Interaction energies and dynamics of acid-base pairs isolated in cavitands

Abstract

The use of capsules and cavitands in physical organic chemistry is briefly reviewed, and their application to the study of salt bridges is introduced. Carboxylate/ammonium ion pairs are generated within an environment that more or less surrounds the functional groups within a synthetic fixed introverted solvent sphere. This is provided by cavitands that fold around amines and present them with a carboxylic acid function. Both organic and water-soluble versions were prepared, and their equilibrium affinities with quinuclidine bases were determined by NMR methods. The association constants range from approximately 10(3) M(-1) in water to more than 10(5) M(-1) in organic solvents. Studies of nitrogen inversion and tumbling of [2.2.2]-diazabicyclooctane within the introverted acids also illustrate the strength of the acid-base interactions. The barriers to in-out exchange of several amine guests were determined to be in the range from 15 to 24 kcal mol(-1). Some parallels with enzymes are drawn: the receptor folds around the guest species; presents them with inwardly directed functionality; and provides a generally hydrophobic environment and a periphery of secondary amide bonds.

FIGURE 1

Deep cavitands 1, introverted acid cavitands H2, and control molecule H3.

FIGURE 2

Side and top views of the X-ray crystal structure of introverted acid H2a with bound chloroform. Ethyl groups have been shown as methyl groups for clarity. Hydrogen bonds are shown as dashed lines.

FIGURE 3

Top and side views of the X-ray crystal structures of octaamide cavitand 1a with bound DABCO (a) and with bound quinuclidine (b). Hydrogen bonds are shown as dashed lines, and methyl groups have been truncated from propionamides.

FIGURE 4

¹H,¹H TOCSY spectrum (CDCl₃, 298 K) showing ³J_H,H coupling between the DABCO methylene protons and the proton shared by the base and the acid of host H2a. This coupling reveals that the acid proton has been at least partially transferred to a nitrogen of DABCO.

FIGURE 5

Modeled structure (HyperChem; MM+ force field) of DABCO bound by H2a. Ethyl groups have been truncated or shown as methyl groups, and one cavitand wall has been removed for clarity. The acid proton (shown in white, CPK style) has been transferred to DABCO, consistent with TOCSY measurements.

FIGURE 6

Competitive binding experiments elucidate the guest binding preference of each host (A and B) and the preferred host selection of each guest (C and D). Equilibrium D provides an estimate of the interaction energy of the quinuclidinium–carboxylate pair, ΔG°_D = 6.8 ± 0.5 kcal mol⁻¹. ΔG° values for A, B, and C were determined by ¹H NMR titration in 5% CD₃OD in CDCl₃, and ΔG°_D was calculated according to the eq 3. Free sodium cations, tetrafluoroborate anions, and chloride anions are not shown.

FIGURE 7

Free energy cycle in deuterated water. ΔG° values refer to the binding energy of each host–guest complex as shown schematically. Measurements were performed at 300 K in 10 mM sodium phosphate buffer, pD 5.25, except where indicated.

FIGURE 8

In the unfunctionalized cavitand (center), DABCO spins rapidly about the vertical axis and tumbles at a slower rate about a horizontal axis. The introverted acid cavitand H2 has no appreciable effect on spinning, but tumbling is dramatically slowed. The ¹H NMR spectrum of DABCO bound by 2 (A) shows four distinct signals for the guest, the further upfield signals H_a′ and H_b′ corresponding to the methylenes deeper in the cavitand. DABCO bound by 1 shows only a single guest peak at 300 K (B), but separate signals are seen at 220 K (B); the coalescence temperature was 230 K.