The copper(II) promoted hydrolysis of benzylpenicillin. Evidence for the participation of a Cu–OH species in the hydrolysis of the β-lactam ring

Abstract

The pK_a of benzylpenicillin (HL ⇄ L^– or H⁺) relating to the carboxyl group ionisation has been determined to be 2.67 ± 0.005 at 10°C and 2.60 ± 0.008 at 5 °C and I= 0.1 mol dm^–3. At a 1 : 1 ligand-to-metal ratio the interaction of copper(II) with benzylpenicillin can be described by the equilibria (i) and (ii) at 10 °C. The pK for the ionization [CuLH_–1]⇄[CuLH_–2]^–+ H⁺ is 4.92 at, L^–+ Cu²⁺⇄[CuLH_–1]+ H⁺; log β_{11 – 1}=–1.41 ± 0.1 (i), L^–+ Cu²⁺⇄[CuLH_–2]^–+ 2H⁺; logβ_{11 –2}=–6.33 ± 0.08 (ii) 10°C and I= 0.1 mol dm^–3. No potentiometric evidence was obtained for a species [CuL]⁺. Possible structures for [CuLH_–1] and [CuLH _–2]^– are considered involving deprotonation of the side chain amide group and a water molecule co-ordinated to copper(II). The copper(II)-promoted hydrolysis of benzylpenicillin to penicilloic acid has been studied over the pH range 4.3–5.3 at 30 °C and I= 0.5 mol dm^–3 using non-complexing 2,6-dimethylpyridine-3-sulphonic acid buffers. The dependence of the rate on the copper concentration and the pH strongly suggests that the complex [CuLH_–2]^– is the active species in the reaction. Hydrolysis of the lactam ring of benzylpenicillin occurs by intramolecular attack of a Cu–OH species on the carbonyl group and not by intermolecular attack of ‘free’ hydroxide ion on the complex. The hydrolysis of [CuLH_–2]^– at pH 6 is some 6 × 10⁶ fold faster than the hydrolysis of the anion L^– at 30 °C.