BETA-SECONDARY AND SOLVENT DEUTERIUM KINETIC ISOTOPE EFFECTS AND THE MECHANISMS OF BASE-CATALYZED AND ACID-CATALYZED HYDROLYSIS OF PENICILLANIC ACID

beta-Secondary and solvent deuterium kinetic isotope effects have been determined at 25 degrees C for the alkaline and acid-catalyzed hydrolysis of penicillanic acid. In order to determine the former isotope effect, [6,6-H-2(2)]dideuteriopenicillanic acid has been synthesized. In alkaline solution, the former isotope effect (corrected to the effect of a single hydrogen orthogonal to the plane of the carbonyl group and for the inductive effect of deuterium) was found to be 0.95 +/- 0.01 and the latter 0.76 +/- 0.01. These values support the B(AC)2 mechanism of hydrolysis with rate-determining formation of the tetrahedral intermediate that has been proposed for other beta-lactams. The measured beta-secondary kinetic isotope for the acid-catalyzed reaction was 1.00 +/- 0.01. This represents a value averaged from experiments in 0.45 M HCl, 0.97 NI HCl, 4.5 M HCl, and 33.3 wt % H2SO4. All precedent suggests that this result would be very unlikely for an associative mechanism, such as that commonly observed (A(AC)2) for amide hydrolysis at these acid concentrations. Semiempirical AM1 calculations suggest that bicyclic beta-lactams are not only very weakly basic (in accord with previous experiment) but also protonate preferentially on nitrogen. This likelihood, taken with the secondary isotope effect, indicates that a likely pathway of acid-catalyzed hydrolysis would be that of an A(AC)1 mechanism with an intermediate acylium ion. If this were so, the calculated beta-secondary isotope effect per hydrogen coplanar with the breaking C-N bond and corrected for the inductive effect of deuterium would be 1.06 +/- 0.01. This suggests an early A(AC)1 transition state, which would be reasonable in this case because of destabilization of the N-protonated amide with respect to the acylium ion because of ring strain. The absence of specific participation by solvent in the transition state, as would be expected of an A(AC)1 but not an associative mechanism, is supported by the strongly inverse solvent deuterium kinetic isotope effect of 0.25 +/- 0.00 in 1 M HCl and 0.22 +/- 0.01 in 33.3 wt % H2SO4.