A General Scheme Based on Empirical Increments for the Prediction of Hydrogen-Bond Associations of Nucleobases and of Synthetic Host-Guest complexes

Association energies ΔGt in chloroform, in part also in carbon tetrachloride, were determined by NMR titrations of suitably substituted nucleosides and several synthetic analogues. Based on these and on many literature data, two simple free energy increments were derived describing the ΔGt values of 58 complexes within 1.8 kJ mol‐1. With chloroform as solvent the increment for the primary interaction between donor and acceptor is 7.9 kJ mol‐1, for the secondary one 2.9 kJ mol‐1, irrespective of whether the latter is attractive or repulsive. Addition of only 1% methanol to CCl4 led to a decrease in association constants by a factor of 25. Calorimetric titrations of G‐C nucleoside derivatives in CCl4 showed substantial contributions from G dimers, in line with NMR titrations, and surprisingly small decreases in entropy. Preliminary NOE measurements allowed us to single out some of the possible association modes; they are also in line with expected self‐ and triple‐association modes of the nucleobases. These modes are generally in accord with nucleobase associations predicted by MM calculations in the literature, which in turn agree with predictions based solely on the increments derived in the present work. Two simple free energy increments have been derived describing the association energies of 58 hydrogen‐ bonded complexes, such as that shown on the right (R = ribosyl derivative), within 1.8 kJmol‐1. With chloroform as solvent, the increment for the primary interaction between donor and acceptor is 7.9 kJmol‐ 1, and 2.9 kJmol‐1 for the secondary one. The merit of this empirical analysis is that it allows experimental stabilities and binding modes in solution to be predicted independently of mechanistic reasoning.