Retardation of acetal hydrolysis by cyclodextrins and its use in probing cyclodextrin–guest binding

Abstract

Hydrolysis of benzaldehyde dimethyl acetal 1 in aqueous acid is slowed down greatly by cyclodextrins (CDs): α-CD, β-CD, hp-β-CD (hydroxypropyl-β-cyclodextrin) and γ-CD. The variations of the observed first-order rate constants (k_obs) with [CD] exhibit saturation behaviour, consistent with 1∶1 binding between 1 and the CDs. In the case of β-CD and hp-β-CD, the binding is relatively strong and the CD-bound acetal is unreactive. In contrast, binding of the acetal by α-CD and γ-CD is much weaker, but only with α-CD does the CD-bound form show significant reactivity. The four CD-mediated reactions have been evaluated as probe reactions for determining dissociation constants of {CD– ‘guest’} complexes. In this approach, added guests attenuate the retarding effect of CD–substrate binding and cause an increase in the rate of acetal hydrolysis. The method works well for aliphatic alcohols and ketones binding to β-CD and hp-β-CD, but it is less successful with α-CD because of the shallow dependence of k_obs on [α-CD] in the probe reaction. With γ-CD, the approach is not applicable at all, because added guests cause a further reduction in the rate of acetal hydrolysis, not an increase. Various implications of these findings are discussed.