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.