Penicillin Hydrolysis A Kinetic Study of a Multistep, Multiproduct Reaction Thomas A. McCarrick and Fred W. McLafferty Cornell University, Ithaca, NY 14853 In designing penicillin derivatives for oral administration, a key problem was acid-catalyzed hydrolysis in the stomach which produces products inactive as antibiotics ( I ) . Classical spectrophotometric techniques were used (2,3) to elucidate successfully these relatively complex reaction pathways (I111).
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times) or stable final products (A reaching a constant value). The yields of the latter can be calculated from these maximum A values, and the yield of IV is obtained by difference. Each final product can he formed (a) directly from BP, (h) through an identified intermediate, or (r, through some other intermediate. By using a sufficiently large excess of acid, each hvdrolvsis step is pseudo-first-order in reactant. makine-eons. . (i)-(3japplic~bl~. k ~ ispthe rate constant ~ O ~ BdecompoP sition
C&CHWNH
IV
The recent availability of a mirroprocessor-controlled rapid-scanning instrument makes it possible for students tn carry out the necessary measuremenm for such a stndy in two of kinetic theory ( 4 . 5 ) tosuch data the hours. Rv. npdication .. reaction pathways for the hydrolysis of potassium benzyl penicillin (BP) can be elucidated. WithO.l M acid B P yields the products pencillenic acid (I,which may be responsible for an allergic reaction to penicillin) (6),penicillic acid (II), penamaldic acid (111), and other cleavage products N. I is an unstable intermediate which dissociates to yield 111; the data indicate as relative rate of B P dissociation vieldina ~this. ~ ~ the ~ ~ I corresponds& the relative amount of 111formed & a f i n 2 oroduct. Careless laboratorv techniaue can affect the results in ways that are easily observed; for example, trace metal ions (e.g., Hg2+) stabilize the intermediate I. ~
~
~
Procedure The time-dependent concentrations of I, 11, and I11 are followed using their distinctive ultraviolet spectra. (See the table.) I t assumed that B P and all products except I, 11, and I11 have the same absorptivities as that of the isolated benzyl group, so that there is no change in the spectrum in converting BP to these other products. Measurement of absorbance values (A) as a function of time at these three wavelengths will show which products are intermediates (decreasingA at longer Molar Ahrpllvlties of Measured Specles BP I
I1 111 IV
322 nm
290 nm
