Timothy A. Gadosy

The binding of alkyl chains to β-cyclodextrin and ‘hydroxypropyl-β-cyclodextrin’

The strength of binding of aliphatic alcohols, alkanesulfonate ions and aryl alkanoates to ‘hydroxypropyl-β-cyclodextrin’ is very similar to that to unmodified β-cyclodextrin (β-CD). The clear inference is that both forms of β-CD bind these guests to the wider opening of the CD cavity that is surrounded by secondary hydroxy groups.

Binding of aliphatic ketones to cyclodextrins in aqueous solution

Dissociation constants (Kd) for the complexation of 22 simple ketones with α-, β- and hydroxypropyl-β- cyclodextrin (α-CD, β-CD, and HP-β-CD) in aqueous solution have been determined. For these constants, there are various correlation involving pKd(=–log Kd) which have the form of linear free energy relationships. In particular, there are strong correlation between the pKd values of ketones (RCOR′) and related secondary alcohols [RCH(OH)R′], including cases where R and R′ form a ring. As with other alkyl derivatives, pKd values for alkan-2-ones and alkan-3-ones increase monotomcally with chain length, with slopes about 0.4, corresponding to Gibbs energy increments of ca. 2.3 kJ mol–1 for each CH2 group that is sequestered by the CD. The strengths of binding of linear derivatives to α-CD and β-CD correlate well, but bulky and cyclic ketones bind more weakly to α-CD, due to its smaller cavity. The pKd values for complexation of 18 of the 22 ketones by HP-β-CD and β-CD are fairly close and linearly related with a slope of 0.96 ± 0.03. These data are a subset of a larger set for 68 aliphatic compounds for which the slope is 0.99 ± 0.02. Thus, the strength of binding of such aliphatics to HP-β-CD and β-CD is generally close, although the penetration of the CD cavity by the guests is not necessarily the same for these two CDs.

Acyl transfer reactions mediated by cyclodextrins. The reaction of external nucleophiles with encapsulated alkanoate esters of varying chain length

The kinetics of the reaction of p-nitrophenyl alkanoates (acetate to decanoate, C2 to C10) with trifluoroethanol (TFE) in the presence of α-, β-, or hydroxypropyl-β-cyclodextrin (α-, β-, or Hp-β-CD) in basic aqueous solution have been measured. The results are analysed to afford rate constants for nucleophilic attack on the free and CD-bound esters (kN and kcN, respectively). Generally speaking, the values of kN and kcN are not very different, so that binding the esters to CDs has only modest effects on their reactivities towards TFE, reacting as its anion. However, there is a general trend in kcN values such that transition-state stabilization increases in a biphasic manner as the alkanoate chain is lengthened from C2 to C10. For short chains ( C6) is quite steep. This same behaviour is observed for all three CDs, with only minor differences between them, and also when the nucleophile is the anion of 2-mercaptoethanol. It is suggested that there is a change in the mode of transition-state binding of the esters from aryl group inclusion (3‡) for the short esters to acyl-group inclusion (4‡) when the acyl chain is lengthened beyond C6.

The kinetics of cleavage of nitrophenyl alkanoates by γ-cyclodextrin and by ‘dimethyl-β-cyclodextrin’ in basic aqueous solution

The cleavage of m- and p-nitrophenyl alkanoates (C2 to C8) in basic solution is accelerated modestly (7–17 times), by γ-cyclodextrin (γ-CD). The effects on the two isomeric series of esters are virtually the same and they hardly vary with the ester chain length. Cleavage of the same esters (C2 to C10) is retarded by ‘dimethyl-β-cyclodextrin’(diMe-β-CD) by up to a factor of 8, but it is not totally inhibited, as was supposed earlier. The effects of this modified cyclodextrin on the two series of esters are very similar, but they vary significantly with the acyl chain lengths. For example, second-order rate constants (k2) for reaction of the esters with diMe-β-CD show little change from C2 to C5, a steep increase from C5 to C7, and then a levelling off. Overall, the behaviours of γ-CD and diMe-β-CD differ significantly from those found earlier for ester cleavage by α-CD, β-CD and ‘hydroxypropyl-β-CD’. These differences are discussed in terms of the relative importance of transition-stage and initial-state binding, and in relation to the structural variations among the five cyclodextrins.

Acyl transfer mediated by complexation. The effect of cyclodextrins on the reaction of nucleophiles with p-nitrophenyl acetate and hexanoate

The kinetics-of the cleavage of p-nitrophenyl acetate (pNPA) and p-nitrophenyl hexanoate (pNPH) by trifluoroethanol (TFE), mercaptoethanol, hydroxylamine or imidazole in the presence of α-cyclodextrin, β-cyclodextrin, or hydroxypropyl-β-cyclodextrin (CDs) have been measured in basic aqueous solution. Detailed studies established that TFE reacts with pNPH bound to the CDs and that the bound ester is almost as reactive as the free ester. Similar behaviour has been observed for pNPA and for reaction with the other nucleophiles, with slight retardations or accelerations. There are only minor differences between the effects of the three cyclodextrins and the four nucleophiles. It seems clear that pNPA and pNPH are bound to the CDs in such a way that their carbonyl groups are exposed to the medium and that transition-state binding differs little from substrate binding, even though the orientation may be different for the two esters.