kinetics of the thermal decompositions of exo- and endo-dicyclopentadiene" J. Org. Chem.; 1967, 32 (3); 526-529.DOI:10.1021/jo01278a003</ref> Being under kinetic control would imply the activation energy, and hence transition state, for the endo species is lower than the exo form and so the endo enantiomer is formed faster. This can be rationalised by looking at the orbital interactions in the two transition states.

The endo transition state is stabilised by the secondary favourable overlap whereas in the exo form there is no such overlap to stabilised the molecule meaning that the transition state is a higher energy, and so is less favourable. This cannot be handled by the simple MM2 calculation however.

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" colspan="2" |Different hydrogenation sites
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh3.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh4.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|1.2489
|1.1303
|-
!Bend
|19.1608
|13.10259
|-
!Torsion
|11.0730
|12.4118
|-
!VDW
|5.7962
|4.4398
|-
!Dipole-Dipole
|0.1622
|0.1410
|-
!Total E (kcal/mol)
|34.9643
|29.2475
|-
|}

The site of initial hydrogenation of the endo dimer can also be determined by calculating the energies of the two possible isomers. From these calculations it is clear that the second molecule is favoured more, as it is ~5.5kcalmol<sup>-1</sup> more stable. The bending energy in both of these molecules is the major difference. This manifests itself in the amount that the atoms are ebent away from their ideal positions, which is 109.5 for an sp3 carbon and 120 for an sp2 carbon. Across all of the key bonds, the second isomer has bond angles that are closer to the ideal than the first isomer; in particular the C-C=C bond angles; in the first molecule they are 107.6 and in the second 112.8. This difference of five degrees is enough to significantly stabilise the second isomer, making hydrogenation at that site the more preferable.

===Atropisomerism in an Intermediate related to the synthesis of Taxol===
In the complete synthesis of Taxol, and important cancer fighting drug, proposed by Pacquette <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 10.1016/S0040-4039(00)92617-0</ref> a key intermediate is either "Precursor 9" or "Precursor 10".

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" |Precursor 10
|style="text-align: center;" |Precursor 9
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol9.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol10.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|2.4687
|2.7846
|-
!Bend
|10.5555
|16.5411
|-
!Torsion
|17.4240
|18.2518
|-
!VDW
|13.1930
|13.1096
|-
!Dipole-Dipole
| -1.8818
| -1.7248
|-
!Total E (kcal/mol)
|39.1215
|47.8395
|-
|}
Precursor 9 and 10 are synthesised using a reversible oxy-Cope rearrangement as demonstrated below. As this process is in equilibrium that, with precursor 10 being more stable, it is predicted that this isomer will be the one produced as all of the molecules attempt to reduce the energy. As analysis of the individual energy componenets shows, this arrangement is a lot less strained than Precursor nine, which requires a lot more bending energy.

The molecule was then optimised with an MMFF94. Rather than rely on a large set of experimentally determined parameters like MM2, MMFF94 minimises the potential of each atom iteratively, attempting to minimise the whole molecule. Although the values produced for these two methods cannot be directly compared, they both correctly identify the correct altropisomer as being lower in energy.
{|class="wikitable" border="1"
! colspan="3" | Comparison of MMFF94 and MM2 minimisations
|-
!Molecule
| Precursor 9
| Precursor 10
|-
!MM2 minimised Energy (kJmol<sup><-1</sup>)
|39.1215
|47.8395
|-
!MMFF94 minimised Energy (kcalmol<sup><-1</sup>)
|58.7513
|70.5377
|-
|}

===Regioselective Addition of Dichlorocarbene to a diene===
Molecule A was initially optimised using a molecular mechanics (MM2) calculation

{| style="wikitable" border="1"
|<jmol>
<jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
It was then further optimised with a MOPAC calculation, which takes into effect stereoelectronic effects. The two were then compared.

{| class="wikitable" border="1"
!colspan="3" | Comparison of two optimisation calculations
|-
! Overlay of two optimised molecules !! MM2 optimised molecule !! MOPAC Optimised Molecule
|-
|[[file:Ohboverlaydiene.png|300px]]
The MM2 optimised molecule is coloured yellow for clarity
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1mopac.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! rowspan="6" | Distances between
corresponding atoms

on the overlaid molecules (Å)
|style="text-align: center;" | C(34)-C(9)
|0.5247
|-
|style="text-align: center;" | C(26)-C(1)
|0.5246
|-
|style="text-align: center;" | H(47)-H(22)
|0.8526
|-
|style="text-align: center;" | H(38)-H(13)
|0.8524
|-
|style="text-align: center;" | Cl(37)-Cl(12)
|0.0689
|}

As can be seen by the comparison above, when using the stereoelectronic interactions, the cyclohexadiene ring on the side with the Cl atom is moved further away from the Cl using the MOPAC calculation than the MM2. This is because the electronic effects included in this calculation include the repulsion between the electron rich Chlorine atom and the electron rich double bond, whereas the MM2 calculation doesn't include this and so a symmetrical molecule is formed.

====MOs====

The MOs of the previously MOPAC optimised molecule where then calculated using Guassian (B3LYP 6-31G)
{| style="wikitable" border="1"
! Homo-1 !! colspan="2" | Homo
|-
|[[File:Ohbclhomo-1.jpg|250px]]
| <jmol>
<jmolApplet>
<title>Orbital</title><color>white</color><size>250</size>
<script>isosurface color orange purple "images/f/f2/Ohbdienemo48.cub.jvxl" translucent; </script>
<uploadedFileContents>Ohbdienemo48.cub.xyz</uploadedFileContents>
</jmolApplet>
</jmol>
|[[File:Ohbclhomo.jpg|250px]]
|-
!Lumo !! Lumo+1 !! Lumo+2
|-
|[[File:Ohbcllumo.jpg|250px]]
|[[File:Ohbcllumo+1.jpg|250px]]
|[[File:Ohbcllumo+2.jpg|250px]]
|-
|colspan="2" | [[File:Ohbclmep.jpg|300px rotate="90"]]
| [[File:Ohbclelevels.png|250px]]
|}

Of the two alekenes, the endo is favoured rather than the exo because
the cl-c sigma star orbital mixes with the exo alkene. This stabilises both orbitals, as shown by the frequency calculation having a higher value than the endo alkene, but reduces the pi bond character of the exo alkene. This is also shown by the comparative lengths of the alkene bonds - the exo is 1.3355A and the endo is 1.33190A. The cycloaddition of the carbene requires an alkene and so favours the endo alkene as it has a higher p character.
The homo is also focused entirely on the endo side of the molecule, with the lumo focused mainly on the exo side. The Homo shows the high pi bond character of the endo alkene. The Homo-1 is mainly focused ont he exo alekene, so shows the pi bond character of the exo alekene. This is lower in energy and so is less likely to rteact with the carbene molecule.

====Glycosidation====

=====Mechanisms=====

[[file:Ohbglymech.gif|800px]]

{|class="wikitable" border="2"
!rowspan="5" |Initial molecule
!colspan="2" | Conformation
|1
|2
|3
|4
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2amm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 11.5430
| 35.5277
| 29.5144
| 46.2672
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -90.51343
| -72.56010
| -85.04737
| -70.57703
|-
!rowspan="5" |Intermediate
!colspan="2" | Conformation
|chemdraw
|chemdraw
|chemdraw
|chemdraw
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2Bmm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 28.4913
| 43.2706
| 41.0918
| 31.8763
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -91.66112
| -66.72331
| -88.08089
| -84.44899

|-
|}

==Comparison of coumpational results to a molecule from literature.==

Computational chemistry can be a powerful tool in the analysis and reproduction of spectra. in this exercise, literature values and spectra are compared to computed data and the effectiveness and accuracy of both methods is compared and contrasted.
In the synthesis of molecule A (right), using Kobayashi aldol chemistry, two stereoisomers are produced. Initially, the syn isomer is formed, with a diasteromic ratio of 1:14, and via a similar synthetic route, the anti isomer is also produced, with a high dr of 1:>50. The high stereoselectivity of both of these reactions is an important step in the synthesis of enationmerically pure natural products.
Initiallyu the models were optimised using an MM2 optimisation within ChemBio 12.0. They were then further optimised using an RB3LYP-6-31G(d,p) method and basis set. After the optimisation, and checking to see that the the two molecules were still distinct, with one syn and one anti form, they were submitted for nmr analysis, to produce a predicted nmr. This was then compared with the reported nmr, with a view to see if the assignments and conclusions made in the literature were correct. There was a good correlations between the predicted and measured nmr peaks, with deviations, as show below, of less than 1ppm for the H nmr and less than 10ppm for the <sup>13</sup>C nmr.
[[File:Ohbccomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each carbon atom]]
[[File:Ohbhcomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each Hydrogen atom]]

This correlation helps confirm that the structures are correct; the different enantiomers are differentiated and assigned correctly. If they were not, and the calculated syn nmr is compared to the measured anti nmr, and vice versa, larger differences are noted. This is highlighted on the graph below. The blue and red graphs are the correctly assigned and matched nmrs, the green and purple nmrs are if they are assigned incorrectly. It can clearly be seen that the green and purple line are consistently higher than their counterparts.
[[file:Ohbcomparisonnmr.png|thumb|900px|none|left|Comparison of correct and incorrect assignment for the two conformers]]
Within the literature all of the hydrogens and carbons are assigned, with the exception of Hydrogen 48. This is because this is a labile proton and so does not show up on measured nmrs due to rapid exchange with the deuterium in the deuterated solvent. However the calculated spectra does not take this into account and so displays the shift value for this hydrogen.

The computed IR spectra are very similar for the two molecules. The OH stretch is increased by 30cm<sup>-1</sup> in the syn form of the molecule and the CH bend region between 1000-1500cm<sup>-1</sup> is also significantly different. This acsn be rationalised by the different atomic orbital overlaps that are occuring due to the different positioning of the methyl group.

As both molecules are chiral, they both rotate light in opposite directions. However due to the large size of this molecule and although it is relatively conformationally limited due to the double bond and ring, the calculation for the syn and anti variants did not converge after 48 a 48 hour run on the SCAN.

==References==
<references></references>

Rep:Mod:benton2

2013-02-08T12:52:46Z

Ohb09: /* MOs */

=Module 1 - Intro=
In this experiment, MM2 is compared to the more advanced MOPAC minimisation technique. A minimised molecule is then analysed and compared to literature.
Molecular mechanics, used here in its MM2 form is a very good first order approximation. Using data from previous experiments and breaking down the overall energy into different categories, such as van der Waals interaction, dipole-dipole, and bending before summing them to provide an overall energy is a very useful and more importantly quick method to calculate a molecules energy. The energy of molecule can then be iteratively reduced by tweaking the position of the atoms and conformations, providing a low energy structure. However it does have its limitations. Firstly, because of the large approximations used, the method is liable to fall, and remain, in an initial, smaller, potential well at a higher energy than the minimum possible. This can be overcome by carefully arranging the molecule by the user of the program to avoid these early, high energy minima, but requires a lot of rearrangement and prioir knowledge of low energy arrangements. As MM2 uses previously aquired data, it is also not that useful in determining new structures, or functional groups for which it does not have the data for.
MOPAC uses a different approach for minimisation. It uses semi empirical quantum chemistry functions to determine the energy of a molecule. This allows more advanced effects to be included in the calculation and allows for analysis of the neighbouring group effect in sacchardie chemistry and regioselectivity effects, as studied here.
Computational chemistry can also predict spectra, and in the last part of the experiment predicted spectra are compared to literature and the results analysed.

==Week 1==

===Hydrogenation of the Cyclopentadiene Dimer===
The endo dimer is primarily produced when cyclopentadiene dimerises, in a ratio of 99.5% to 0.5% <ref>
Małgorzata E Jamróz, Sławomir Gałka, Jan Cz Dobrowolski,
On dicyclopentadiene isomers,
Journal of Molecular Structure: THEOCHEM,
Volume 634, Issues 1–3, 5 September 2003,
Pages 225-233, ISSN 0166-1280,
<DOI|10.1016/S0166-1280(03)00348-8>
</ref>(at least when thermally initiated; photo initiation produces a racemic mixture of the two isomers<ref>
The Photosensitited Dimerization of Cyclopentadiene
Nicholas J. Turro and George S. Hammond
Journal of the American Chemical Society 1962 84 (14), 2841-2842
<DOI|10.1021/ja00873a050>
</ref>)
{| class="wikitable" border="1"

! rowspan="2" | Molecule
|style="text-align: center;" |Exo
|style="text-align: center;" |Endo
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbexodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Total E (kcal/mol)
|33.9975
|31.8764
|-
|}
[[file:Endoexoohb.bmp|thumb|left|500px]]
The small energy difference calculated by the MM2 forcefield does not highlight why the endo for is favoured over the exo form as it shows the exo form is lower in energy. While the difference between the two energies is relatively trivial, the high enationmeric excess of the products suggest that this is only part of the story, and suggest that this reaction is under kinetic rather than thermodynamic control.<ref> W.C.Herndon, C.R.Grayson, J.M.Manion; "Retro-Diels-Alder reactions. III. Kinetics of the thermal decompositions of exo- and endo-dicyclopentadiene" J. Org. Chem.; 1967, 32 (3); 526-529.DOI:10.1021/jo01278a003</ref> Being under kinetic control would imply the activation energy, and hence transition state, for the endo species is lower than the exo form and so the endo enantiomer is formed faster. This can be rationalised by looking at the orbital interactions in the two transition states.

The endo transition state is stabilised by the secondary favourable overlap whereas in the exo form there is no such overlap to stabilised the molecule meaning that the transition state is a higher energy, and so is less favourable. This cannot be handled by the simple MM2 calculation however.

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" colspan="2" |Different hydrogenation sites
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh3.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh4.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|1.2489
|1.1303
|-
!Bend
|19.1608
|13.10259
|-
!Torsion
|11.0730
|12.4118
|-
!VDW
|5.7962
|4.4398
|-
!Dipole-Dipole
|0.1622
|0.1410
|-
!Total E (kcal/mol)
|34.9643
|29.2475
|-
|}

The site of initial hydrogenation of the endo dimer can also be determined by calculating the energies of the two possible isomers. From these calculations it is clear that the second molecule is favoured more, as it is ~5.5kcalmol<sup>-1</sup> more stable. The bending energy in both of these molecules is the major difference. This manifests itself in the amount that the atoms are ebent away from their ideal positions, which is 109.5 for an sp3 carbon and 120 for an sp2 carbon. Across all of the key bonds, the second isomer has bond angles that are closer to the ideal than the first isomer; in particular the C-C=C bond angles; in the first molecule they are 107.6 and in the second 112.8. This difference of five degrees is enough to significantly stabilise the second isomer, making hydrogenation at that site the more preferable.

