Z-effect reversal in carboxylic acid associates

The carboxylic group is a common fragment in synthetic compounds and biomolecules. Its conformation is assumed to be dominantly cis due to so-called Z-effect. However, in this study, we show that the nature of the H-bond acceptor in RCOOH center dot center dot center dot X directly affects the conformational preference of the resulting supermolecule. This result is evident from the statistical analysis of available crystallographic data and was quantified using accurate quantum chemical calculations. We propose the term supramolecular stereoelectronic effect'' for the observed conformational preference. The likely reason for this is the interaction of the O-H center dot center dot center dot X hydrogen bond with the C=O double bond in the trans conformation, which in case of anionic X is strong enough to reverse the Z-effect. Explicit consideration of trans COOH center dot center dot center dot X stabilization can help crystal structure predictions and biomolecular simulations. In particular, this effect plays a key role in the transition between the T-6 and R-6 forms of human insulin.