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 (acce ptor) hydrogen bonds in hydroxyethers 10alpha-(hydroxymethyl)-2-oxabic yclo[4.4.0]decane (1) and -tert-butyl-2-(hydroxymethyl)-1-methoxycyclo hexane (2) have been determined from changes in H-1 NMR vicinal coupli ng constants in a broad range of solvents (CCl4 to D2O). Various solve nt polarity scales exhibited no direct correlation to changes in hydro gen bond DELTAG values. Rather, a linear relationship between DELTAG a nd the solvent's hydrogen bond basicity scale (beta(KT)) was demonstra ted; slightly improved correlations could be achieved in certain cases by adding a solvent polarity term (either epsilon(K), or pi) or a sol vent 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 i n CDCl3 enabled determination of DELTAH and DELTAS values that were es sentially intrinsic due to the limited assumptions attendant to the ev aluation 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 CDCl 3, -3.5 +/- 0.5 and -2.4 +/- 0.5 cal mol-1 K-1, respectively, are esse ntially equal despite a difference in the number of internal rotations compromised by hydrogen-bonding in each molecule. The lack of sensiti vity to the number of internal rotations and the attenuated DELTAS rel ative to that calculated in the gas phase indicated that losses in ent ropy attendant to changes in internal rotations may be of a smaller ma gnitude than previously thought in the liquid phase. The predominance of beta(KT) as a determinant of hydrogen bond free energies demonstrat ed that local dielectric has little effect on the strengths of hydroge n bonds. Thus, gas-phase DELTAH values may be accessible in macromolec ules depending upon the bonding geometry, the number of local acceptor s, and the reorganizational energy expended to form the bond. These re sults have significance for the incorporation of solvation treatments into computer models, the prediction of biological structure and stabi lity, and the design of small molecule and macromolecular architecture s for molecular recognition.