Alcohol-catalysed hydrolysis of benzylpenicillin

Abstract

The hydrolysis of benzylpenicillin is catalysed by alkoxide ions and other oxygen bases. Catalysis occurs by a nucleophilic pathway and the intermediate ester can be detected in some cases. The Brsnsted Pnuc for alkoxide ions is 0.97, and is compatible with rate-limiting ring opening of the plactam. A solvent isotope effect of 3.2 for the trifluoroethanol-catalysed reaction suggests protonation by water occurs to the departing p-lactam nitrogen. Penicillin is not a particularly effective acylating agent of alcohols.

Theoretical study of thiolysis in penicillins and cephalosporines

“…Special attention has been given to nucleophilic substitution reactions of the ␤-lactam carbonyl with hydroxyl groups [3][4][5][6][7][8][9][10][11]; in fact, the magnitude of the kinetic constants of alkaline hydrolysis of these substances was initially used as a measure of the bactericidal power of the antibiotics [12,13]. The ␤-lactam carbonyl of penicillins and cephalosporins can also undergo other nucleophilic substitution reactions with amines [8,14,15], alcohols [16], and thiols [17][18][19] in aqueous solution. All involve the transfer of acyl groups via a covalent bond between the carbon atom in the carbonyl group and the attacking nucleophile to form a tetrahedral intermediate T that subsequently undergoes cleavage of the C N bond in the ␤-lactam ring (see Scheme 1).…”

“…16.1 kcal/mol [8] mainly due to the desolvation of the hydroxyl group in the attacking nucleophile [10,11]. On the other hand, the rate-determining step in aminolysis, alcoholysis, and thiolysis processes is the cleavage of the tetrahedral intermediate, which is facilitated by the transfer of a proton from a water molecule in the solvent to the ␤-lactam nitrogen (3) [14][15][16] and subject to a somewhat lower energy barrier [8,17]. In cephalosporins with appropriate leaving groups at position 3 , nucleophilic hydrolysis is accompanied by a nonconcerted process involving the release of the group at 3 to form an enamine intermediate (4) that evolves to 5-exomethylene-1,3-thiazine (5) as end product [9,[21][22][23][24].…”

Penicillin degradation catalysed by Zn(II) ions in methanol

“…Penicillins in general undergo pH-dependent hydrolysis, with negligible spontaneous degradation or water-catalysed degradation. The common mechanism of hydrolysis has been described by different authors [3][4][5][6]. The ␣-amino penicillins such as ampicillin and amoxicillin can also undergo autoaminolysis in an aqueous solution by means of a nucleophilic attack of the amino group of the lateral chain of a molecule, on the ␤-lactam bond of a second molecule of antibiotic [7][8][9].…”

“…Also well documented are the reactions of penicillins catalysed by alkoxide ions in aqueous solution, and certain mechanisms of the reaction have been proposed [6,[13][14][15]. In the methanolysis of benzylpenicillin, the increase in light absorption at 280 nm has been attributed to the formation of the penicilloyl ester, which gives way to the penamaldic derivative of the antibiotic.…”

The Chemistry of 2‐Azetidinones (β‐Lactams)

“…For example, nucleophilic substitution at the b-lactam carbonyl center of penicillins occurs, in water, with amines [208], alcohols [209], and thiols [210] proton transfer to nitrogen changes from an unfavorable to a thermodynamically favorable process. Thus, many of these reactions require general acid catalysis and protonation of the amine nitrogen leaving group to facilitate CÀN bond fission and avoid amine anion expulsion.…”