===Atropisomerism in an Intermediate related to the synthesis of Taxol===
In the complete synthesis of Taxol, and important cancer fighting drug, proposed by Pacquette <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 10.1016/S0040-4039(00)92617-0</ref> a key intermediate is either "Precursor 9" or "Precursor 10".

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" |Precursor 10
|style="text-align: center;" |Precursor 9
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol9.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol10.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|2.4687
|2.7846
|-
!Bend
|10.5555
|16.5411
|-
!Torsion
|17.4240
|18.2518
|-
!VDW
|13.1930
|13.1096
|-
!Dipole-Dipole
| -1.8818
| -1.7248
|-
!Total E (kcal/mol)
|39.1215
|47.8395
|-
|}
Precursor 9 and 10 are synthesised using a reversible oxy-Cope rearrangement as demonstrated below. As this process is in equilibrium that, with precursor 10 being more stable, it is predicted that this isomer will be the one produced as all of the molecules attempt to reduce the energy. As analysis of the individual energy componenets shows, this arrangement is a lot less strained than Precursor nine, which requires a lot more bending energy.

The molecule was then optimised with an MMFF94. Rather than rely on a large set of experimentally determined parameters like MM2, MMFF94 minimises the potential of each atom iteratively, attempting to minimise the whole molecule. Although the values produced for these two methods cannot be directly compared, they both correctly identify the correct altropisomer as being lower in energy.
{|class="wikitable" border="1"
! colspan="3" | Comparison of MMFF94 and MM2 minimisations
|-
!Molecule
| Precursor 9
| Precursor 10
|-
!MM2 minimised Energy (kJmol<sup><-1</sup>)
|39.1215
|47.8395
|-
!MMFF94 minimised Energy (kcalmol<sup><-1</sup>)
|58.7513
|70.5377
|-
|}

===Regioselective Addition of Dichlorocarbene to a diene===
Molecule A was initially optimised using a molecular mechanics (MM2) calculation

{| style="wikitable" border="1"
|<jmol>
<jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
It was then further optimised with a MOPAC calculation, which takes into effect stereoelectronic effects. The two were then compared.

{| class="wikitable" border="1"
!colspan="3" | Comparison of two optimisation calculations
|-
! Overlay of two optimised molecules !! MM2 optimised molecule !! MOPAC Optimised Molecule
|-
|[[file:Ohboverlaydiene.png|300px]]
The MM2 optimised molecule is coloured yellow for clarity
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>150</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>150</size>
<script></script>
<uploadedFileContents>Ohbdiene1mopac.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! rowspan="6" | Distances between
corresponding atoms

on the overlaid molecules (Å)
|style="text-align: center;" | C(34)-C(9)
|0.5247
|-
|style="text-align: center;" | C(26)-C(1)
|0.5246
|-
|style="text-align: center;" | H(47)-H(22)
|0.8526
|-
|style="text-align: center;" | H(38)-H(13)
|0.8524
|-
|style="text-align: center;" | Cl(37)-Cl(12)
|0.0689
|}

As can be seen by the comparison above, when using the stereoelectronic interactions, the cyclohexadiene ring on the side with the Cl atom is moved further away from the Cl using the MOPAC calculation than the MM2. This is because the electronic effects included in this calculation include the repulsion between the electron rich Chlorine atom and the electron rich double bond, whereas the MM2 calculation doesn't include this and so a symmetrical molecule is formed.

====MOs====

The MOs of the previously MOPAC optimised molecule where then calculated using Guassian (B3LYP 6-31G)
{| style="wikitable" border="1"
! Homo-1 !! colspan="2" | Homo
|-
|[[File:Ohbclhomo-1.jpg|250px]]
| <jmol>
<jmolApplet>
<title>Orbital</title><color>white</color><size>250</size>
<script>isosurface color orange purple "images/f/f2/Ohbdienemo48.cub.jvxl" translucent; </script>
<uploadedFileContents>Ohbdienemo48.cub.xyz</uploadedFileContents>
</jmolApplet>
</jmol>
|[[File:Ohbclhomo.jpg|250px]]
|-
!Lumo !! Lumo+1 !! Lumo+2
|-
|[[File:Ohbcllumo.jpg|250px]]
|[[File:Ohbcllumo+1.jpg|250px]]
|[[File:Ohbcllumo+2.jpg|250px]]
|-
|colspan="2" | [[File:Ohbclmep.jpg|300px rotate="90"]]
| [[File:Ohbclelevels.png|250px]]
|}

Of the two alekenes, the endo is favoured rather than the exo because
the cl-c sigma star orbital mixes with the exo alkene. This stabilises both orbitals, as shown by the frequency calculation having a higher value than the endo alkene, but reduces the pi bond character of the exo alkene. This is also shown by the comparative lengths of the alkene bonds - the exo is 1.3355A and the endo is 1.33190A. The cycloaddition of the carbene requires an alkene and so favours the endo alkene as it has a higher p character.
The homo is also focused entirely on the endo side of the molecule, with the lumo focused mainly on the exo side. The Homo shows the high pi bond character of the endo alkene. The Homo-1 is mainly focused ont he exo alekene, so shows the pi bond character of the exo alekene. This is lower in energy and so is less likely to rteact with the carbene molecule.

====Glycosidation====

=====Mechanisms=====

[[file:Ohbglymech.gif|800px]]

{|class="wikitable" border="2"
!rowspan="5" |Initial molecule
!colspan="2" | Conformation
|1
|2
|3
|4
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2amm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 11.5430
| 35.5277
| 29.5144
| 46.2672
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -90.51343
| -72.56010
| -85.04737
| -70.57703
|-
!rowspan="5" |Intermediate
!colspan="2" | Conformation
|chemdraw
|chemdraw
|chemdraw
|chemdraw
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2Bmm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 28.4913
| 43.2706
| 41.0918
| 31.8763
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -91.66112
| -66.72331
| -88.08089
| -84.44899

|-
|}

==Comparison of coumpational results to a molecule from literature.==

Computational chemistry can be a powerful tool in the analysis and reproduction of spectra. in this exercise, literature values and spectra are compared to computed data and the effectiveness and accuracy of both methods is compared and contrasted.
In the synthesis of molecule A (right), using Kobayashi aldol chemistry, two stereoisomers are produced. Initially, the syn isomer is formed, with a diasteromic ratio of 1:14, and via a similar synthetic route, the anti isomer is also produced, with a high dr of 1:>50. The high stereoselectivity of both of these reactions is an important step in the synthesis of enationmerically pure natural products.
Initiallyu the models were optimised using an MM2 optimisation within ChemBio 12.0. They were then further optimised using an RB3LYP-6-31G(d,p) method and basis set. After the optimisation, and checking to see that the the two molecules were still distinct, with one syn and one anti form, they were submitted for nmr analysis, to produce a predicted nmr. This was then compared with the reported nmr, with a view to see if the assignments and conclusions made in the literature were correct. There was a good correlations between the predicted and measured nmr peaks, with deviations, as show below, of less than 1ppm for the H nmr and less than 10ppm for the <sup>13</sup>C nmr.
[[File:Ohbccomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each carbon atom]]
[[File:Ohbhcomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each Hydrogen atom]]

This correlation helps confirm that the structures are correct; the different enantiomers are differentiated and assigned correctly. If they were not, and the calculated syn nmr is compared to the measured anti nmr, and vice versa, larger differences are noted. This is highlighted on the graph below. The blue and red graphs are the correctly assigned and matched nmrs, the green and purple nmrs are if they are assigned incorrectly. It can clearly be seen that the green and purple line are consistently higher than their counterparts.
[[file:Ohbcomparisonnmr.png|thumb|900px|none|left|Comparison of correct and incorrect assignment for the two conformers]]
Within the literature all of the hydrogens and carbons are assigned, with the exception of Hydrogen 48. This is because this is a labile proton and so does not show up on measured nmrs due to rapid exchange with the deuterium in the deuterated solvent. However the calculated spectra does not take this into account and so displays the shift value for this hydrogen.

The computed IR spectra are very similar for the two molecules. The OH stretch is increased by 30cm<sup>-1</sup> in the syn form of the molecule and the CH bend region between 1000-1500cm<sup>-1</sup> is also significantly different. This acsn be rationalised by the different atomic orbital overlaps that are occuring due to the different positioning of the methyl group.

As both molecules are chiral, they both rotate light in opposite directions. However due to the large size of this molecule and although it is relatively conformationally limited due to the double bond and ring, the calculation for the syn and anti variants did not converge after 48 a 48 hour run on the SCAN.

==References==
<references></references>

Rep:Mod:benton2

2013-02-08T12:50:00Z

Ohb09: /* Atropisomerism in an Intermediate related to the synthesis of Taxol */

=Module 1 - Intro=
In this experiment, MM2 is compared to the more advanced MOPAC minimisation technique. A minimised molecule is then analysed and compared to literature.
Molecular mechanics, used here in its MM2 form is a very good first order approximation. Using data from previous experiments and breaking down the overall energy into different categories, such as van der Waals interaction, dipole-dipole, and bending before summing them to provide an overall energy is a very useful and more importantly quick method to calculate a molecules energy. The energy of molecule can then be iteratively reduced by tweaking the position of the atoms and conformations, providing a low energy structure. However it does have its limitations. Firstly, because of the large approximations used, the method is liable to fall, and remain, in an initial, smaller, potential well at a higher energy than the minimum possible. This can be overcome by carefully arranging the molecule by the user of the program to avoid these early, high energy minima, but requires a lot of rearrangement and prioir knowledge of low energy arrangements. As MM2 uses previously aquired data, it is also not that useful in determining new structures, or functional groups for which it does not have the data for.
MOPAC uses a different approach for minimisation. It uses semi empirical quantum chemistry functions to determine the energy of a molecule. This allows more advanced effects to be included in the calculation and allows for analysis of the neighbouring group effect in sacchardie chemistry and regioselectivity effects, as studied here.
Computational chemistry can also predict spectra, and in the last part of the experiment predicted spectra are compared to literature and the results analysed.

==Week 1==

===Hydrogenation of the Cyclopentadiene Dimer===
The endo dimer is primarily produced when cyclopentadiene dimerises, in a ratio of 99.5% to 0.5% <ref>
Małgorzata E Jamróz, Sławomir Gałka, Jan Cz Dobrowolski,
On dicyclopentadiene isomers,
Journal of Molecular Structure: THEOCHEM,
Volume 634, Issues 1–3, 5 September 2003,
Pages 225-233, ISSN 0166-1280,
<DOI|10.1016/S0166-1280(03)00348-8>
</ref>(at least when thermally initiated; photo initiation produces a racemic mixture of the two isomers<ref>
The Photosensitited Dimerization of Cyclopentadiene
Nicholas J. Turro and George S. Hammond
Journal of the American Chemical Society 1962 84 (14), 2841-2842
<DOI|10.1021/ja00873a050>
</ref>)
{| class="wikitable" border="1"

! rowspan="2" | Molecule
|style="text-align: center;" |Exo
|style="text-align: center;" |Endo
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbexodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Total E (kcal/mol)
|33.9975
|31.8764
|-
|}
[[file:Endoexoohb.bmp|thumb|left|500px]]
The small energy difference calculated by the MM2 forcefield does not highlight why the endo for is favoured over the exo form as it shows the exo form is lower in energy. While the difference between the two energies is relatively trivial, the high enationmeric excess of the products suggest that this is only part of the story, and suggest that this reaction is under kinetic rather than thermodynamic control.<ref> W.C.Herndon, C.R.Grayson, J.M.Manion; "Retro-Diels-Alder reactions. III. Kinetics of the thermal decompositions of exo- and endo-dicyclopentadiene" J. Org. Chem.; 1967, 32 (3); 526-529.DOI:10.1021/jo01278a003</ref> Being under kinetic control would imply the activation energy, and hence transition state, for the endo species is lower than the exo form and so the endo enantiomer is formed faster. This can be rationalised by looking at the orbital interactions in the two transition states.

The endo transition state is stabilised by the secondary favourable overlap whereas in the exo form there is no such overlap to stabilised the molecule meaning that the transition state is a higher energy, and so is less favourable. This cannot be handled by the simple MM2 calculation however.

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" colspan="2" |Different hydrogenation sites
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh3.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh4.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|1.2489
|1.1303
|-
!Bend
|19.1608
|13.10259
|-
!Torsion
|11.0730
|12.4118
|-
!VDW
|5.7962
|4.4398
|-
!Dipole-Dipole
|0.1622
|0.1410
|-
!Total E (kcal/mol)
|34.9643
|29.2475
|-
|}

The site of initial hydrogenation of the endo dimer can also be determined by calculating the energies of the two possible isomers. From these calculations it is clear that the second molecule is favoured more, as it is ~5.5kcalmol<sup>-1</sup> more stable. The bending energy in both of these molecules is the major difference. This manifests itself in the amount that the atoms are ebent away from their ideal positions, which is 109.5 for an sp3 carbon and 120 for an sp2 carbon. Across all of the key bonds, the second isomer has bond angles that are closer to the ideal than the first isomer; in particular the C-C=C bond angles; in the first molecule they are 107.6 and in the second 112.8. This difference of five degrees is enough to significantly stabilise the second isomer, making hydrogenation at that site the more preferable.

===Atropisomerism in an Intermediate related to the synthesis of Taxol===
In the complete synthesis of Taxol, and important cancer fighting drug, proposed by Pacquette <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 10.1016/S0040-4039(00)92617-0</ref> a key intermediate is either "Precursor 9" or "Precursor 10".

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" |Precursor 10
|style="text-align: center;" |Precursor 9
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol9.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol10.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|2.4687
|2.7846
|-
!Bend
|10.5555
|16.5411
|-
!Torsion
|17.4240
|18.2518
|-
!VDW
|13.1930
|13.1096
|-
!Dipole-Dipole
| -1.8818
| -1.7248
|-
!Total E (kcal/mol)
|39.1215
|47.8395
|-
|}
Precursor 9 and 10 are synthesised using a reversible oxy-Cope rearrangement as demonstrated below. As this process is in equilibrium that, with precursor 10 being more stable, it is predicted that this isomer will be the one produced as all of the molecules attempt to reduce the energy. As analysis of the individual energy componenets shows, this arrangement is a lot less strained than Precursor nine, which requires a lot more bending energy.

