Rep:Mod:3344665
The Hydrogenation of Cyclopentadiene Dimer
Aims
The dimerisation of Cyclopentadiene is a Diels-Alder cycloaddition reaction.The reaction can produce two products, the Endo and the Exo form
, which are conformational isomers of each other. Both products are not equally likely to form, the Endo product is primarily the one formed. The aim is to use Molecular Mechanics (MM2) calculations to suggest if this is a kinetically or thermodynamically controlled reaction. Also, the hydrogenation of the Endo product is investigated to determine which of the two alkenes is more stable.
Endo vs. Exo
Using ChemBio3D both structures were drawn, making sure that the conformation drawn was a reasonable one to ensure an accurate calculation. The Molecular Mechanics (MM2) force field, which will optimize the geometry of the products, was run to minimize the energy of both Endo and Exo structures. The Table 1 below summarizes the energies obtained.
| Energy | Exo-Product (kcal mol-1) | Endo-Product (kcal mol-1) | Energy Difference (kcal mol-1) | |
| Stretch | 1.285 | 1.251 | - 0.034 | |
| Bend | 20.582 | 20.844 | 0.262 | |
| Stretch-Bend | -0.838 | -0.836 | 0.002 | |
| Torsion | 7.655 | 9.511 | 1.856 | |
| Non-1,4 VDW | -1.418 | -1.541 | -0.123 | |
| 1,4 VDW | 4.233 | 4.321 | 0.088 | |
| Dipole-Dipole | 0.378 | 0.448 | 0.07 | |
| Total Energy | 31.877 | 33.998 | 2.121 |
The calculations indicate that the Exo product is the most stable one as its total energy is lower compared to the Endo product, the difference in total energy being 2.121 kcal/mol. It is known form literature[1] that the Diels-Alder reaction favors the Endo isomer, but the calculation show that it is higher energy isomer, therefore indicating that the reaction is kinetically controlled. With the Exo isomer being the thermodynamic product and the Endo isomer the Kinetic product.
The energy component with the largest difference is the Torsion energy, this energy contribution arise from deviations of the optimum dihedral angle[2] of 180° (antiperiplanar arrangement). The difference in torsion energy comes from the overlap of carbon atoms in the Endo product with an dihedral angle of 46°, this overlap does not occur in the Exo product, therefore, it will be lower in energy. Also, there is an additional steric clash of the hydrogens on the central C-C bond, the dihedral angle between the hydrogens in the Exo product is 78° compared to 45° for the Endo,thus raising its torsional energy more.
Hydrogenation
The Hydrogenation of the Endo isomer is investigated by using MM2 force field calculations to minimize the energy of the mono-hydrogenated product. The Table 2 below shows the respective energies of the structures obtained by hydrogenating the five-membered ring (structure 3) or hydrogenating the six-membered ring (structure 4).
| Energy | Structure 3 (kca/mol) | Structure 4 (kca/mol) | |
| Stretch | 1.277 | 1.096 | |
| Bend | 19.857 | 14.524 | |
| Stretch-Bend | -0.834 | -0.549 | |
| Torsion | 10.81 | 12.498 | |
| Non-1,4 VDW | -1.221 | -1.069 | |
| 1,4 VDW | 5.633 | 4.512 | |
| Dipole-Dipole | 0.1621 | 0.14 | |
| Total Energy | 35.685 | 31.152 |
The data indicates that Structure 4 is the thermodynamic product as its total steric energy is lower compared to structure 3, the difference in energy to Structure 3 is E= 4.533 kcal/mol. From the individual components of the total energy it can be seen that the largest difference arises from the bending and torsional energies and to a smaller extent the 1,4 VDW energy.
The component with the largest difference between structures 3 and 4 is the Bend energy. This energy arises form deviations of the bond angles from ideality[2], which in the case of an sp2 hybridized carbon, is a deviation from 120° of the C-C-C alkene bonds. Structure 3 shows significant deviation of the bong angles of the alkene carbons, 107.7° and 127.0°, compared to Structure 4 with bond angles of 112° and 125°.
Thee deviations in the bond angles can be used to indicate (or at least suggest prior to experimentation) which product is the kinetic one. Given that the largest deviations are on structure 3, the hydrogenation may be faster on this alkene due to release of strain thus forming structure 4.
Stereochemistry and Reactivity of an Intermediate in the Synthesis of Taxol
Aims
In the total synthesis of Taxol a key intermediate displays atropisomerism. The aim is to use MM2 and MMFF94 molecular mechanics force fields to determine the most stable isomer. Also, the alkene displays a great resistance to functionalisation, which at first glance appears odd as the release of strain on the bridgehead alkene would favor functionalisation. This aspect will also be investigated using molecular mechanics.
Atropisomerism
Atropisomers are stereoisomers where the element of chirality is located on an axis or plane of symmetry and not on a single atom. This from of isomerism comes about due to "the potential energy barrier between two adjacent minima of the molecular entity as a function of torsional angle[3]", which means that the isomerism arises from the sterically hindered rotation about a bond (or bonds) which prevents interconversion at a particular temperature. In the case of the Taxol intermediate the atropisomerism arises from the restricted rotation about the bonds connected to the carbonyl, which leads to one isomer having the CO group down and the other isomer with the CO up.
Analysis
Using ChemBio3D the structures 9 and 10 were optimized by using MM2 and MMFF94 force-field calculations. The minimized conformations can be viewed by clicking the corresponding header on the table below.
Table 3 MM2 and MMFF94 derived energies for Taxol intermediate
| Carbonyl Down | Carbonyl Up | |||
| Energy | MM2 (kcal/mol) | MMFF94 (kcal/mol | MM2 (kcal/mol) | MMFF94 (kcal/mol |
| Stretch | 2.622 | - | 2.783 | - |
| Bend | 11.338 | - | 16.543 | - |
| Stretch-Bend | 0.344 | - | 0.429 | - |
| Torsion | 19.672 | - | 18.256 | - |
| Non 1.4 VDW | -2.16 | - | -1.559 | - |
| 1.4 VDW | 12.87 | - | 13.112 | - |
| Dipole-Dipole | -2.002 | - | -1.725 | - |
| Total Energy | 42.683 | 60.557 | 47.839 | 70.534 |
As can be seen the carbonyl down structure is the lowest in energy, with a difference of 5.156 kcal/mol compared to carbonyl up. Both atropisomers show similar conformations for the five and six-membered rings in their structure, with a chair conformation being the most stable. Although, the carbonyl down isomer could also have its six-membered ring in a twist boat conformation, but this was higher in energy (MM2 Total energy= 54.238 kcal/mol.