Re-evaluation of Cyclodextrin as a Model of Chymotrypsin: Acceleration and Inhibition of Tertiary Anilide Hydrolysis

David R.J. Palmer, Erwin Buncel, Gregory R.J. Thatcher

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

The hydrolysis of p-nitro-N-methyltrifluoroacetanilide (1), p-chloro-N-methyltrifluoroacetanilide (2), N-methyltrifluoroacetanilide (3), and p-methoxy-N-methyltrifluoroacetanilide (4) in the presence and absence of α-and β-cyclodextrin has been studied at 7.5 < pH < 10.6. For 1–3, cyclodextrin (CD) exhibits simple Michaelis-Menten saturation kinetics, with no evidence for reaction via other than 1:1 CD-substrate complexes. The behavior of CD with 4 is more complex. Moreover, CD catalyzes the hydrolysis of 1 but inhibits the hydrolysis of 2–4 across the pH range studied. The nature of the buffer catalysis in the absence of CD, exhibited in the hydrolysis of 1, also shows marked differences with that exhibited by 2–4. The data are most simply interpreted by a mechanism in which CD accelerates formation of a tetrahedral intermediate 5; in the case of 1, the rate of breakdown of this intermediate is greater than the rate of buffer-catalyzed breakdown of the hydrolysis intermediate. The CD cavity may provide an environment complementary to the transition state for expulsion of the anilide leaving group. These results are compared with the previously reported effects of CDs on trifluoroacetanilide and phenyl ester hydrolysis and proposals of CD as a model of chymotrypsin.

Original languageEnglish (US)
Pages (from-to)5286-5291
Number of pages6
JournalJournal of Organic Chemistry
Volume59
Issue number18
DOIs
StatePublished - Sep 1 1994
Externally publishedYes

ASJC Scopus subject areas

  • Organic Chemistry

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