Unless otherwise stated the methods used in this module can be found here Mod:organic. The second part of this module, including the miniproject can be found at Mod:frisbee0702part2
Hydrogenation of Cyclopentadiene Dimer
Introduction
Fig 1
The dimerisation of cyclopentadiene is an example of a cycloaddition specifically the Diels-Alder reaction. This being a 4n+2 electron , thermally driven process proceeds via Huckel topology [1] with only suprafacial components and as such the hydrogens on the newly formed σ bond will be syn to one another. As shown in fig 1 this can give two possible isomers with isomer 2 forming the majority of the product. Similarly hydrogenation of 2 can give either product 3 or 4 depending upon which of the two double bonds is attacked.
This section attempts to rationalise, through the use of molecular modelling, the preferance for product 2 over product 1 and also to predict the product of the hydrogenation of 2.
Results and Discussion
As can be seen from the table below, 2 is the higher energy dimeristion product and hence is thermodynamically less favourable than 1. However this contradicts the experimental observation that 2 is the major product, thus the reaction must be kinetically controlled, with the formation of 2 proceeding through a lower energy transition state(fig 2). Modelling predicts that isomer 3 will form upon monhydration as this has the lowest energy. However experimenatally [2] its is known to go to isomer 4. Therefore hydrogenation must also be a kineticvally controlled process.
fig 2
Dimer
Image
Total Energy/ Kcal mol-1
Stretch
Bending
Torsion
Van der Waals
H-bonding
1
Dimer1
31.8834
1.2923
20.5870
7.6715
4.2320
0.3778
2
Dimer2
34.0153
1.2454
20.8603
9.5039
4.3012
0.4480
3
Dimer3
31.1540
1.0963
14.5074
12.4972
4.5124
0.1407
4
Dimer4
35.9322
1.2067
18.8637
12.2396
5.7649
0.1632
Nucleophilic Addition to Pyridinium Rings
Introduction
fig 3
The two examples shown in fig 3 both show stereoselective addition to pyridinium rings.Macrocycles conatining similar pyridinium rings have found use in synthesis as chiral transfer agents[3]. In the first example there is a 19:1 ratio[4] of products in favour of the C4 substituted ring. This section aims to explain both the stereoselectivity and the regioselectivity of both reactions through the use of MM2 modelling.
Results and Discussion
From the molecular model below, it can clearly be seen that in A, the carbonyl oxygen is orientated so that it is slightly above the plane of the pyridinium ring. It has been reported[5] that the mechanism for addition proceeds via a six membered ring transition state form by coordination of the magnesium atom in the Grignard reagent to the carbonyl oxygen. Therefore the orientation of the carbonyl directs the incoming methyl group so that it adds above the plane of the ring (i.e. on the same face as the carbonyl). As coordination to the carbonyl facilitates addition to the ring, this same mechanism is responsible for the regioselectivity shown in the ratio of products.
The model of B shows a more twisted molecule again with the carbonyl oxygen above the plane of the pyridinium ring. A similar method of addition occurs here with hydrogen bonding between the amine hydrogen and the carbonyl oxygen giving a six membered transition state again, leading to the stereochemistry of the product.
Taxol (also known as paclitaxel) is a cancer treatment drug that works by inhibiting the reproduction of cancer cells within the body. One of the intermediates in its synthesis can exists in two isomers, differing only in the orientation of the carbonyl bond. Upon standing [7] conversion to the more stable isomer occurs. Furthermore the alkene bond has been observed to react abnormally slow. This section attempts to predict and rationalise the isomerisation of the intermediate and to also explain the slow reactivity of the double bond.
Results and Disscussion
Molecular modelling show that isomer A is higher in enegy than isomer B, most likely due to the steric clash of the carbonyl and one of the bridgehead methyls. Thus it is reasonable to predict that upon standing A will isomerise to B in order to reduce this steric contribution and hence lower the overall energy.
Bredt’s rule [8] forbids double bonds at a bridgehead, yet in there is clearly one in both isomers and its slow reactivity indicates it to be a stable feature of the molecule. In fact it has been shown [9] that there are a series of medium sized polycyclic compounds where a bridgehead alkene is actually preferred. These are known as “hyperstable alkenes” and possess less strain than in their hydrogenated form, so any reaction of the double bond will be unfavourable.
Models for the hydrogenated forms of A and B are shown below. It can be seen that the hydrogenated form of isomer a is considerably higher in energy and possesses more strain. Thus A is a hyperstable alkene and as such resistant to attack on the double bond. In comparison the hydrogenated form of isomer B is has a lower overall energy. However this energy difference is low and there is also more torsional strian than in the alkene form. Thus reaction of the alkene will occur slowly.