The molecule was then optimised with an MMFF94. Rather than rely on a large set of experimentally determined parameters like MM2, MMFF94 minimises the potential of each atom iteratively, attempting to minimise the whole molecule. Although the values produced for these two methods cannot be directly compared, they both correctly identify the correct altropisomer as being lower in energy.
{|class="wikitable" border="1"
! colspan="3" | Comparison of MMFF94 and MM2 minimisations
|-
!Molecule
| Precursor 9
| Precursor 10
|-
!MM2 minimised Energy (kJmol<sup><-1</sup>)
|39.1215
|47.8395
|-
!MMFF94 minimised Energy (kcalmol<sup><-1</sup>)
|58.7513
|70.5377
|-
|}

===Regioselective Addition of Dichlorocarbene to a diene===
Molecule A was initially optimised using a molecular mechanics (MM2) calculation

{| style="wikitable" border="1"
|<jmol>
<jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
It was then further optimised with a MOPAC calculation, which takes into effect stereoelectronic effects. The two were then compared.

{| class="wikitable" border="1"
!colspan="3" | Comparison of two optimisation calculations
|-
! Overlay of two optimised molecules !! MM2 optimised molecule !! MOPAC Optimised Molecule
|-
|[[file:Ohboverlaydiene.png|300px]]
The MM2 optimised molecule is coloured yellow for clarity
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>150</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>150</size>
<script></script>
<uploadedFileContents>Ohbdiene1mopac.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! rowspan="6" | Distances between
corresponding atoms

on the overlaid molecules (Å)
|style="text-align: center;" | C(34)-C(9)
|0.5247
|-
|style="text-align: center;" | C(26)-C(1)
|0.5246
|-
|style="text-align: center;" | H(47)-H(22)
|0.8526
|-
|style="text-align: center;" | H(38)-H(13)
|0.8524
|-
|style="text-align: center;" | Cl(37)-Cl(12)
|0.0689
|}

As can be seen by the comparison above, when using the stereoelectronic interactions, the cyclohexadiene ring on the side with the Cl atom is moved further away from the Cl using the MOPAC calculation than the MM2. This is because the electronic effects included in this calculation include the repulsion between the electron rich Chlorine atom and the electron rich double bond, whereas the MM2 calculation doesn't include this and so a symmetrical molecule is formed.

====MOs====

The MOs of the previously MOPAC optimised molecule where then calculated using Guassian (B3LYP 6-31G)
{| style="wikitable" border="1"
! Homo-1 !! colspan="2" | Homo
|-
|[[File:Ohbclhomo-1.jpg|250px]]
| <jmol>
<jmolApplet>
<title>Orbital</title><color>white</color><size>250</size>
<script>isosurface color orange purple "images/f/f2/Ohbdienemo48.cub.jvxl" translucent; </script>
<uploadedFileContents>Ohbdienemo48.cub.xyz</uploadedFileContents>
</jmolApplet>
</jmol>
|[[File:Ohbclhomo.jpg|250px]]
|-
!Lumo !! Lumo+1 !! Lumo+2
|-
|[[File:Ohbcllumo.jpg|250px]]
|[[File:Ohbcllumo+1.jpg|250px]]
|[[File:Ohbcllumo+2.jpg|250px]]
|-
|colspan="3" | [[File:Ohbclmep.jpg|300px rotate="90"]]
|}

[[File:Ohbclelevels.png|250px]]

Of the two alekenes, the endo is favoured rather than the exo because
the cl-c sigma star orbital mixes with the exo alkene. This stabilises both orbitals, as shown by the frequency calculation having a higher value than the endo alkene, but reduces the pi bond character of the exo alkene. This is also shown by the comparative lengths of the alkene bonds - the exo is 1.3355A and the endo is 1.33190A. The cycloaddition of the carbene requires an alkene and so favours the endo alkene as it has a higher p character.
The homo is also focused entirely on the endo side of the molecule, with the lumo focused mainly on the exo side. The Homo shows the high pi bond character of the endo alkene. The Homo-1 is mainly focused ont he exo alekene, so shows the pi bond character of the exo alekene. This is lower in energy and so is less likely to rteact with the carbene molecule.

====Glycosidation====

=====Mechanisms=====

[[file:Ohbglymech.gif|800px]]

{|class="wikitable" border="2"
!rowspan="5" |Initial molecule
!colspan="2" | Conformation
|1
|2
|3
|4
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2amm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 11.5430
| 35.5277
| 29.5144
| 46.2672
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -90.51343
| -72.56010
| -85.04737
| -70.57703
|-
!rowspan="5" |Intermediate
!colspan="2" | Conformation
|chemdraw
|chemdraw
|chemdraw
|chemdraw
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2Bmm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 28.4913
| 43.2706
| 41.0918
| 31.8763
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -91.66112
| -66.72331
| -88.08089
| -84.44899

|-
|}

==Comparison of coumpational results to a molecule from literature.==

Computational chemistry can be a powerful tool in the analysis and reproduction of spectra. in this exercise, literature values and spectra are compared to computed data and the effectiveness and accuracy of both methods is compared and contrasted.
In the synthesis of molecule A (right), using Kobayashi aldol chemistry, two stereoisomers are produced. Initially, the syn isomer is formed, with a diasteromic ratio of 1:14, and via a similar synthetic route, the anti isomer is also produced, with a high dr of 1:>50. The high stereoselectivity of both of these reactions is an important step in the synthesis of enationmerically pure natural products.
Initiallyu the models were optimised using an MM2 optimisation within ChemBio 12.0. They were then further optimised using an RB3LYP-6-31G(d,p) method and basis set. After the optimisation, and checking to see that the the two molecules were still distinct, with one syn and one anti form, they were submitted for nmr analysis, to produce a predicted nmr. This was then compared with the reported nmr, with a view to see if the assignments and conclusions made in the literature were correct. There was a good correlations between the predicted and measured nmr peaks, with deviations, as show below, of less than 1ppm for the H nmr and less than 10ppm for the <sup>13</sup>C nmr.
[[File:Ohbccomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each carbon atom]]
[[File:Ohbhcomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each Hydrogen atom]]

This correlation helps confirm that the structures are correct; the different enantiomers are differentiated and assigned correctly. If they were not, and the calculated syn nmr is compared to the measured anti nmr, and vice versa, larger differences are noted. This is highlighted on the graph below. The blue and red graphs are the correctly assigned and matched nmrs, the green and purple nmrs are if they are assigned incorrectly. It can clearly be seen that the green and purple line are consistently higher than their counterparts.
[[file:Ohbcomparisonnmr.png|thumb|900px|none|left|Comparison of correct and incorrect assignment for the two conformers]]
Within the literature all of the hydrogens and carbons are assigned, with the exception of Hydrogen 48. This is because this is a labile proton and so does not show up on measured nmrs due to rapid exchange with the deuterium in the deuterated solvent. However the calculated spectra does not take this into account and so displays the shift value for this hydrogen.

The computed IR spectra are very similar for the two molecules. The OH stretch is increased by 30cm<sup>-1</sup> in the syn form of the molecule and the CH bend region between 1000-1500cm<sup>-1</sup> is also significantly different. This acsn be rationalised by the different atomic orbital overlaps that are occuring due to the different positioning of the methyl group.

As both molecules are chiral, they both rotate light in opposite directions. However due to the large size of this molecule and although it is relatively conformationally limited due to the double bond and ring, the calculation for the syn and anti variants did not converge after 48 a 48 hour run on the SCAN.

==References==
<references></references>

Rep:Mod:benton2

2013-02-08T12:49:37Z

Ohb09: /* Hydrogenation of the Cyclopentadiene Dimer */

=Module 1 - Intro=
In this experiment, MM2 is compared to the more advanced MOPAC minimisation technique. A minimised molecule is then analysed and compared to literature.
Molecular mechanics, used here in its MM2 form is a very good first order approximation. Using data from previous experiments and breaking down the overall energy into different categories, such as van der Waals interaction, dipole-dipole, and bending before summing them to provide an overall energy is a very useful and more importantly quick method to calculate a molecules energy. The energy of molecule can then be iteratively reduced by tweaking the position of the atoms and conformations, providing a low energy structure. However it does have its limitations. Firstly, because of the large approximations used, the method is liable to fall, and remain, in an initial, smaller, potential well at a higher energy than the minimum possible. This can be overcome by carefully arranging the molecule by the user of the program to avoid these early, high energy minima, but requires a lot of rearrangement and prioir knowledge of low energy arrangements. As MM2 uses previously aquired data, it is also not that useful in determining new structures, or functional groups for which it does not have the data for.
MOPAC uses a different approach for minimisation. It uses semi empirical quantum chemistry functions to determine the energy of a molecule. This allows more advanced effects to be included in the calculation and allows for analysis of the neighbouring group effect in sacchardie chemistry and regioselectivity effects, as studied here.
Computational chemistry can also predict spectra, and in the last part of the experiment predicted spectra are compared to literature and the results analysed.

==Week 1==

===Hydrogenation of the Cyclopentadiene Dimer===
The endo dimer is primarily produced when cyclopentadiene dimerises, in a ratio of 99.5% to 0.5% <ref>
Małgorzata E Jamróz, Sławomir Gałka, Jan Cz Dobrowolski,
On dicyclopentadiene isomers,
Journal of Molecular Structure: THEOCHEM,
Volume 634, Issues 1–3, 5 September 2003,
Pages 225-233, ISSN 0166-1280,
<DOI|10.1016/S0166-1280(03)00348-8>
</ref>(at least when thermally initiated; photo initiation produces a racemic mixture of the two isomers<ref>
The Photosensitited Dimerization of Cyclopentadiene
Nicholas J. Turro and George S. Hammond
Journal of the American Chemical Society 1962 84 (14), 2841-2842
<DOI|10.1021/ja00873a050>
</ref>)
{| class="wikitable" border="1"

! rowspan="2" | Molecule
|style="text-align: center;" |Exo
|style="text-align: center;" |Endo
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbexodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Total E (kcal/mol)
|33.9975
|31.8764
|-
|}
[[file:Endoexoohb.bmp|thumb|left|500px]]
The small energy difference calculated by the MM2 forcefield does not highlight why the endo for is favoured over the exo form as it shows the exo form is lower in energy. While the difference between the two energies is relatively trivial, the high enationmeric excess of the products suggest that this is only part of the story, and suggest that this reaction is under kinetic rather than thermodynamic control.<ref> W.C.Herndon, C.R.Grayson, J.M.Manion; "Retro-Diels-Alder reactions. III. Kinetics of the thermal decompositions of exo- and endo-dicyclopentadiene" J. Org. Chem.; 1967, 32 (3); 526-529.DOI:10.1021/jo01278a003</ref> Being under kinetic control would imply the activation energy, and hence transition state, for the endo species is lower than the exo form and so the endo enantiomer is formed faster. This can be rationalised by looking at the orbital interactions in the two transition states.

The endo transition state is stabilised by the secondary favourable overlap whereas in the exo form there is no such overlap to stabilised the molecule meaning that the transition state is a higher energy, and so is less favourable. This cannot be handled by the simple MM2 calculation however.

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" colspan="2" |Different hydrogenation sites
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh3.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh4.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|1.2489
|1.1303
|-
!Bend
|19.1608
|13.10259
|-
!Torsion
|11.0730
|12.4118
|-
!VDW
|5.7962
|4.4398
|-
!Dipole-Dipole
|0.1622
|0.1410
|-
!Total E (kcal/mol)
|34.9643
|29.2475
|-
|}

The site of initial hydrogenation of the endo dimer can also be determined by calculating the energies of the two possible isomers. From these calculations it is clear that the second molecule is favoured more, as it is ~5.5kcalmol<sup>-1</sup> more stable. The bending energy in both of these molecules is the major difference. This manifests itself in the amount that the atoms are ebent away from their ideal positions, which is 109.5 for an sp3 carbon and 120 for an sp2 carbon. Across all of the key bonds, the second isomer has bond angles that are closer to the ideal than the first isomer; in particular the C-C=C bond angles; in the first molecule they are 107.6 and in the second 112.8. This difference of five degrees is enough to significantly stabilise the second isomer, making hydrogenation at that site the more preferable.

===Atropisomerism in an Intermediate related to the synthesis of Taxol===
In the complete synthesis of Taxol, and important cancer fighting drug, proposed by Pacquette <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 10.1016/S0040-4039(00)92617-0</ref> a key intermediate is either "Precursor 9" or "Precursor 10".

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" |Precursor 10
|style="text-align: center;" |Precursor 9
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol9.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol10.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|2.4687
|2.7846
|-
!Bend
|10.5555
|16.5411
|-
!Torsion
|17.4240
|18.2518
|-
!VDW
|13.1930
|13.1096
|-
!Dipole-Dipole
| -1.8818
| -1.7248
|-
!Total E (kcal/mol)
|39.1215
|47.8395
|-
|}
Precursor 9 and 10 are synthesised using a reversible oxy-Cope rearrangement as demonstrated below. As this process is in equilibrium that, with precursor 10 being more stable, it is predicted that this isomer will be the one produced as all of the molecules attempt to reduce the energy. As analysis of the individual energy componenets shows, this arrangement is a lot less strained than Precursor nine, which requires a lot more bending energy.

The molecule was then optimised with an MMFF94. Rather than rely ona large set of experimentally determined parameters like MM2, MMFF94 minimises the potential of each atom iteratively, attempting to minimise the whole molecule. Although the values produced for these two methods cannot be directly compared, they both correctly identify the correct altropisomer as being lower in energy.
{|class="wikitable" border="1"
! colspan="3" | Comparison of MMFF94 and MM2 minimisations
|-
!Molecule
| Precursor 9
| Precursor 10
|-
!MM2 minimised Energy (kJmol<sup><-1</sup>)
|39.1215
|47.8395
|-
!MMFF94 minimised Energy (kcalmol<sup><-1</sup>)
|58.7513
|70.5377
|-
|}

===Regioselective Addition of Dichlorocarbene to a diene===
Molecule A was initially optimised using a molecular mechanics (MM2) calculation

{| style="wikitable" border="1"
|<jmol>
<jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
It was then further optimised with a MOPAC calculation, which takes into effect stereoelectronic effects. The two were then compared.

