Altogether, these data suggest that the crucial factors that dictate the covalent mechanism of action within this series of carbamate ChEIs are the size and bulkiness of the carbamate Ndialkyl substituents. Significant steric clash prevents the approach to the catalytic Ser198, and efficient binding and activation by the oxyanion hole. The intrinsic reactivity of the warhead itself should be approximately the same for different carbamate N-dialkyl substituents and was found to be energetically comparable with the behaviour observed in solution.