Entropic strain and conformational preference in the hydrolysis of some N-alkyl-6-acetylaminotriazinediones

Article abstract of DOI:10.1039/a700736a

The rate-pH profiles for hydrolysis of the title compounds 1 show four distinct regions: k_A, k_B and k_C for rate plateaux corresponding to cationic, neutral and anionic species, plus k_D for attack of OH^- on the anion. At the ends of the pH scale the reaction is much slower than for model amides of comparable pK_lg, due to exceptional charge dispersal in reactant and leaving group. The plateau rates k_B and k_C are due to hydrolysis by water, not to some kinetically equivalent process, and are much faster than model calculations would predict. This is traced to intramolecular general base catalysis via solvent bridges, and leads to remarkable rate enhancements in aqueous alcohols. The considerable, and quite independent, variations in k_B, k_C and acid pK_a with only alkyl substitution in the amide moiety points to a dominant effect of conformation which has been explored using a number of techniques, notably octanol-water partitioning, and appears best rationalised in terms of Taft's 'steric hindrance of motions' or Tillett's 'entropic strain'. The overall picture for the effect of pH is of successively increasing C-O bond formation in the transition state along the sequence k_A → k_B → k_C but with C-N bond breaking quite out of line and largely dependent on conformational factors. Given pK_cat < 0, the presence of effective intramolecular general base catalysis in k_B is unexpected. We explain this as being due to a unique feature of 1 whereby catalyst and leaving group are part of the same conjugated structure, leading to pK_cat → pK_lg as C-N bond-breaking proceeds. Further light on k_B comes from the ring-N-methylated analogue 3d, which cannot form the intramolecular hydrogen bond found elsewhere and whose otherwise similar rate-pH profile shows an anomalous 'apparent pK_a' that can be explained as a consequence of this.