A COMPREHENSIVE DESCRIPTION OF THE FREE-ENERGY OF AN INTRAMOLECULAR HYDROGEN-BOND AS A FUNCTION OF SOLVATION - NMR-STUDY

Free energies of intramolecular hydroxyl (donor)-to-ether oxygen (acceptor) hydrogen bonds in hydroxyethers 10alpha-(hydroxymethyl)-2-oxabicyclo[4.4.0]decane (1) and 4-tert-butyl-2-(hydroxymethyl)-1-methoxycyclohexane (2) have been determined from changes in H-1 NMR vicinal coupling constants in a broad range of solvents (CCl4 to D2O). Various solvent polarity scales exhibited no direct correlation to changes in hydrogen bond DELTAG values. Rather, a linear relationship between DELTAG and the solvent's hydrogen bond basicity scale (beta(KT)) was demonstrated; slightly improved correlations could be achieved in certain cases by adding a solvent polarity term (either epsilon(K), or pi) or a solvent hydrogen bond acidity term (E(T)(30)) to the beta(KT) term. A van't Hoff analysis of the hydrogen bond thermodynamics of both 1 and 2 in CDCl3 enabled determination of DELTAH and DELTAS values that were essentially intrinsic due to the limited assumptions attendant to the evaluation of intramolecular hydrogen bonds. The intrinsic DELTAG values for both 1 and 2 ranged from -2.3 (CCl4) to -0.5 kcal mol-1 (D2O) to define the accessible range of strengths for a hydroxyl-ether hydrogen bond in liquid phase. The intrinsic DELTAS values for 1 and 2 in CDCl3, -3.5 +/- 0.5 and -2.4 +/- 0.5 cal mol-1 K-1, respectively, are essentially equal despite a difference in the number of internal rotations compromised by hydrogen-bonding in each molecule. The lack of sensitivity to the number of internal rotations and the attenuated DELTAS relative to that calculated in the gas phase indicated that losses in entropy attendant to changes in internal rotations may be of a smaller magnitude than previously thought in the liquid phase. The predominance of beta(KT) as a determinant of hydrogen bond free energies demonstrated that local dielectric has little effect on the strengths of hydrogen bonds. Thus, gas-phase DELTAH values may be accessible in macromolecules depending upon the bonding geometry, the number of local acceptors, and the reorganizational energy expended to form the bond. These results have significance for the incorporation of solvation treatments into computer models, the prediction of biological structure and stability, and the design of small molecule and macromolecular architectures for molecular recognition.