On the thermodynamic equilibrium between (R)‐2‐hydroxyacyl‐CoA and 2‐enoyl‐CoA

A combined experimental and computational approach has been applied to investigate the equilibria between several α‐hydroxyacyl‐CoA compounds and their 2‐enoyl‐CoA derivatives. In contrast to those of their β, γ and δ counterparts, the equilibria for the α‐compounds are relatively poorly characterized, but qualitatively they appear to be unusually sensitive to substituents. Using a variety of techniques, we have succeeded in measuring the equilibrium constants for the reactions beginning from 2‐hydroxyglutaryl‐CoA and lactyl‐CoA. A complementary computational evaluation of the equilibrium constants shows quantitative agreement with the measured values. By examining the computational results, we arrive at an explanation of the substituent sensitivity and provide a prediction for the, as yet unmeasured, equilibrium involving 2‐hydroxyisocaproyl‐CoA.