Collect. Czech. Chem. Commun. 2004, 69, 2147-2173

Hydrogen Bonding Contribution to Lipophilicity Parameters. Hydrogen Acceptor and Hydrogen Acceptor Donor Parameters

Marvin Charton* and Barbara I. Charton

Chemical Department, Pratt Institute, Brooklyn, NY 11205, U.S.A.


In our analysis of the composition of lipophilicity parameters by the intermolecular force (IMF) model we have made use of nH, the number of OH and/or NH bonds, as a measure of the hydrogen donor capacity of a substituent; and nn, the number of lone pairs on O and/or N atoms in the substituent, as a measure of the hydrogen acceptor capacity of the substituent. The basis of this method is the reasonable assumption that in 55.6 molar water hydrogen bonding is maximized. The method does not account however for differences in the energy of different types of hydrogen bonds, but further assumes that these differences are to a first approximation negligible. In order to improve the model we have defined a scale of group hydrogen bonding acceptor parameters, ηXHA, and overall hydrogen bond parameters ηXHAD from the water/1-octanol partition coefficients of AkX where Ak is alkyl. These parameters should account for both the extent of hydrogen bonding in water and for the difference in hydrogen bond energies of the various types of hydrogen bonds encountered. Correlations of log P values for Ph(CH2)nX, X1(CH2)X2, and substituted amino acids Xaa with the IMF equation using the ηXHA and ηXHAD parameters demonstrated their use. Correlation of log P values for PhX suggested that for many groups separate sets of ηXHA and ηXHAD values are required when they are bonded to sp2 hybridized carbon rather than sp3 hybridized carbon.

Keywords: Hydrogen bonds; Lipophilicity; Intermolecular force model; Partition coefficient; Substituent effects.

References: 24 live references.