Thermodynamic 2D Description of H-bonding

That hydrogen bonding plays an important role in chemical processes, including enzymatic catalysis, is well known. This observation has inspired many approaches to take such interactions into account in QSAR and molecular modeling investigations. Up to now, the number of atoms that can participate in H-bonding has been used most often as the simplest descriptor of this interaction . Of course, such indicator variables are primitive, and do not reflect the influence of substituents near H-bond acceptors or donors.

On the basis of their own experimental measurements and published thermodynamic data on hydrogen bonding, Raevsky et al found that H-bond strength depends on the nature of substituents near the atoms that participate in bond formation [1,2]. The enthalpy values in measured H-bond complexes cover a wide range; they vary from 0.9 to 15.9 kcal/mol for "O-H…O"; from 0.1 to 19.1 kcal/mol for "O-H…N"; from 0.5 to 10.5 kcal/mol for "N-H…O", and from 0.5 to 11.5 kcal for "N-H…N".

Using a multiplicative approach to describe experimental thermodynamic parameters for about 14 thousand H-bond complexes, Raevsky et al. [3-5]: created uniform enthalpy (DH) and free energy (DG) H-bond scales:

D H = k₁(kcal/mol)E_aE_d       (1)

D G = k₂(kcal/mol)C_aC_d+ k3(kcal/mol)       (2)

where E_a is the enthalpy acceptor factor , E_d is the enthalpy donor factor , C_a is the free energy acceptor factor, and C_d is the free energy donor factor. Later Raevsky proposed also overall H-bond acceptor scale based on correlation of experimental property values with free energy acceptor factors to estimate an ability of different weak neutral and ionized acceptor atoms. H-bond factors can quantitatively characterize the acceptor or donor strength of any atom in any molecule.

Large data bases for these factor values as well as a program to estimate such values for atoms in organic molecules are contained in the program HYBOT (HYdrogen BOnd Thermodynamics) for Windows 95/98/2000/NT or for UNIX or for LINUX [6]. Besides HYBOT also calculates descriptors connected with steric and electrostatic interactions. Fig. below presents the results of calculation of molecular and atomic descriptors by means of HYBOT (version 2.3, 2003).

References:

1. Raevsky, O.A. and  Novikov, V.V., H-Bond Description by Multiplicative Apprtoach, Khim-Pharm. Z. (russ.),  16 (1982) 583; Chem.Abst. 97(1982) 33128d;
2. Raevsky, O.A., Avidon V.V.  and  Novikov, V.P., H-bond descriptors for QSAR, Khim-Pharm. Z.(russ),  16 (1982) 968; Chem.Abst. 97 (1982) 181323d.
3. Raevsky, O.A. in Hadzi, D. and Jerman Blazic, B. (eds.), QSAR Description of Molecular Structure, in "QSAR in Drug Design and Toxicology", Elsevier, Amsterdam, 1987, pp.31-36.
4. Raevsky, O.A., Grigor’ev, V.Ju., Kireev, D.B. and Zefirov, N.S., Complete Thermodynamic Description of H-bonding in the framework of multiplicative approach,  Quant. Struct.-Act.Relat., 11 (1992) 49.
5. Raevsky, O.A., Molecular Structure Descriptors in the Computer-Aided Design of Biologically Active Compounds, Russ. Chem. Rew , 68 (1999) 437.
6. Raevsky, O.A., Grigor’ev, V.Ju. and Trepalin, S.V., HYBOT  program package, Registration by Russian State Patent Agency N 990090 of  26.02.99; Raevsky, O.A., Skvortsov, V.S., Grigor’ev, V.Ju. and Trepalin, HYBOT in UNIX/LINUX  , Registration by Russian State Patent Agency N 2002610496 of 05.02.02. ( raevsky@ipac.ac.ru)