4.4 Component L incorporating an amide binding site—reverse recognition site
4.4.8 Computational study
In order to investigate the reduced reactivity of the bound maleimide 202
further, electronic structure calculations were applied. Given the large size of the system, semi-empirical methods were used for these calculations. A semi-empirical method that was capable of locating a high quality transition state structure for the dipolar cycloaddition was desired. Hence, the transition state for the dipolar
cycloaddition between N-phenylmaleimide and diphenylnitrone was located using
density functional methods (B3LYP/6-31G+(d,p)). The available semi-empirical methods—AM1,127 PM3,128 RM1129 and PM6130—were then screened against this
transition state structure. The RM1 method gave the closest match to the DFT transition state structure and it was therefore decided to proceed with the calculations involving the macrocycle using this method.
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(a) N O NH O N O O 229 228 (b) (c)Figure 4.17 Stick representations of the calculated (RM1 semi-empirical method) transition state structures leading to the trans diastereoisomer for (a) the reaction between model nitrone 228 and model maleimide 229 and (b) the reaction between model nitrone 228 and the complex between model maleimide 229 and macrocycle 130. The tert-butyl group of 228 is essentially in van der Waals contact with the diethylene glycol loop in macrocycle 130, as illustrated in the space filling model (c). Carbon atoms are coloured orange in linear components and green in macrocycles, oxygen atoms red, nitrogen atoms blue and hydrogen atoms white (most hydrogen atoms have been removed for clarity). Hydrogen bonds are shown as dashed lines and forming bonds as dotted lines.
The transition states accessed by the dipolar cycloaddition reaction between a model maleimide 229 and a model nitrone 228 were calculated using RM1 in the presence and in the absence of macrocycle 130. The transition state structures located are shown in Figure 4.17. It is immediately apparent from the calculated structures that the association of macrocycle 130 with the amide-binding site exerts a remote steric effect on the transition state. The tert-butyl group of the nitrone is located close to the bottom diethylene glycol loop of the macrocycle—in fact, in that region, part of the diethylene glycol loop and the tert-butyl group are essentially in van der Waals contact. This interaction is undoubtedly somewhat destabilising to the transition state in the reaction between [130!202] and 201 when
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compared to the reaction between 202 and 201 in isolation. This observation also helps to explain the change observed in the diastereoselectivity of the cycloaddition between thread 224 (7:1 trans/cis) and rotaxane 200 (1:1.4 trans/cis). The same kind of observation was made between thread 173 and rotaxane 174, and between thread 184 and rotaxane 183. In the rotaxane, the cis diastereoisomer is slightly favoured, probably reflecting the fact that the tert-butyl group on the nitrone interacts more unfavourably with the macrocycle in the trans transition state compared with either the carboxymethylene or the propyloxy groups of the nitrone in the cis transition state.The results of these calculations suggest that in the framework of the self- replicating rotaxane, the reactive site on the linear component L must be placed sufficiently far away from the binding site to prevent the introduction of a supramolecular steric effect131 through the proximity of the macrocyclic component M.
4.5Conclusions
A number of systems have been devised in order to integrate self-replication with the formation of rotaxanes. Some of the macrocycle/guest pairs presented in Chapter 3 have been successfully incorporated to construct rotaxanes. But ultimately, despite careful design, the rotaxane synthesised did not replicate as expected. This failure is a consequence of deficiencies in two important design criteria.
As a result of solubility and synthetic difficulty, a compromise had to be found with respect to the macrocycle binding site—substituting a pyridone with an amide. This compromise is clearly sub-optimal, since the association constant for
the pseudorotaxane complex [L!M] must be as high as possible. This requirement
is essential since the formation of this complex shuts down all kinetic pathways that involve free L and, hence, lead to the thread T. The depletion of free L therefore concentrates the kinetic flux in the autocatalytic cycle involving the rotaxane R.
The second reason for this failure is traced to a deleterious supramolecular steric effect, operating through the proximity of the macrocyclic component M of the pseudorotaxane [L!M] to the transition state for the stoppering reaction. This supramolecular steric effect, identified computationally, renders the linear
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component L much less reactive within the [L!M] complex. The activation barrier for the reaction of the [L!M] complex is higher than that for the reaction of L is absence of macrocycle. Therefore the rate for rotaxane formation is lower than that of thread formation. The product ratio is determined by the relative heights of the barriers and not by the relative stabilities of the intermediates; this observation is an illustration of the Curtin-Hammett principle.129