Macrobicyclic compounds of type shown in Fig. 1. have been hypothesized to interconvert from an in-in form to an out-out form via a process termed homeomorphic isomerism. This mechanism requires one of the three bridges to be threaded through a ring, formed by the macrobicycle, and proceeds via a ''cross-chain'' type of intermediate (Fig. 1; middle). Structural evidence for this mechanism is lacking and our objective was to investigate if this hypothesized intermediate could be observed computationally. At which cage size is the homeomorphic isomerism process feasible? Amine, phosphine, arsine, stibnine, and bismuthine macrobicycles were studied. Macrobicycles ranging from 4 methylene linkers up to 20 were explored. To answer these questions, a combination of calculation methods were used. Simulated annealing (SA) was used to address the conformational space. Density functional theory was used to probe the relative stability of in-in and out-out isomers. Our data support homeomorphic isomerism for all of these macrobicyclic compounds including amines which are known to have a low inversion barrier at the nitrogen atom. Homeomorphic isomerism was observed for all cages with n &gt; 13 (n = number of CH2 groups in a chain connecting the heteroatoms). The frequency of cross-chain isomers is increased when the cage size is expanded. The pyramidal inversion pathway does co-exist for amines but is not observed for other cage types. In terms of relative stability, statistical analysis showed that the in-in species are significantly more stable than out-out isomers but that the topology of the cage impacts the energetics drastically. Dispersion interactions are vital in understanding the energetic stability. These investigations allow us to design appropriately sized macrobicycles that can have the homeomorphic mechanism turned on or off based on size.

Elucidating homeomorphic isomerism in macrobicycles of the pnictogen-series

2019 Spring National Meeting

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