{| class="wikitable" border="1"
!colspan="3" | Comparison of two optimisation calculations
|-
! Overlay of two optimised molecules !! MM2 optimised molecule !! MOPAC Optimised Molecule
|-
|[[file:Ohboverlaydiene.png|300px]]
The MM2 optimised molecule is coloured yellow for clarity
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>150</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>150</size>
<script></script>
<uploadedFileContents>Ohbdiene1mopac.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! rowspan="6" | Distances between
corresponding atoms

on the overlaid molecules (Å)
|style="text-align: center;" | C(34)-C(9)
|0.5247
|-
|style="text-align: center;" | C(26)-C(1)
|0.5246
|-
|style="text-align: center;" | H(47)-H(22)
|0.8526
|-
|style="text-align: center;" | H(38)-H(13)
|0.8524
|-
|style="text-align: center;" | Cl(37)-Cl(12)
|0.0689
|}

As can be seen by the comparison above, when using the stereoelectronic interactions, the cyclohexadiene ring on the side with the Cl atom is moved further away from the Cl using the MOPAC calculation than the MM2. This is because the electronic effects included in this calculation include the repulsion between the electron rich Chlorine atom and the electron rich double bond, whereas the MM2 calculation doesn't include this and so a symmetrical molecule is formed.

====MOs====

The MOs of the previously MOPAC optimised molecule where then calculated using Guassian (B3LYP 6-31G)
{| style="wikitable" border="1"
! Homo-1 !! colspan="2" | Homo
|-
|[[File:Ohbclhomo-1.jpg|250px]]
| <jmol>
<jmolApplet>
<title>Orbital</title><color>white</color><size>250</size>
<script>isosurface color orange purple "images/f/f2/Ohbdienemo48.cub.jvxl" translucent; </script>
<uploadedFileContents>Ohbdienemo48.cub.xyz</uploadedFileContents>
</jmolApplet>
</jmol>
|[[File:Ohbclhomo.jpg|250px]]
|-
!Lumo !! Lumo+1 !! Lumo+2
|-
|[[File:Ohbcllumo.jpg|250px]]
|[[File:Ohbcllumo+1.jpg|250px]]
|[[File:Ohbcllumo+2.jpg|250px]]
|-
|colspan="3" | [[File:Ohbclmep.jpg|300px rotate="90"]]
|}

[[File:Ohbclelevels.png|250px]]

Of the two alekenes, the endo is favoured rather than the exo because
the cl-c sigma star orbital mixes with the exo alkene. This stabilises both orbitals, as shown by the frequency calculation having a higher value than the endo alkene, but reduces the pi bond character of the exo alkene. This is also shown by the comparative lengths of the alkene bonds - the exo is 1.3355A and the endo is 1.33190A. The cycloaddition of the carbene requires an alkene and so favours the endo alkene as it has a higher p character.
The homo is also focused entirely on the endo side of the molecule, with the lumo focused mainly on the exo side. The Homo shows the high pi bond character of the endo alkene. The Homo-1 is mainly focused ont he exo alekene, so shows the pi bond character of the exo alekene. This is lower in energy and so is less likely to rteact with the carbene molecule.

====Glycosidation====

=====Mechanisms=====

[[file:Ohbglymech.gif|800px]]

{|class="wikitable" border="2"
!rowspan="5" |Initial molecule
!colspan="2" | Conformation
|1
|2
|3
|4
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2amm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 11.5430
| 35.5277
| 29.5144
| 46.2672
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -90.51343
| -72.56010
| -85.04737
| -70.57703
|-
!rowspan="5" |Intermediate
!colspan="2" | Conformation
|chemdraw
|chemdraw
|chemdraw
|chemdraw
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2Bmm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 28.4913
| 43.2706
| 41.0918
| 31.8763
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -91.66112
| -66.72331
| -88.08089
| -84.44899

|-
|}

==Comparison of coumpational results to a molecule from literature.==

Computational chemistry can be a powerful tool in the analysis and reproduction of spectra. in this exercise, literature values and spectra are compared to computed data and the effectiveness and accuracy of both methods is compared and contrasted.
In the synthesis of molecule A (right), using Kobayashi aldol chemistry, two stereoisomers are produced. Initially, the syn isomer is formed, with a diasteromic ratio of 1:14, and via a similar synthetic route, the anti isomer is also produced, with a high dr of 1:>50. The high stereoselectivity of both of these reactions is an important step in the synthesis of enationmerically pure natural products.
Initiallyu the models were optimised using an MM2 optimisation within ChemBio 12.0. They were then further optimised using an RB3LYP-6-31G(d,p) method and basis set. After the optimisation, and checking to see that the the two molecules were still distinct, with one syn and one anti form, they were submitted for nmr analysis, to produce a predicted nmr. This was then compared with the reported nmr, with a view to see if the assignments and conclusions made in the literature were correct. There was a good correlations between the predicted and measured nmr peaks, with deviations, as show below, of less than 1ppm for the H nmr and less than 10ppm for the <sup>13</sup>C nmr.
[[File:Ohbccomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each carbon atom]]
[[File:Ohbhcomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each Hydrogen atom]]

This correlation helps confirm that the structures are correct; the different enantiomers are differentiated and assigned correctly. If they were not, and the calculated syn nmr is compared to the measured anti nmr, and vice versa, larger differences are noted. This is highlighted on the graph below. The blue and red graphs are the correctly assigned and matched nmrs, the green and purple nmrs are if they are assigned incorrectly. It can clearly be seen that the green and purple line are consistently higher than their counterparts.
[[file:Ohbcomparisonnmr.png|thumb|900px|none|left|Comparison of correct and incorrect assignment for the two conformers]]
Within the literature all of the hydrogens and carbons are assigned, with the exception of Hydrogen 48. This is because this is a labile proton and so does not show up on measured nmrs due to rapid exchange with the deuterium in the deuterated solvent. However the calculated spectra does not take this into account and so displays the shift value for this hydrogen.

The computed IR spectra are very similar for the two molecules. The OH stretch is increased by 30cm<sup>-1</sup> in the syn form of the molecule and the CH bend region between 1000-1500cm<sup>-1</sup> is also significantly different. This acsn be rationalised by the different atomic orbital overlaps that are occuring due to the different positioning of the methyl group.

As both molecules are chiral, they both rotate light in opposite directions. However due to the large size of this molecule and although it is relatively conformationally limited due to the double bond and ring, the calculation for the syn and anti variants did not converge after 48 a 48 hour run on the SCAN.

==References==
<references></references>

Rep:Mod:benton2

2013-02-08T12:43:15Z

Ohb09: /* Regioselective Addition of Dichlorocarbene to a diene */

=Module 1 - Intro=
In this experiment, MM2 is compared to the more advanced MOPAC minimisation technique. A minimised molecule is then analysed and compared to literature.
Molecular mechanics, used here in its MM2 form is a very good first order approximation. Using data from previous experiments and breaking down the overall energy into different categories, such as van der Waals interaction, dipole-dipole, and bending before summing them to provide an overall energy is a very useful and more importantly quick method to calculate a molecules energy. The energy of molecule can then be iteratively reduced by tweaking the position of the atoms and conformations, providing a low energy structure. However it does have its limitations. Firstly, because of the large approximations used, the method is liable to fall, and remain, in an initial, smaller, potential well at a higher energy than the minimum possible. This can be overcome by carefully arranging the molecule by the user of the program to avoid these early, high energy minima, but requires a lot of rearrangement and prioir knowledge of low energy arrangements. As MM2 uses previously aquired data, it is also not that useful in determining new structures, or functional groups for which it does not have the data for.
MOPAC uses a different approach for minimisation. It uses semi empirical quantum chemistry functions to determine the energy of a molecule. This allows more advanced effects to be included in the calculation and allows for analysis of the neighbouring group effect in sacchardie chemistry and regioselectivity effects, as studied here.
Computational chemistry can also predict spectra, and in the last part of the experiment predicted spectra are compared to literature and the results analysed.

==Week 1==

===Hydrogenation of the Cyclopentadiene Dimer===
The endo dimer is primarily produced when cyclopentadiene dimerises, in a ratio of 99.5% to 0.5% <ref>
Małgorzata E Jamróz, Sławomir Gałka, Jan Cz Dobrowolski,
On dicyclopentadiene isomers,
Journal of Molecular Structure: THEOCHEM,
Volume 634, Issues 1–3, 5 September 2003,
Pages 225-233, ISSN 0166-1280,
<DOI|10.1016/S0166-1280(03)00348-8>
</ref>(at least when thermally initiated; photo initiation produces a racemic mixture of the two isomers<ref>
The Photosensitited Dimerization of Cyclopentadiene
Nicholas J. Turro and George S. Hammond
Journal of the American Chemical Society 1962 84 (14), 2841-2842
<DOI|10.1021/ja00873a050>
</ref>)
{| class="wikitable" border="1"

! rowspan="2" | Molecule
|style="text-align: center;" |Exo
|style="text-align: center;" |Endo
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbexodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Total E (kcal/mol)
|33.9975
|31.8764
|-
|}
[[file:Endoexoohb.bmp|thumb|left|500px]]
The small energy difference calculated by the MM2 forcefield does not highlight why the endo for is favoured over the exo form as it shows the exo form is lower in energy. While the difference between the two energies is relatively trivial, the high enationmeric excess of the products suggest that this is only part of the story, and suggest that this reaction is under kinetic rather than thermodynamic control.<ref> W.C.Herndon, C.R.Grayson, J.M.Manion; "Retro-Diels-Alder reactions. III. Kinetics of the thermal decompositions of exo- and endo-dicyclopentadiene" J. Org. Chem.; 1967, 32 (3); 526-529.DOI:10.1021/jo01278a003</ref> Being under kinetic control would imply the activation energy, and hence transition state, for the endo species is lower than the exo form and so the endo enantiomer is formed faster. This can be rationalised by looking at the orbital interactions in the two transition states.

The endo transition state is stabilised by the secondary favourable overlap whereas in the exo form there is no such overlap to stabilised the molecule meaning that the transition state is a higher energy, and so is less favourable.

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" colspan="2" |Different hydrogenation sites
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh3.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh4.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|1.2489
|1.1303
|-
!Bend
|19.1608
|13.10259
|-
!Torsion
|11.0730
|12.4118
|-
!VDW
|5.7962
|4.4398
|-
!Dipole-Dipole
|0.1622
|0.1410
|-
!Total E (kcal/mol)
|34.9643
|29.2475
|-
|}

The site of initial hydrogenation of the endo dimer can also be determined by calculating the energies of the two possible isomers. From these calculations it is clear that the second molecule is favoured more, as it is ~5.5kcalmol<sup>-1</sup> more stable. The bending energy in both of these molecules is the major difference. This manifests itself in the amount that the atoms are ebent away from their ideal positions, which is 109.5 for an sp3 carbon and 120 for an sp2 carbon. Across all of the key bonds, the second isomer has bond angles that are closer to the ideal than the first isomer; in particular the C-C=C bond angles; in the first molecule they are 107.6 and in the second 112.8. This difference of five degrees is enough to significantly stabilise the second isomer, making hydrogenation at that site the more preferable.

===Atropisomerism in an Intermediate related to the synthesis of Taxol===
In the complete synthesis of Taxol, and important cancer fighting drug, proposed by Pacquette <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 10.1016/S0040-4039(00)92617-0</ref> a key intermediate is either "Precursor 9" or "Precursor 10".

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" |Precursor 10
|style="text-align: center;" |Precursor 9
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol9.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol10.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|2.4687
|2.7846
|-
!Bend
|10.5555
|16.5411
|-
!Torsion
|17.4240
|18.2518
|-
!VDW
|13.1930
|13.1096
|-
!Dipole-Dipole
| -1.8818
| -1.7248
|-
!Total E (kcal/mol)
|39.1215
|47.8395
|-
|}
Precursor 9 and 10 are synthesised using a reversible oxy-Cope rearrangement as demonstrated below. As this process is in equilibrium that, with precursor 10 being more stable, it is predicted that this isomer will be the one produced as all of the molecules attempt to reduce the energy. As analysis of the individual energy componenets shows, this arrangement is a lot less strained than Precursor nine, which requires a lot more bending energy.

The molecule was then optimised with an MMFF94. Rather than rely ona large set of experimentally determined parameters like MM2, MMFF94 minimises the potential of each atom iteratively, attempting to minimise the whole molecule. Although the values produced for these two methods cannot be directly compared, they both correctly identify the correct altropisomer as being lower in energy.
{|class="wikitable" border="1"
! colspan="3" | Comparison of MMFF94 and MM2 minimisations
|-
!Molecule
| Precursor 9
| Precursor 10
|-
!MM2 minimised Energy (kJmol<sup><-1</sup>)
|39.1215
|47.8395
|-
!MMFF94 minimised Energy (kcalmol<sup><-1</sup>)
|58.7513
|70.5377
|-
|}

===Regioselective Addition of Dichlorocarbene to a diene===
Molecule A was initially optimised using a molecular mechanics (MM2) calculation

{| style="wikitable" border="1"
|<jmol>
<jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
It was then further optimised with a MOPAC calculation, which takes into effect stereoelectronic effects. The two were then compared.

{| class="wikitable" border="1"
!colspan="3" | Comparison of two optimisation calculations
|-
! Overlay of two optimised molecules !! MM2 optimised molecule !! MOPAC Optimised Molecule
|-
|[[file:Ohboverlaydiene.png|300px]]
The MM2 optimised molecule is coloured yellow for clarity
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>150</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>150</size>
<script></script>
<uploadedFileContents>Ohbdiene1mopac.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! rowspan="6" | Distances between
corresponding atoms

on the overlaid molecules (Å)
|style="text-align: center;" | C(34)-C(9)
|0.5247
|-
|style="text-align: center;" | C(26)-C(1)
|0.5246
|-
|style="text-align: center;" | H(47)-H(22)
|0.8526
|-
|style="text-align: center;" | H(38)-H(13)
|0.8524
|-
|style="text-align: center;" | Cl(37)-Cl(12)
|0.0689
|}

As can be seen by the comparison above, when using the stereoelectronic interactions, the cyclohexadiene ring on the side with the Cl atom is moved further away from the Cl using the MOPAC calculation than the MM2. This is because the electronic effects included in this calculation include the repulsion between the electron rich Chlorine atom and the electron rich double bond, whereas the MM2 calculation doesn't include this and so a symmetrical molecule is formed.

