Influence of Equatorial CH⋅⋅⋅O Interactions on Secondary Kinetic Isotope Effects for Methyl Transfer

DFT calculations for methyl cation complexed within a constrained cage of water molecules permit the controlled manipulation of the “axial” donor/acceptor distance and the “equatorial” distance to hydrogen‐bond acceptors. The kinetic isotope effect k(CH(3))/k(CT(3)) for methyl transfer within a cage with a short axial distance becomes less inverse for shorter equatorial C⋅⋅⋅O distances: a decrease of 0.5 Å results in a 3 % increase at 298 K. Kinetic isotope effects in AdoMet‐dependent methyltransferases may be m∧odulated by CH⋅⋅⋅O hydrogen bonding, and factors other than axial compression may contribute, at least partially, to recently reported isotope‐effect variations for catechol‐O‐methyltransferase and its mutant structures.