Substituent effects on conformational preference inα-substitutedα-fluorophenylacetic acid methyl ester model systems for chiral derivatizing agents

In connection with study of chiral derivatizing agents (CDAs) for NMR determination of absolute configuration of organic compounds, factors controlling the conformational preference between syn- and anti-forms in α-substituted α-fluorophenylacetic acid methyl ester (FC(X)(Ph)COOMe) model systems were theoretically investigated. Substituents X at the stereogenic carbon atom were X = H, CCH and CH3, the electronic and steric properties of which were significantly different from each other. The model system with X = CCH and that with X = CH3 were found to be possible candidates for fluorine-containing CDAs. The syn conformation is stable compared with the anti one by 0.7 kcal mol−1 for the ester with X = CCH. On the other hand, the anti conformation is stable compared with the syn one by 0.5 kcal mol−1 for the ester with X = CH3. Both natural bond orbital (NBO) analysis and deletion of selected orbitals based on the donor–acceptor NBO scheme were adopted for semi-quantitative estimation of factors responsible for the conformational preference as well as a qualitative inspection of occupied canonical molecular orbitals (MOs). It was shown that [σ–(σ* + π*)(CO)] and [σ–σ*(Ph) and π(Ph)–σ*] hyperconjugations are the main factors controlling the conformational preferences between the syn and anti conformations. Other types of effects such as electrostatic effects were also investigated. The role of the fluorine atom was also clarified. Copyright © 2009 John Wiley & Sons, Ltd.