====MOs====

The MOs of the previously MOPAC optimised molecule where then calculated using Guassian (B3LYP 6-31G)
{| style="wikitable" border="1"
! Homo-1 !! colspan="2" | Homo
|-
|[[File:Ohbclhomo-1.jpg|250px]]
| <jmol>
<jmolApplet>
<title>Orbital</title><color>white</color><size>250</size>
<script>isosurface color orange purple "images/f/f2/Ohbdienemo48.cub.jvxl" translucent; </script>
<uploadedFileContents>Ohbdienemo48.cub.xyz</uploadedFileContents>
</jmolApplet>
</jmol>
|[[File:Ohbclhomo.jpg|250px]]
|-
!Lumo !! Lumo+1 !! Lumo+2
|-
|[[File:Ohbcllumo.jpg|250px]]
|[[File:Ohbcllumo+1.jpg|250px]]
|[[File:Ohbcllumo+2.jpg|250px]]
|-
|colspan="3" | [[File:Ohbclmep.jpg|300px rotate="90"]]
|}

[[File:Ohbclelevels.png|250px]]

Of the two alekenes, the endo is favoured rather than the exo because
the cl-c sigma star orbital mixes with the exo alkene. This stabilises both orbitals, as shown by the frequency calculation having a higher value than the endo alkene, but reduces the pi bond character of the exo alkene. This is also shown by the comparative lengths of the alkene bonds - the exo is 1.3355A and the endo is 1.33190A. The cycloaddition of the carbene requires an alkene and so favours the endo alkene as it has a higher p character.
The homo is also focused entirely on the endo side of the molecule, with the lumo focused mainly on the exo side. The Homo shows the high pi bond character of the endo alkene. The Homo-1 is mainly focused ont he exo alekene, so shows the pi bond character of the exo alekene. This is lower in energy and so is less likely to rteact with the carbene molecule.

====Glycosidation====

=====Mechanisms=====

[[file:Ohbglymech.gif|800px]]

{|class="wikitable" border="2"
!rowspan="5" |Initial molecule
!colspan="2" | Conformation
|1
|2
|3
|4
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2amm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 11.5430
| 35.5277
| 29.5144
| 46.2672
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -90.51343
| -72.56010
| -85.04737
| -70.57703
|-
!rowspan="5" |Intermediate
!colspan="2" | Conformation
|chemdraw
|chemdraw
|chemdraw
|chemdraw
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2Bmm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 28.4913
| 43.2706
| 41.0918
| 31.8763
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -91.66112
| -66.72331
| -88.08089
| -84.44899

|-
|}

==Comparison of coumpational results to a molecule from literature.==

Computational chemistry can be a powerful tool in the analysis and reproduction of spectra. in this exercise, literature values and spectra are compared to computed data and the effectiveness and accuracy of both methods is compared and contrasted.
In the synthesis of molecule A (right), using Kobayashi aldol chemistry, two stereoisomers are produced. Initially, the syn isomer is formed, with a diasteromic ratio of 1:14, and via a similar synthetic route, the anti isomer is also produced, with a high dr of 1:>50. The high stereoselectivity of both of these reactions is an important step in the synthesis of enationmerically pure natural products.
Initiallyu the models were optimised using an MM2 optimisation within ChemBio 12.0. They were then further optimised using an RB3LYP-6-31G(d,p) method and basis set. After the optimisation, and checking to see that the the two molecules were still distinct, with one syn and one anti form, they were submitted for nmr analysis, to produce a predicted nmr. This was then compared with the reported nmr, with a view to see if the assignments and conclusions made in the literature were correct. There was a good correlations between the predicted and measured nmr peaks, with deviations, as show below, of less than 1ppm for the H nmr and less than 10ppm for the <sup>13</sup>C nmr.
[[File:Ohbccomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each carbon atom]]
[[File:Ohbhcomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each Hydrogen atom]]

This correlation helps confirm that the structures are correct; the different enantiomers are differentiated and assigned correctly. If they were not, and the calculated syn nmr is compared to the measured anti nmr, and vice versa, larger differences are noted. This is highlighted on the graph below. The blue and red graphs are the correctly assigned and matched nmrs, the green and purple nmrs are if they are assigned incorrectly. It can clearly be seen that the green and purple line are consistently higher than their counterparts.
[[file:Ohbcomparisonnmr.png|thumb|900px|none|left|Comparison of correct and incorrect assignment for the two conformers]]
Within the literature all of the hydrogens and carbons are assigned, with the exception of Hydrogen 48. This is because this is a labile proton and so does not show up on measured nmrs due to rapid exchange with the deuterium in the deuterated solvent. However the calculated spectra does not take this into account and so displays the shift value for this hydrogen.

The computed IR spectra are very similar for the two molecules. The OH stretch is increased by 30cm<sup>-1</sup> in the syn form of the molecule and the CH bend region between 1000-1500cm<sup>-1</sup> is also significantly different. This acsn be rationalised by the different atomic orbital overlaps that are occuring due to the different positioning of the methyl group.

As both molecules are chiral, they both rotate light in opposite directions. However due to the large size of this molecule and although it is relatively conformationally limited due to the double bond and ring, the calculation for the syn and anti variants did not converge after 48 a 48 hour run on the SCAN.

==References==
<references></references>

Rep:Mod:benton2

2013-02-08T12:42:47Z

Ohb09: /* Atropisomerism in an Intermediate related to the synthesis of Taxol */

=Module 1 - Intro=
In this experiment, MM2 is compared to the more advanced MOPAC minimisation technique. A minimised molecule is then analysed and compared to literature.
Molecular mechanics, used here in its MM2 form is a very good first order approximation. Using data from previous experiments and breaking down the overall energy into different categories, such as van der Waals interaction, dipole-dipole, and bending before summing them to provide an overall energy is a very useful and more importantly quick method to calculate a molecules energy. The energy of molecule can then be iteratively reduced by tweaking the position of the atoms and conformations, providing a low energy structure. However it does have its limitations. Firstly, because of the large approximations used, the method is liable to fall, and remain, in an initial, smaller, potential well at a higher energy than the minimum possible. This can be overcome by carefully arranging the molecule by the user of the program to avoid these early, high energy minima, but requires a lot of rearrangement and prioir knowledge of low energy arrangements. As MM2 uses previously aquired data, it is also not that useful in determining new structures, or functional groups for which it does not have the data for.
MOPAC uses a different approach for minimisation. It uses semi empirical quantum chemistry functions to determine the energy of a molecule. This allows more advanced effects to be included in the calculation and allows for analysis of the neighbouring group effect in sacchardie chemistry and regioselectivity effects, as studied here.
Computational chemistry can also predict spectra, and in the last part of the experiment predicted spectra are compared to literature and the results analysed.

==Week 1==

===Hydrogenation of the Cyclopentadiene Dimer===
The endo dimer is primarily produced when cyclopentadiene dimerises, in a ratio of 99.5% to 0.5% <ref>
Małgorzata E Jamróz, Sławomir Gałka, Jan Cz Dobrowolski,
On dicyclopentadiene isomers,
Journal of Molecular Structure: THEOCHEM,
Volume 634, Issues 1–3, 5 September 2003,
Pages 225-233, ISSN 0166-1280,
<DOI|10.1016/S0166-1280(03)00348-8>
</ref>(at least when thermally initiated; photo initiation produces a racemic mixture of the two isomers<ref>
The Photosensitited Dimerization of Cyclopentadiene
Nicholas J. Turro and George S. Hammond
Journal of the American Chemical Society 1962 84 (14), 2841-2842
<DOI|10.1021/ja00873a050>
</ref>)
{| class="wikitable" border="1"

! rowspan="2" | Molecule
|style="text-align: center;" |Exo
|style="text-align: center;" |Endo
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbexodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Total E (kcal/mol)
|33.9975
|31.8764
|-
|}
[[file:Endoexoohb.bmp|thumb|left|500px]]
The small energy difference calculated by the MM2 forcefield does not highlight why the endo for is favoured over the exo form as it shows the exo form is lower in energy. While the difference between the two energies is relatively trivial, the high enationmeric excess of the products suggest that this is only part of the story, and suggest that this reaction is under kinetic rather than thermodynamic control.<ref> W.C.Herndon, C.R.Grayson, J.M.Manion; "Retro-Diels-Alder reactions. III. Kinetics of the thermal decompositions of exo- and endo-dicyclopentadiene" J. Org. Chem.; 1967, 32 (3); 526-529.DOI:10.1021/jo01278a003</ref> Being under kinetic control would imply the activation energy, and hence transition state, for the endo species is lower than the exo form and so the endo enantiomer is formed faster. This can be rationalised by looking at the orbital interactions in the two transition states.

The endo transition state is stabilised by the secondary favourable overlap whereas in the exo form there is no such overlap to stabilised the molecule meaning that the transition state is a higher energy, and so is less favourable.

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" colspan="2" |Different hydrogenation sites
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh3.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh4.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|1.2489
|1.1303
|-
!Bend
|19.1608
|13.10259
|-
!Torsion
|11.0730
|12.4118
|-
!VDW
|5.7962
|4.4398
|-
!Dipole-Dipole
|0.1622
|0.1410
|-
!Total E (kcal/mol)
|34.9643
|29.2475
|-
|}

The site of initial hydrogenation of the endo dimer can also be determined by calculating the energies of the two possible isomers. From these calculations it is clear that the second molecule is favoured more, as it is ~5.5kcalmol<sup>-1</sup> more stable. The bending energy in both of these molecules is the major difference. This manifests itself in the amount that the atoms are ebent away from their ideal positions, which is 109.5 for an sp3 carbon and 120 for an sp2 carbon. Across all of the key bonds, the second isomer has bond angles that are closer to the ideal than the first isomer; in particular the C-C=C bond angles; in the first molecule they are 107.6 and in the second 112.8. This difference of five degrees is enough to significantly stabilise the second isomer, making hydrogenation at that site the more preferable.

===Atropisomerism in an Intermediate related to the synthesis of Taxol===
In the complete synthesis of Taxol, and important cancer fighting drug, proposed by Pacquette <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 10.1016/S0040-4039(00)92617-0</ref> a key intermediate is either "Precursor 9" or "Precursor 10".

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" |Precursor 10
|style="text-align: center;" |Precursor 9
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol9.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol10.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|2.4687
|2.7846
|-
!Bend
|10.5555
|16.5411
|-
!Torsion
|17.4240
|18.2518
|-
!VDW
|13.1930
|13.1096
|-
!Dipole-Dipole
| -1.8818
| -1.7248
|-
!Total E (kcal/mol)
|39.1215
|47.8395
|-
|}
Precursor 9 and 10 are synthesised using a reversible oxy-Cope rearrangement as demonstrated below. As this process is in equilibrium that, with precursor 10 being more stable, it is predicted that this isomer will be the one produced as all of the molecules attempt to reduce the energy. As analysis of the individual energy componenets shows, this arrangement is a lot less strained than Precursor nine, which requires a lot more bending energy.

The molecule was then optimised with an MMFF94. Rather than rely ona large set of experimentally determined parameters like MM2, MMFF94 minimises the potential of each atom iteratively, attempting to minimise the whole molecule. Although the values produced for these two methods cannot be directly compared, they both correctly identify the correct altropisomer as being lower in energy.
{|class="wikitable" border="1"
! colspan="3" | Comparison of MMFF94 and MM2 minimisations
|-
!Molecule
| Precursor 9
| Precursor 10
|-
!MM2 minimised Energy (kJmol<sup><-1</sup>)
|39.1215
|47.8395
|-
!MMFF94 minimised Energy (kcalmol<sup><-1</sup>)
|58.7513
|70.5377
|-
|}

===Regioselective Addition of Dichlorocarbene to a diene===
Molecule A was initially optimised using a molecular mechanics calculation

{| style="wikitable" border="1"
|<jmol>
<jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
It was then further optimised with a MOPAC calculation, which takes into effect stereoelectronic effects. The two were then compared.

{| class="wikitable" border="1"
!colspan="3" | Comparison of two optimisation calculations
|-
! Overlay of two optimised molecules !! MM2 optimised molecule !! MOPAC Optimised Molecule
|-
|[[file:Ohboverlaydiene.png|300px]]
The MM2 optimised molecule is coloured yellow for clarity
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>150</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>150</size>
<script></script>
<uploadedFileContents>Ohbdiene1mopac.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! rowspan="6" | Distances between
corresponding atoms

on the overlaid molecules (Å)
|style="text-align: center;" | C(34)-C(9)
|0.5247
|-
|style="text-align: center;" | C(26)-C(1)
|0.5246
|-
|style="text-align: center;" | H(47)-H(22)
|0.8526
|-
|style="text-align: center;" | H(38)-H(13)
|0.8524
|-
|style="text-align: center;" | Cl(37)-Cl(12)
|0.0689
|}

As can be seen by the comparison above, when using the stereoelectronic interactions, the cyclohexadiene ring on the side with the Cl atom is moved further away from the Cl using the MOPAC calculation than the MM2. This is because the electronic effects included in this calculation include the repulsion between the electron rich Chlorine atom and the electron rich double bond, whereas the MM2 calculation doesn't include this and so a symmetrical molecule is formed.

====MOs====

The MOs of the previously MOPAC optimised molecule where then calculated using Guassian (B3LYP 6-31G)
{| style="wikitable" border="1"
! Homo-1 !! colspan="2" | Homo
|-
|[[File:Ohbclhomo-1.jpg|250px]]
| <jmol>
<jmolApplet>
<title>Orbital</title><color>white</color><size>250</size>
<script>isosurface color orange purple "images/f/f2/Ohbdienemo48.cub.jvxl" translucent; </script>
<uploadedFileContents>Ohbdienemo48.cub.xyz</uploadedFileContents>
</jmolApplet>
</jmol>
|[[File:Ohbclhomo.jpg|250px]]
|-
!Lumo !! Lumo+1 !! Lumo+2
|-
|[[File:Ohbcllumo.jpg|250px]]
|[[File:Ohbcllumo+1.jpg|250px]]
|[[File:Ohbcllumo+2.jpg|250px]]
|-
|colspan="3" | [[File:Ohbclmep.jpg|300px rotate="90"]]
|}

[[File:Ohbclelevels.png|250px]]

Of the two alekenes, the endo is favoured rather than the exo because
the cl-c sigma star orbital mixes with the exo alkene. This stabilises both orbitals, as shown by the frequency calculation having a higher value than the endo alkene, but reduces the pi bond character of the exo alkene. This is also shown by the comparative lengths of the alkene bonds - the exo is 1.3355A and the endo is 1.33190A. The cycloaddition of the carbene requires an alkene and so favours the endo alkene as it has a higher p character.
The homo is also focused entirely on the endo side of the molecule, with the lumo focused mainly on the exo side. The Homo shows the high pi bond character of the endo alkene. The Homo-1 is mainly focused ont he exo alekene, so shows the pi bond character of the exo alekene. This is lower in energy and so is less likely to rteact with the carbene molecule.

