| Abstract
| - We have synthesized 1-(2-hydroxyacetyl)piperidine-2-one (2) and 1-(2-hydroxyacetyl)azepan-2-one (3).Equilibrium (Kf) between the free alcohol (open form) and the tetrahedral intermediate (cyclol) is readilyestablished, and both forms are observed in the D2O 1H NMR spectra of 2 and 3. Therefore, theirinterconversion can be considered as an almost thermoneutral non-identical one. Pseudo-first-order rateconstants (kobs) were obtained by simulating the AB 1H NMR system observed for the cyclol. By bestfitting the experimental points of a kobs versus pD profile to the equation kobs = 0.5k0r + 0.5krKac/(Kac +[D+]) + 0.5kfKao/(Kao+ [D+]), the parameters involved were obtained: rate constants of rupture andformation (k0r and k0f = Kfk0r) catalyzed by water, rate constants of rupture (kr) and formation (kf) fromthe conjugated bases of the cyclol form and the open form, and their acidity equilibrium constants Kacand Kao. The system studied mimics the serine alcohol attack on the peptide bond and its reverse reactionin serine protease enzymes. In fact, the reaction rates are similar or perhaps even faster than the onesobtained for enzymatic reactions. The results also show the participation of water molecules formingcatalytic proton bridges in stable potentials with the two interconverted forms. The position change ofthe bridged proton is sensitive to lactam ring size, and it is manifested by considerable change in the pKavalues of both cyclol and open forms. Other evidence such as kinetics, ΔS°, ΔS⧧, and proton inventoryexperiments and semiempirical molecular calculations support this proposal.
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