Solvent Effects on the Barrier to Rotation in Carbamates.

In the 40 years since the inception of dynamic NMR methods, much effort has been invested to quantify and understand the barrier to rotation about the C-N bond in amides.1 Carbamates, which also exhibit the approximately planar N-CdO framework responsible for hindered rotation in amides, have received considerably less attention, although they are important biologically as anticonvulsants, local anesthetics, sedatives, muscle relaxants,2 enzyme inhibitors,3 and surrogates for amides in enzyme mimetics.4 Although amides and carbamates share common features, the additional oxygen of the carbamate functionality exerts unique steric and electronic perturbations. One consequence of this difference is that the barriers to rotation in carbamates are usually 3-4 kcal/mol (about 15-20%) lower than those in the corresponding amides. During a study on the catalysis of cis-trans amide and carbamate isomerization, we observed that the barriers to rotation (∆G‡) in prolyl carbamates were surprisingly insensitive to solvent effects. This behavior contrasts that of amides, where it is common for ∆G‡ to increase by as much as 3 kcal/mol (>100-fold rate decrease) upon a change in environment from a nonpolar, non-hydrogen bonding solvent to water.5 In this paper, we report the first systematic investigation of solvent effects on ∆G‡ for hindered C-N bond rotation in carbamates and that this process occurs with a negative ∆S‡ for acyclic tertiary carbamates in aqueous solution. We began our investigation by studying the effect of solvent on ∆G‡ for the interconversion of the cis and trans forms of the related proline derivatives 1 and 2 (eq 1). The