====Glycosidation====

=====Mechanisms=====

[[file:Ohbglymech.gif|800px]]

{|class="wikitable" border="2"
!rowspan="5" |Initial molecule
!colspan="2" | Conformation
|1
|2
|3
|4
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2amm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 11.5430
| 35.5277
| 29.5144
| 46.2672
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -90.51343
| -72.56010
| -85.04737
| -70.57703
|-
!rowspan="5" |Intermediate
!colspan="2" | Conformation
|chemdraw
|chemdraw
|chemdraw
|chemdraw
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2Bmm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 28.4913
| 43.2706
| 41.0918
| 31.8763
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -91.66112
| -66.72331
| -88.08089
| -84.44899

|-
|}

==Comparison of coumpational results to a molecule from literature.==

Computational chemistry can be a powerful tool in the analysis and reproduction of spectra. in this exercise, literature values and spectra are compared to computed data and the effectiveness and accuracy of both methods is compared and contrasted.
In the synthesis of molecule A (right), using Kobayashi aldol chemistry, two stereoisomers are produced. Initially, the syn isomer is formed, with a diasteromic ratio of 1:14, and via a similar synthetic route, the anti isomer is also produced, with a high dr of 1:>50. The high stereoselectivity of both of these reactions is an important step in the synthesis of enationmerically pure natural products.
Initiallyu the models were optimised using an MM2 optimisation within ChemBio 12.0. They were then further optimised using an RB3LYP-6-31G(d,p) method and basis set. After the optimisation, and checking to see that the the two molecules were still distinct, with one syn and one anti form, they were submitted for nmr analysis, to produce a predicted nmr. This was then compared with the reported nmr, with a view to see if the assignments and conclusions made in the literature were correct. There was a good correlations between the predicted and measured nmr peaks, with deviations, as show below, of less than 1ppm for the H nmr and less than 10ppm for the <sup>13</sup>C nmr.
[[File:Ohbccomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each carbon atom]]
[[File:Ohbhcomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each Hydrogen atom]]

This correlation helps confirm that the structures are correct; the different enantiomers are differentiated and assigned correctly. If they were not, and the calculated syn nmr is compared to the measured anti nmr, and vice versa, larger differences are noted. This is highlighted on the graph below. The blue and red graphs are the correctly assigned and matched nmrs, the green and purple nmrs are if they are assigned incorrectly. It can clearly be seen that the green and purple line are consistently higher than their counterparts.
[[file:Ohbcomparisonnmr.png|thumb|900px|none|left|Comparison of correct and incorrect assignment for the two conformers]]
Within the literature all of the hydrogens and carbons are assigned, with the exception of Hydrogen 48. This is because this is a labile proton and so does not show up on measured nmrs due to rapid exchange with the deuterium in the deuterated solvent. However the calculated spectra does not take this into account and so displays the shift value for this hydrogen.

The computed IR spectra are very similar for the two molecules. The OH stretch is increased by 30cm<sup>-1</sup> in the syn form of the molecule and the CH bend region between 1000-1500cm<sup>-1</sup> is also significantly different. This acsn be rationalised by the different atomic orbital overlaps that are occuring due to the different positioning of the methyl group.

As both molecules are chiral, they both rotate light in opposite directions. However due to the large size of this molecule and although it is relatively conformationally limited due to the double bond and ring, the calculation for the syn and anti variants did not converge after 48 a 48 hour run on the SCAN.

==References==
<references></references>

Rep:Mod:benton2

2013-02-08T12:36:33Z

Ohb09: /* Atropisomerism in an Intermediate related to the synthesis of Taxol */

=Module 1 - Intro=
In this experiment, MM2 is compared to the more advanced MOPAC minimisation technique. A minimised molecule is then analysed and compared to literature.
Molecular mechanics, used here in its MM2 form is a very good first order approximation. Using data from previous experiments and breaking down the overall energy into different categories, such as van der Waals interaction, dipole-dipole, and bending before summing them to provide an overall energy is a very useful and more importantly quick method to calculate a molecules energy. The energy of molecule can then be iteratively reduced by tweaking the position of the atoms and conformations, providing a low energy structure. However it does have its limitations. Firstly, because of the large approximations used, the method is liable to fall, and remain, in an initial, smaller, potential well at a higher energy than the minimum possible. This can be overcome by carefully arranging the molecule by the user of the program to avoid these early, high energy minima, but requires a lot of rearrangement and prioir knowledge of low energy arrangements. As MM2 uses previously aquired data, it is also not that useful in determining new structures, or functional groups for which it does not have the data for.
MOPAC uses a different approach for minimisation. It uses semi empirical quantum chemistry functions to determine the energy of a molecule. This allows more advanced effects to be included in the calculation and allows for analysis of the neighbouring group effect in sacchardie chemistry and regioselectivity effects, as studied here.
Computational chemistry can also predict spectra, and in the last part of the experiment predicted spectra are compared to literature and the results analysed.

==Week 1==

===Hydrogenation of the Cyclopentadiene Dimer===
The endo dimer is primarily produced when cyclopentadiene dimerises, in a ratio of 99.5% to 0.5% <ref>
Małgorzata E Jamróz, Sławomir Gałka, Jan Cz Dobrowolski,
On dicyclopentadiene isomers,
Journal of Molecular Structure: THEOCHEM,
Volume 634, Issues 1–3, 5 September 2003,
Pages 225-233, ISSN 0166-1280,
<DOI|10.1016/S0166-1280(03)00348-8>
</ref>(at least when thermally initiated; photo initiation produces a racemic mixture of the two isomers<ref>
The Photosensitited Dimerization of Cyclopentadiene
Nicholas J. Turro and George S. Hammond
Journal of the American Chemical Society 1962 84 (14), 2841-2842
<DOI|10.1021/ja00873a050>
</ref>)
{| class="wikitable" border="1"

! rowspan="2" | Molecule
|style="text-align: center;" |Exo
|style="text-align: center;" |Endo
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbexodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Total E (kcal/mol)
|33.9975
|31.8764
|-
|}
[[file:Endoexoohb.bmp|thumb|left|500px]]
The small energy difference calculated by the MM2 forcefield does not highlight why the endo for is favoured over the exo form as it shows the exo form is lower in energy. While the difference between the two energies is relatively trivial, the high enationmeric excess of the products suggest that this is only part of the story, and suggest that this reaction is under kinetic rather than thermodynamic control.<ref> W.C.Herndon, C.R.Grayson, J.M.Manion; "Retro-Diels-Alder reactions. III. Kinetics of the thermal decompositions of exo- and endo-dicyclopentadiene" J. Org. Chem.; 1967, 32 (3); 526-529.DOI:10.1021/jo01278a003</ref> Being under kinetic control would imply the activation energy, and hence transition state, for the endo species is lower than the exo form and so the endo enantiomer is formed faster. This can be rationalised by looking at the orbital interactions in the two transition states.

The endo transition state is stabilised by the secondary favourable overlap whereas in the exo form there is no such overlap to stabilised the molecule meaning that the transition state is a higher energy, and so is less favourable.

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" colspan="2" |Different hydrogenation sites
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh3.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh4.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|1.2489
|1.1303
|-
!Bend
|19.1608
|13.10259
|-
!Torsion
|11.0730
|12.4118
|-
!VDW
|5.7962
|4.4398
|-
!Dipole-Dipole
|0.1622
|0.1410
|-
!Total E (kcal/mol)
|34.9643
|29.2475
|-
|}

The site of initial hydrogenation of the endo dimer can also be determined by calculating the energies of the two possible isomers. From these calculations it is clear that the second molecule is favoured more, as it is ~5.5kcalmol<sup>-1</sup> more stable. The bending energy in both of these molecules is the major difference. This manifests itself in the amount that the atoms are ebent away from their ideal positions, which is 109.5 for an sp3 carbon and 120 for an sp2 carbon. Across all of the key bonds, the second isomer has bond angles that are closer to the ideal than the first isomer; in particular the C-C=C bond angles; in the first molecule they are 107.6 and in the second 112.8. This difference of five degrees is enough to significantly stabilise the second isomer, making hydrogenation at that site the more preferable.

===Atropisomerism in an Intermediate related to the synthesis of Taxol===
In the complete synthesis of Taxol, and important cancer fighting drug, proposed by Pacquette <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 10.1016/S0040-4039(00)92617-0</ref> a key intermediate is either "Precursor 9" or "Precursor 10"

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" |Precursor 10
|style="text-align: center;" |Precursor 9
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol9.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol10.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|2.4687
|2.7846
|-
!Bend
|10.5555
|16.5411
|-
!Torsion
|17.4240
|18.2518
|-
!VDW
|13.1930
|13.1096
|-
!Dipole-Dipole
| -1.8818
| -1.7248
|-
!Total E (kcal/mol)
|39.1215
|47.8395
|-
|}

{|class="wikitable" border="1"
! colspan="3" | Comparison of MMFF94 and MM2 minimisations
|-
!Molecule
| Precursor 9
| Precursor 10
|-
!MM2 minimised Energy (kJmol<sup><-1</sup>)
|39.1215
|47.8395
|-
!MMFF94 minimised Energy (kcalmol<sup><-1</sup>)
|58.7513
|70.5377
|-
|}

===Regioselective Addition of Dichlorocarbene to a diene===
Molecule A was initially optimised using a molecular mechanics calculation

{| style="wikitable" border="1"
|<jmol>
<jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
It was then further optimised with a MOPAC calculation, which takes into effect stereoelectronic effects. The two were then compared.

{| class="wikitable" border="1"
!colspan="3" | Comparison of two optimisation calculations
|-
! Overlay of two optimised molecules !! MM2 optimised molecule !! MOPAC Optimised Molecule
|-
|[[file:Ohboverlaydiene.png|300px]]
The MM2 optimised molecule is coloured yellow for clarity
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>150</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>150</size>
<script></script>
<uploadedFileContents>Ohbdiene1mopac.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! rowspan="6" | Distances between
corresponding atoms

on the overlaid molecules (Å)
|style="text-align: center;" | C(34)-C(9)
|0.5247
|-
|style="text-align: center;" | C(26)-C(1)
|0.5246
|-
|style="text-align: center;" | H(47)-H(22)
|0.8526
|-
|style="text-align: center;" | H(38)-H(13)
|0.8524
|-
|style="text-align: center;" | Cl(37)-Cl(12)
|0.0689
|}

As can be seen by the comparison above, when using the stereoelectronic interactions, the cyclohexadiene ring on the side with the Cl atom is moved further away from the Cl using the MOPAC calculation than the MM2. This is because the electronic effects included in this calculation include the repulsion between the electron rich Chlorine atom and the electron rich double bond, whereas the MM2 calculation doesn't include this and so a symmetrical molecule is formed.

====MOs====

The MOs of the previously MOPAC optimised molecule where then calculated using Guassian (B3LYP 6-31G)
{| style="wikitable" border="1"
! Homo-1 !! colspan="2" | Homo
|-
|[[File:Ohbclhomo-1.jpg|250px]]
| <jmol>
<jmolApplet>
<title>Orbital</title><color>white</color><size>250</size>
<script>isosurface color orange purple "images/f/f2/Ohbdienemo48.cub.jvxl" translucent; </script>
<uploadedFileContents>Ohbdienemo48.cub.xyz</uploadedFileContents>
</jmolApplet>
</jmol>
|[[File:Ohbclhomo.jpg|250px]]
|-
!Lumo !! Lumo+1 !! Lumo+2
|-
|[[File:Ohbcllumo.jpg|250px]]
|[[File:Ohbcllumo+1.jpg|250px]]
|[[File:Ohbcllumo+2.jpg|250px]]
|-
|colspan="3" | [[File:Ohbclmep.jpg|300px rotate="90"]]
|}

[[File:Ohbclelevels.png|250px]]

Of the two alekenes, the endo is favoured rather than the exo because
the cl-c sigma star orbital mixes with the exo alkene. This stabilises both orbitals, as shown by the frequency calculation having a higher value than the endo alkene, but reduces the pi bond character of the exo alkene. This is also shown by the comparative lengths of the alkene bonds - the exo is 1.3355A and the endo is 1.33190A. The cycloaddition of the carbene requires an alkene and so favours the endo alkene as it has a higher p character.
The homo is also focused entirely on the endo side of the molecule, with the lumo focused mainly on the exo side. The Homo shows the high pi bond character of the endo alkene. The Homo-1 is mainly focused ont he exo alekene, so shows the pi bond character of the exo alekene. This is lower in energy and so is less likely to rteact with the carbene molecule.

