Figure 1: Optimized 3D structures for 22 (position a only, top) and the corresponding energetic profile.
A subset of molecules contain additional SNAr functionality (2 , 4 & 18 )[54] and Michael acceptor groups (7 & 13 ).[55] We also predicted the SNAr reactivity of compounds 2 , 4 and 18 using our previously reported QM-QSAR method (Figure 4).[54] All 3 compounds were re-simulated using the methodology previously described and it was observed that only compound 18 was predicted to have a barrier to reactivity likely to result in a significant LLNA response. Compound 18 , which contains bromide leaving group was predicted to have a barrier of 10.5 kcal/mol while compounds 2 and 4 , the chloride leaving groups, have predicted barriers of >16 kcal/mol. Compounds 7 and 13 were not simulated as they consist of Michael acceptors connected to aliphatic carbons and couples with their small solvent accessible surfaces are not predicted to be sensitizers.