Neutral and Alkaline Hydrolyses of Model -Lactam Antibiotics. An ab Initio Study of Water Catalysis
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文摘
The effect of an ancillary water molecule on the neutral andalkaline hydrolysis mechanisms of asimple s/gifchars/beta2.gif" BORDER=0 ALIGN="middle">-lactam molecule (N-methylazetidinone) has beenstudied at the Hartree-Fock and MP2 levels usingthe 6-31G* and 6-31+G* basis sets. The results have beencompared with a nonassisted study carried outpreviously. Solvent effects have been also considered by means ofa polarizable continuum model. In theneutral hydrolysis, the additional water molecule diminishes thefree-energy barriers only when correlationenergy is taken into account. Concerted and stepwise mechanismshave been described. The correspondingbarriers are close, and the actual mechanism could be conditioned bythe molecular environment, solution,protein, etc. Using the results of a molecular dynamics simulationof N-methylazetidinone in aqueous solution,it has been shown that the stepwise process is more likely to occur insuch conditions. In the alkaline hydrolysis,the first reaction step consists of the formation of a tetrahedralintermediate which requires a desolvation ofthe hydroxyl anion difficult to reproduce by calculation.Afterward, the hydrolysis reaction proceeds througheither concerted or stepwise mechanisms for ring opening and protontransfer. The concerted channel presentsa very low energy barrier, and the species involved are dependent onthe calculation level. The stepwisemechanism is virtually the same as that previously reported for thenonassisted hydrolysis, the relative energyof all the points along the path being diminished and the energybarriers remaining essentially unaltered.
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