====Glycosidation====

=====Mechanisms=====

[[file:Ohbglymech.gif|800px]]

{|class="wikitable" border="2"
!rowspan="5" |Initial molecule
!colspan="2" | Conformation
|1
|2
|3
|4
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2amm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 11.5430
| 35.5277
| 29.5144
| 46.2672
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -90.51343
| -72.56010
| -85.04737
| -70.57703
|-
!rowspan="5" |Intermediate
!colspan="2" | Conformation
|chemdraw
|chemdraw
|chemdraw
|chemdraw
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2Bmm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 28.4913
| 43.2706
| 41.0918
| 31.8763
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -91.66112
| -66.72331
| -88.08089
| -84.44899

|-
|}

==Comparison of coumpational results to a molecule from literature.==

Computational chemistry can be a powerful tool in the analysis and reproduction of spectra. in this exercise, literature values and spectra are compared to computed data and the effectiveness and accuracy of both methods is compared and contrasted.
In the synthesis of molecule A (right), using Kobayashi aldol chemistry, two stereoisomers are produced. Initially, the syn isomer is formed, with a diasteromic ratio of 1:14, and via a similar synthetic route, the anti isomer is also produced, with a high dr of 1:>50. The high stereoselectivity of both of these reactions is an important step in the synthesis of enationmerically pure natural products.
Initiallyu the models were optimised using an MM2 optimisation within ChemBio 12.0. They were then further optimised using an RB3LYP-6-31G(d,p) method and basis set. After the optimisation, and checking to see that the the two molecules were still distinct, with one syn and one anti form, they were submitted for nmr analysis, to produce a predicted nmr. This was then compared with the reported nmr, with a view to see if the assignments and conclusions made in the literature were correct. There was a good correlations between the predicted and measured nmr peaks, with deviations, as show below, of less than 1ppm for the H nmr and less than 10ppm for the <sup>13</sup>C nmr.
[[File:Ohbccomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each carbon atom]]
[[File:Ohbhcomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each Hydrogen atom]]

This correlation helps confirm that the structures are correct; the different enantiomers are differentiated and assigned correctly. If they were not, and the calculated syn nmr is compared to the measured anti nmr, and vice versa, larger differences are noted. This is highlighted on the graph below. The blue and red graphs are the correctly assigned and matched nmrs, the green and purple nmrs are if they are assigned incorrectly. It can clearly be seen that the green and purple line are consistently higher than their counterparts.
[[file:Ohbcomparisonnmr.png|thumb|900px|none|left|Comparison of correct and incorrect assignment for the two conformers]]
Within the literature all of the hydrogens and carbons are assigned, with the exception of Hydrogen 48. This is because this is a labile proton and so does not show up on measured nmrs due to rapid exchange with the deuterium in the deuterated solvent. However the calculated spectra does not take this into account and so displays the shift value for this hydrogen.

The computed IR spectra are very similar for the two molecules. The OH stretch is increased by 30cm<sup>-1</sup> in the syn form of the molecule and the CH bend region between 1000-1500cm<sup>-1</sup> is also significantly different. This acsn be rationalised by the different atomic orbital overlaps that are occuring due to the different positioning of the methyl group.

As both molecules are chiral, they both rotate light in opposite directions. However due to the large size of this molecule and although it is relatively conformationally limited due to the double bond and ring, the calculation for the syn and anti variants did not converge after 48 a 48 hour run on the SCAN.

==References==
<references></references>

Rep:Mod:benton2

2013-02-08T12:35:58Z

Ohb09: /* Atropisomerism in an Intermediate related to the synthesis of Taxol */

=Module 1 - Intro=
In this experiment, MM2 is compared to the more advanced MOPAC minimisation technique. A minimised molecule is then analysed and compared to literature.
Molecular mechanics, used here in its MM2 form is a very good first order approximation. Using data from previous experiments and breaking down the overall energy into different categories, such as van der Waals interaction, dipole-dipole, and bending before summing them to provide an overall energy is a very useful and more importantly quick method to calculate a molecules energy. The energy of molecule can then be iteratively reduced by tweaking the position of the atoms and conformations, providing a low energy structure. However it does have its limitations. Firstly, because of the large approximations used, the method is liable to fall, and remain, in an initial, smaller, potential well at a higher energy than the minimum possible. This can be overcome by carefully arranging the molecule by the user of the program to avoid these early, high energy minima, but requires a lot of rearrangement and prioir knowledge of low energy arrangements. As MM2 uses previously aquired data, it is also not that useful in determining new structures, or functional groups for which it does not have the data for.
MOPAC uses a different approach for minimisation. It uses semi empirical quantum chemistry functions to determine the energy of a molecule. This allows more advanced effects to be included in the calculation and allows for analysis of the neighbouring group effect in sacchardie chemistry and regioselectivity effects, as studied here.
Computational chemistry can also predict spectra, and in the last part of the experiment predicted spectra are compared to literature and the results analysed.

==Week 1==

===Hydrogenation of the Cyclopentadiene Dimer===
The endo dimer is primarily produced when cyclopentadiene dimerises, in a ratio of 99.5% to 0.5% <ref>
Małgorzata E Jamróz, Sławomir Gałka, Jan Cz Dobrowolski,
On dicyclopentadiene isomers,
Journal of Molecular Structure: THEOCHEM,
Volume 634, Issues 1–3, 5 September 2003,
Pages 225-233, ISSN 0166-1280,
<DOI|10.1016/S0166-1280(03)00348-8>
</ref>(at least when thermally initiated; photo initiation produces a racemic mixture of the two isomers<ref>
The Photosensitited Dimerization of Cyclopentadiene
Nicholas J. Turro and George S. Hammond
Journal of the American Chemical Society 1962 84 (14), 2841-2842
<DOI|10.1021/ja00873a050>
</ref>)
{| class="wikitable" border="1"

! rowspan="2" | Molecule
|style="text-align: center;" |Exo
|style="text-align: center;" |Endo
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbexodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Total E (kcal/mol)
|33.9975
|31.8764
|-
|}
[[file:Endoexoohb.bmp|thumb|left|500px]]
The small energy difference calculated by the MM2 forcefield does not highlight why the endo for is favoured over the exo form as it shows the exo form is lower in energy. While the difference between the two energies is relatively trivial, the high enationmeric excess of the products suggest that this is only part of the story, and suggest that this reaction is under kinetic rather than thermodynamic control.<ref> W.C.Herndon, C.R.Grayson, J.M.Manion; "Retro-Diels-Alder reactions. III. Kinetics of the thermal decompositions of exo- and endo-dicyclopentadiene" J. Org. Chem.; 1967, 32 (3); 526-529.DOI:10.1021/jo01278a003</ref> Being under kinetic control would imply the activation energy, and hence transition state, for the endo species is lower than the exo form and so the endo enantiomer is formed faster. This can be rationalised by looking at the orbital interactions in the two transition states.

The endo transition state is stabilised by the secondary favourable overlap whereas in the exo form there is no such overlap to stabilised the molecule meaning that the transition state is a higher energy, and so is less favourable.

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" colspan="2" |Different hydrogenation sites
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh3.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh4.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|1.2489
|1.1303
|-
!Bend
|19.1608
|13.10259
|-
!Torsion
|11.0730
|12.4118
|-
!VDW
|5.7962
|4.4398
|-
!Dipole-Dipole
|0.1622
|0.1410
|-
!Total E (kcal/mol)
|34.9643
|29.2475
|-
|}

The site of initial hydrogenation of the endo dimer can also be determined by calculating the energies of the two possible isomers. From these calculations it is clear that the second molecule is favoured more, as it is ~5.5kcalmol<sup>-1</sup> more stable. The bending energy in both of these molecules is the major difference. This manifests itself in the amount that the atoms are ebent away from their ideal positions, which is 109.5 for an sp3 carbon and 120 for an sp2 carbon. Across all of the key bonds, the second isomer has bond angles that are closer to the ideal than the first isomer; in particular the C-C=C bond angles; in the first molecule they are 107.6 and in the second 112.8. This difference of five degrees is enough to significantly stabilise the second isomer, making hydrogenation at that site the more preferable.

===Atropisomerism in an Intermediate related to the synthesis of Taxol===
In the complete synthesis of Taxol, and important cancer fighting drug, proposed by Pacquette <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 10.1016/S0040-4039(00)92617-0</ref> a key intermediate is either "Precursor 9" or "Precursor 10"

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" |Precursor 9
|style="text-align: center;" |Precursor 10
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol10.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol9.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|2.4687
|2.7846
|-
!Bend
|10.5555
|16.5411
|-
!Torsion
|17.4240
|18.2518
|-
!VDW
|13.1930
|13.1096
|-
!Dipole-Dipole
| -1.8818
| -1.7248
|-
!Total E (kcal/mol)
|39.1215
|47.8395
|-
|}

{|class="wikitable" border="1"
! colspan="3" | Comparison of MMFF94 and MM2 minimisations
|-
!Molecule
| Precursor 9
| Precursor 10
|-
!MM2 minimised Energy (kJmol<sup><-1</sup>)
|39.1215
|47.8395
|-
!MMFF94 minimised Energy (kcalmol<sup><-1</sup>)
|58.7513
|70.5377
|-
|}

===Regioselective Addition of Dichlorocarbene to a diene===
Molecule A was initially optimised using a molecular mechanics calculation

{| style="wikitable" border="1"
|<jmol>
<jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
It was then further optimised with a MOPAC calculation, which takes into effect stereoelectronic effects. The two were then compared.

{| class="wikitable" border="1"
!colspan="3" | Comparison of two optimisation calculations
|-
! Overlay of two optimised molecules !! MM2 optimised molecule !! MOPAC Optimised Molecule
|-
|[[file:Ohboverlaydiene.png|300px]]
The MM2 optimised molecule is coloured yellow for clarity
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>150</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>150</size>
<script></script>
<uploadedFileContents>Ohbdiene1mopac.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! rowspan="6" | Distances between
corresponding atoms

on the overlaid molecules (Å)
|style="text-align: center;" | C(34)-C(9)
|0.5247
|-
|style="text-align: center;" | C(26)-C(1)
|0.5246
|-
|style="text-align: center;" | H(47)-H(22)
|0.8526
|-
|style="text-align: center;" | H(38)-H(13)
|0.8524
|-
|style="text-align: center;" | Cl(37)-Cl(12)
|0.0689
|}

As can be seen by the comparison above, when using the stereoelectronic interactions, the cyclohexadiene ring on the side with the Cl atom is moved further away from the Cl using the MOPAC calculation than the MM2. This is because the electronic effects included in this calculation include the repulsion between the electron rich Chlorine atom and the electron rich double bond, whereas the MM2 calculation doesn't include this and so a symmetrical molecule is formed.

====MOs====

The MOs of the previously MOPAC optimised molecule where then calculated using Guassian (B3LYP 6-31G)
{| style="wikitable" border="1"
! Homo-1 !! colspan="2" | Homo
|-
|[[File:Ohbclhomo-1.jpg|250px]]
| <jmol>
<jmolApplet>
<title>Orbital</title><color>white</color><size>250</size>
<script>isosurface color orange purple "images/f/f2/Ohbdienemo48.cub.jvxl" translucent; </script>
<uploadedFileContents>Ohbdienemo48.cub.xyz</uploadedFileContents>
</jmolApplet>
</jmol>
|[[File:Ohbclhomo.jpg|250px]]
|-
!Lumo !! Lumo+1 !! Lumo+2
|-
|[[File:Ohbcllumo.jpg|250px]]
|[[File:Ohbcllumo+1.jpg|250px]]
|[[File:Ohbcllumo+2.jpg|250px]]
|-
|colspan="3" | [[File:Ohbclmep.jpg|300px rotate="90"]]
|}

[[File:Ohbclelevels.png|250px]]

Of the two alekenes, the endo is favoured rather than the exo because
the cl-c sigma star orbital mixes with the exo alkene. This stabilises both orbitals, as shown by the frequency calculation having a higher value than the endo alkene, but reduces the pi bond character of the exo alkene. This is also shown by the comparative lengths of the alkene bonds - the exo is 1.3355A and the endo is 1.33190A. The cycloaddition of the carbene requires an alkene and so favours the endo alkene as it has a higher p character.
The homo is also focused entirely on the endo side of the molecule, with the lumo focused mainly on the exo side. The Homo shows the high pi bond character of the endo alkene. The Homo-1 is mainly focused ont he exo alekene, so shows the pi bond character of the exo alekene. This is lower in energy and so is less likely to rteact with the carbene molecule.

====Glycosidation====

=====Mechanisms=====

[[file:Ohbglymech.gif|800px]]

{|class="wikitable" border="2"
!rowspan="5" |Initial molecule
!colspan="2" | Conformation
|1
|2
|3
|4
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2amm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 11.5430
| 35.5277
| 29.5144
| 46.2672
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -90.51343
| -72.56010
| -85.04737
| -70.57703
|-
!rowspan="5" |Intermediate
!colspan="2" | Conformation
|chemdraw
|chemdraw
|chemdraw
|chemdraw
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2Bmm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 28.4913
| 43.2706
| 41.0918
| 31.8763
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -91.66112
| -66.72331
| -88.08089
| -84.44899

|-
|}

==Comparison of coumpational results to a molecule from literature.==

Computational chemistry can be a powerful tool in the analysis and reproduction of spectra. in this exercise, literature values and spectra are compared to computed data and the effectiveness and accuracy of both methods is compared and contrasted.
In the synthesis of molecule A (right), using Kobayashi aldol chemistry, two stereoisomers are produced. Initially, the syn isomer is formed, with a diasteromic ratio of 1:14, and via a similar synthetic route, the anti isomer is also produced, with a high dr of 1:>50. The high stereoselectivity of both of these reactions is an important step in the synthesis of enationmerically pure natural products.
Initiallyu the models were optimised using an MM2 optimisation within ChemBio 12.0. They were then further optimised using an RB3LYP-6-31G(d,p) method and basis set. After the optimisation, and checking to see that the the two molecules were still distinct, with one syn and one anti form, they were submitted for nmr analysis, to produce a predicted nmr. This was then compared with the reported nmr, with a view to see if the assignments and conclusions made in the literature were correct. There was a good correlations between the predicted and measured nmr peaks, with deviations, as show below, of less than 1ppm for the H nmr and less than 10ppm for the <sup>13</sup>C nmr.
[[File:Ohbccomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each carbon atom]]
[[File:Ohbhcomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each Hydrogen atom]]

This correlation helps confirm that the structures are correct; the different enantiomers are differentiated and assigned correctly. If they were not, and the calculated syn nmr is compared to the measured anti nmr, and vice versa, larger differences are noted. This is highlighted on the graph below. The blue and red graphs are the correctly assigned and matched nmrs, the green and purple nmrs are if they are assigned incorrectly. It can clearly be seen that the green and purple line are consistently higher than their counterparts.
[[file:Ohbcomparisonnmr.png|thumb|900px|none|left|Comparison of correct and incorrect assignment for the two conformers]]
Within the literature all of the hydrogens and carbons are assigned, with the exception of Hydrogen 48. This is because this is a labile proton and so does not show up on measured nmrs due to rapid exchange with the deuterium in the deuterated solvent. However the calculated spectra does not take this into account and so displays the shift value for this hydrogen.

The computed IR spectra are very similar for the two molecules. The OH stretch is increased by 30cm<sup>-1</sup> in the syn form of the molecule and the CH bend region between 1000-1500cm<sup>-1</sup> is also significantly different. This acsn be rationalised by the different atomic orbital overlaps that are occuring due to the different positioning of the methyl group.

