The aminolysis of N-aroyl beta-lactams occurs by a concerted mechanism.
N-aroyl beta-lactams are imides with exo- and endocyclic acyl centres which react with amines in aqueous solution to give the ring opened beta-lactam aminolysis product. Unlike the strongly base catalysed aminolysis of beta-lactam antiobiotics, such as penicillins and cephaloridines, the rate law for the aminolysis of N-aroyl beta-lactams is dominated by a term with a first-order dependence on amine concentration in its free base form, indicative of an uncatalysed aminolysis reaction. The second-order rate constants for this uncatalysed aminolysis of N-p-methoxybenzoyl beta-lactam with a series of substituted amines generates a Brønsted betanuc value of +0.90. This is indicative of a large development of positive effective charge on the amine nucleophile in the transition state. Similarly, the rate constants for the reaction of 2-cyanoethylamine with substituted N-aroyl beta-lactams gives a Brønsted betalg value of -1.03 for different amide leaving groups and is indicative of considerable change in effective charge on the leaving group in the transition state. These observations are compatible with either a late transition state for the formation of the tetrahedral intermediate of a stepwise mechanism or a concerted mechanism with simultaneous bond formation and fission in which the amide leaving group is expelled as an anion. Amide anion expulsion is also indicated by an insignificant solvent kinetic isotope effect, kH2ORNH2/kD2ORNH2, of 1.01 for the aminolysis of N-benzoyl beta-lactam with 2-methoxyethylamine. The Brønsted betalg value decreases from -1.03 to -0.71 as the amine nucleophile is changed from 2-cyanoethylamine to propylamine. The Brønsted betanuc value is more invariant although it changes from +0.90 to +0.85 on changing the amide leaving group from p-methoxy to p-chloro substituted. The sensitivity of the Brønsted betanuc and betalg values to the nucleofugality of the amide leaving group and the nucleophilicity of the amine nucleophiles, respectively, indicate coupled bond formation and bond fission processes.
Tsang
Wing Y
WY
Department of Chemical and Biological Sciences, The University of Huddersfield, Queensgate, Huddersfield HD1 3DH, UK.
Ahmed
Naveed
N
Page
Michael I
MI
D000577:Amides / Q000737:chemistry; D000588:Amines / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000737:chemistry*; D002384:Catalysis; D002509:Cephaloridine / Q000737:chemistry; D002713:Chlorine / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007554:Isotopes / Q000737:chemistry; D007700:Kinetics; D008956:Models, Chemical; D010406:Penicillins / Q000737:chemistry; D012997:Solvents / Q000737:chemistry; D047090:beta-Lactams / Q000737:chemistry*
D000577:Amides; D000588:Amines; D000900:Anti-Bacterial Agents; D007554:Isotopes; D010406:Penicillins; D012997:Solvents; D047090:beta-Lactams; D002713:Chlorine; D002509:Cephaloridine