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

Abstract

The rate–pH profiles for hydrolysis of the title compounds 1 show four distinct regions: kA, kB and kC for rate plateaux corresponding to cationic, neutral and anionic species, plus kD 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 pKlg, due to exceptional charge dispersal in reactant and leaving group. The plateau rates kB and kC 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 kB, kC and acid pKa 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 kA → kB → kC but with C–N bond breaking quite out of line and largely dependent on conformational factors.Given pKcat < 0, the presence of effective intramolecular general base catalysis in kB 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 pKcat → pK lg as C–N bond-breaking proceeds. Further light on kB 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 pKa’ that can be explained as a consequence of this.