As both molecules are chiral, they both rotate light in opposite directions. However due to the large size of this molecule and although it is relatively conformationally limited due to the double bond and ring, the calculation for the syn and anti variants did not converge after 48 a 48 hour run on the SCAN.

==References==
<references></references>

File:Ohboxycope.bmp

2013-02-08T12:11:42Z

Ohb09:

Rep:Mod:benton2

2013-02-08T12:03:11Z

Ohb09: /* Hydrogenation of the Cyclopentadiene Dimer */

=Module 1 - Intro=
In this experiment, MM2 is compared to the more advanced MOPAC minimisation technique. A minimised molecule is then analysed and compared to literature.
Molecular mechanics, used here in its MM2 form is a very good first order approximation. Using data from previous experiments and breaking down the overall energy into different categories, such as van der Waals interaction, dipole-dipole, and bending before summing them to provide an overall energy is a very useful and more importantly quick method to calculate a molecules energy. The energy of molecule can then be iteratively reduced by tweaking the position of the atoms and conformations, providing a low energy structure. However it does have its limitations. Firstly, because of the large approximations used, the method is liable to fall, and remain, in an initial, smaller, potential well at a higher energy than the minimum possible. This can be overcome by carefully arranging the molecule by the user of the program to avoid these early, high energy minima, but requires a lot of rearrangement and prioir knowledge of low energy arrangements. As MM2 uses previously aquired data, it is also not that useful in determining new structures, or functional groups for which it does not have the data for.
MOPAC uses a different approach for minimisation. It uses semi empirical quantum chemistry functions to determine the energy of a molecule. This allows more advanced effects to be included in the calculation and allows for analysis of the neighbouring group effect in sacchardie chemistry and regioselectivity effects, as studied here.
Computational chemistry can also predict spectra, and in the last part of the experiment predicted spectra are compared to literature and the results analysed.

==Week 1==

===Hydrogenation of the Cyclopentadiene Dimer===
The endo dimer is primarily produced when cyclopentadiene dimerises, in a ratio of 99.5% to 0.5% <ref>
Małgorzata E Jamróz, Sławomir Gałka, Jan Cz Dobrowolski,
On dicyclopentadiene isomers,
Journal of Molecular Structure: THEOCHEM,
Volume 634, Issues 1–3, 5 September 2003,
Pages 225-233, ISSN 0166-1280,
<DOI|10.1016/S0166-1280(03)00348-8>
</ref>(at least when thermally initiated; photo initiation produces a racemic mixture of the two isomers<ref>
The Photosensitited Dimerization of Cyclopentadiene
Nicholas J. Turro and George S. Hammond
Journal of the American Chemical Society 1962 84 (14), 2841-2842
<DOI|10.1021/ja00873a050>
</ref>)
{| class="wikitable" border="1"

! rowspan="2" | Molecule
|style="text-align: center;" |Exo
|style="text-align: center;" |Endo
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbexodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendodimer.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Total E (kcal/mol)
|33.9975
|31.8764
|-
|}
[[file:Endoexoohb.bmp|thumb|left|500px]]
The small energy difference calculated by the MM2 forcefield does not highlight why the endo for is favoured over the exo form as it shows the exo form is lower in energy. While the difference between the two energies is relatively trivial, the high enationmeric excess of the products suggest that this is only part of the story, and suggest that this reaction is under kinetic rather than thermodynamic control.<ref> W.C.Herndon, C.R.Grayson, J.M.Manion; "Retro-Diels-Alder reactions. III. Kinetics of the thermal decompositions of exo- and endo-dicyclopentadiene" J. Org. Chem.; 1967, 32 (3); 526-529.DOI:10.1021/jo01278a003</ref> Being under kinetic control would imply the activation energy, and hence transition state, for the endo species is lower than the exo form and so the endo enantiomer is formed faster. This can be rationalised by looking at the orbital interactions in the two transition states.

The endo transition state is stabilised by the secondary favourable overlap whereas in the exo form there is no such overlap to stabilised the molecule meaning that the transition state is a higher energy, and so is less favourable.

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" colspan="2" |Different hydrogenation sites
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh3.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbendoh4.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|1.2489
|1.1303
|-
!Bend
|19.1608
|13.10259
|-
!Torsion
|11.0730
|12.4118
|-
!VDW
|5.7962
|4.4398
|-
!Dipole-Dipole
|0.1622
|0.1410
|-
!Total E (kcal/mol)
|34.9643
|29.2475
|-
|}

The site of initial hydrogenation of the endo dimer can also be determined by calculating the energies of the two possible isomers. From these calculations it is clear that the second molecule is favoured more, as it is ~5.5kcalmol<sup>-1</sup> more stable. The bending energy in both of these molecules is the major difference. This manifests itself in the amount that the atoms are ebent away from their ideal positions, which is 109.5 for an sp3 carbon and 120 for an sp2 carbon. Across all of the key bonds, the second isomer has bond angles that are closer to the ideal than the first isomer; in particular the C-C=C bond angles; in the first molecule they are 107.6 and in the second 112.8. This difference of five degrees is enough to significantly stabilise the second isomer, making hydrogenation at that site the more preferable.

===Atropisomerism in an Intermediate related to the synthesis of Taxol===
In the complete synthesis of Taxol, and important cancer fighting drug, proposed by Pacquette <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 10.1016/S0040-4039(00)92617-0</ref> a key intermediate is either "Precursor 9" or "Precursor 10"

{| class="wikitable" border="1"
! rowspan="2" | Molecule
|style="text-align: center;" |Precursor 9
|style="text-align: center;" |Precursor 10
|-
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol9.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbtaxol10.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Optimisation
|MM2 E minimisation
|MM2 E minimisation
|-
!Stretch
|2.4687
|2.7846
|-
!Bend
|10.5555
|16.5411
|-
!Torsion
|17.4240
|18.2518
|-
!VDW
|13.1930
|13.1096
|-
!Dipole-Dipole
| -1.8818
| -1.7248
|-
!Total E (kcal/mol)
|39.1215
|47.8395
|-
|}

{|class="wikitable" border="1"
! colspan="3" | Comparison of MMFF94 and MM2 minimisations
|-
!Molecule
| Precursor 9
| Precursor 10
|-
!MM2 minimised Energy (kJmol<sup><-1</sup>)
|39.1215
|47.8395
|-
!MMFF94 minimised Energy (kcalmol<sup><-1</sup>)
|58.7513
|70.5377
|-
|}

===Regioselective Addition of Dichlorocarbene to a diene===
Molecule A was initially optimised using a molecular mechanics calculation

{| style="wikitable" border="1"
|<jmol>
<jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>300</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|}
It was then further optimised with a MOPAC calculation, which takes into effect stereoelectronic effects. The two were then compared.

{| class="wikitable" border="1"
!colspan="3" | Comparison of two optimisation calculations
|-
! Overlay of two optimised molecules !! MM2 optimised molecule !! MOPAC Optimised Molecule
|-
|[[file:Ohboverlaydiene.png|300px]]
The MM2 optimised molecule is coloured yellow for clarity
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>150</size>
<script></script>
<uploadedFileContents>Ohbdiene1.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol><jmolApplet>
<title>Molecule A</title><color>#FFF0F5</color><size>150</size>
<script></script>
<uploadedFileContents>Ohbdiene1mopac.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! rowspan="6" | Distances between
corresponding atoms

on the overlaid molecules (Å)
|style="text-align: center;" | C(34)-C(9)
|0.5247
|-
|style="text-align: center;" | C(26)-C(1)
|0.5246
|-
|style="text-align: center;" | H(47)-H(22)
|0.8526
|-
|style="text-align: center;" | H(38)-H(13)
|0.8524
|-
|style="text-align: center;" | Cl(37)-Cl(12)
|0.0689
|}

As can be seen by the comparison above, when using the stereoelectronic interactions, the cyclohexadiene ring on the side with the Cl atom is moved further away from the Cl using the MOPAC calculation than the MM2. This is because the electronic effects included in this calculation include the repulsion between the electron rich Chlorine atom and the electron rich double bond, whereas the MM2 calculation doesn't include this and so a symmetrical molecule is formed.

====MOs====

The MOs of the previously MOPAC optimised molecule where then calculated using Guassian (B3LYP 6-31G)
{| style="wikitable" border="1"
! Homo-1 !! colspan="2" | Homo
|-
|[[File:Ohbclhomo-1.jpg|250px]]
| <jmol>
<jmolApplet>
<title>Orbital</title><color>white</color><size>250</size>
<script>isosurface color orange purple "images/f/f2/Ohbdienemo48.cub.jvxl" translucent; </script>
<uploadedFileContents>Ohbdienemo48.cub.xyz</uploadedFileContents>
</jmolApplet>
</jmol>
|[[File:Ohbclhomo.jpg|250px]]
|-
!Lumo !! Lumo+1 !! Lumo+2
|-
|[[File:Ohbcllumo.jpg|250px]]
|[[File:Ohbcllumo+1.jpg|250px]]
|[[File:Ohbcllumo+2.jpg|250px]]
|-
|colspan="3" | [[File:Ohbclmep.jpg|300px rotate="90"]]
|}

[[File:Ohbclelevels.png|250px]]

Of the two alekenes, the endo is favoured rather than the exo because
the cl-c sigma star orbital mixes with the exo alkene. This stabilises both orbitals, as shown by the frequency calculation having a higher value than the endo alkene, but reduces the pi bond character of the exo alkene. This is also shown by the comparative lengths of the alkene bonds - the exo is 1.3355A and the endo is 1.33190A. The cycloaddition of the carbene requires an alkene and so favours the endo alkene as it has a higher p character.
The homo is also focused entirely on the endo side of the molecule, with the lumo focused mainly on the exo side. The Homo shows the high pi bond character of the endo alkene. The Homo-1 is mainly focused ont he exo alekene, so shows the pi bond character of the exo alekene. This is lower in energy and so is less likely to rteact with the carbene molecule.

====Glycosidation====

=====Mechanisms=====

[[file:Ohbglymech.gif|800px]]

{|class="wikitable" border="2"
!rowspan="5" |Initial molecule
!colspan="2" | Conformation
|1
|2
|3
|4
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2amm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 11.5430
| 35.5277
| 29.5144
| 46.2672
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4AMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -90.51343
| -72.56010
| -85.04737
| -70.57703
|-
!rowspan="5" |Intermediate
!colspan="2" | Conformation
|chemdraw
|chemdraw
|chemdraw
|chemdraw
|-
! rowspan="2" | MM2 minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2Bmm2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMM2.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
! Total Energy Kcalmol<sup>-1</sup>
| 28.4913
| 43.2706
| 41.0918
| 31.8763
|-
! rowspan="2" | MOPAC minimisation
! Molecule
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB4BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB2BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB1BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|<jmol>
<jmolApplet>
<title>Optimised</title><color>#FFF0F5</color><size>200</size>
<script></script>
<uploadedFileContents>OHB3BMOPAC.mol</uploadedFileContents>
</jmolApplet>
</jmol>
|-
!Heat of formation Kcalmol<sup>-1</sup>
| -91.66112
| -66.72331
| -88.08089
| -84.44899

|-
|}

==Comparison of coumpational results to a molecule from literature.==

Computational chemistry can be a powerful tool in the analysis and reproduction of spectra. in this exercise, literature values and spectra are compared to computed data and the effectiveness and accuracy of both methods is compared and contrasted.
In the synthesis of molecule A (right), using Kobayashi aldol chemistry, two stereoisomers are produced. Initially, the syn isomer is formed, with a diasteromic ratio of 1:14, and via a similar synthetic route, the anti isomer is also produced, with a high dr of 1:>50. The high stereoselectivity of both of these reactions is an important step in the synthesis of enationmerically pure natural products.
Initiallyu the models were optimised using an MM2 optimisation within ChemBio 12.0. They were then further optimised using an RB3LYP-6-31G(d,p) method and basis set. After the optimisation, and checking to see that the the two molecules were still distinct, with one syn and one anti form, they were submitted for nmr analysis, to produce a predicted nmr. This was then compared with the reported nmr, with a view to see if the assignments and conclusions made in the literature were correct. There was a good correlations between the predicted and measured nmr peaks, with deviations, as show below, of less than 1ppm for the H nmr and less than 10ppm for the <sup>13</sup>C nmr.
[[File:Ohbccomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each carbon atom]]
[[File:Ohbhcomparison.png|thumb|900px|none|left|Difference in measured and calculated chemical shift values in ppm, for each Hydrogen atom]]

This correlation helps confirm that the structures are correct; the different enantiomers are differentiated and assigned correctly. If they were not, and the calculated syn nmr is compared to the measured anti nmr, and vice versa, larger differences are noted. This is highlighted on the graph below. The blue and red graphs are the correctly assigned and matched nmrs, the green and purple nmrs are if they are assigned incorrectly. It can clearly be seen that the green and purple line are consistently higher than their counterparts.
[[file:Ohbcomparisonnmr.png|thumb|900px|none|left|Comparison of correct and incorrect assignment for the two conformers]]
Within the literature all of the hydrogens and carbons are assigned, with the exception of Hydrogen 48. This is because this is a labile proton and so does not show up on measured nmrs due to rapid exchange with the deuterium in the deuterated solvent. However the calculated spectra does not take this into account and so displays the shift value for this hydrogen.

The computed IR spectra are very similar for the two molecules. The OH stretch is increased by 30cm<sup>-1</sup> in the syn form of the molecule and the CH bend region between 1000-1500cm<sup>-1</sup> is also significantly different. This acsn be rationalised by the different atomic orbital overlaps that are occuring due to the different positioning of the methyl group.

As both molecules are chiral, they both rotate light in opposite directions. However due to the large size of this molecule and although it is relatively conformationally limited due to the double bond and ring, the calculation for the syn and anti variants did not converge after 48 a 48 hour run on the SCAN.

==References==
<references></references>

Rep:Mod:benton2

2013-02-08T11:54:03Z

Ohb09: /* Hydrogenation of the Cyclopentadiene Dimer */

Rep:Mod:benton2

2013-02-08T11:50:58Z

Ohb09: /* Hydrogenation of the Cyclopentadiene Dimer */

Rep:Mod:benton2

2013-02-08T11:50:27Z

Ohb09: /* Hydrogenation of the Cyclopentadiene Dimer */

Rep:Mod:benton2

2013-02-08T11:49:41Z

Ohb09: /* Hydrogenation of the Cyclopentadiene Dimer */