Hydrogen bonding molecular electrostatic potentials

Because lipophilicity is so frequently correlated with potency in traditional QSAR applications, much attention has been paid to this property in CoMFA as well. Hydrophobic interactions are well described by an H2O molecular field computed by means of a combination of steric and hydrogen bond potential functions.9. i7o goth experimental octanol/water log P values and binding data also correlated with log P are well explained. These results are understood by recalling that log P is correlated with a combination of volume or surface area and hydrogen bonding ability. Because these individual properties are accounted by the steric and hydrogen bond or electrostatic potential functions, the hydrophobic effect is also accounted for. 

Our discussion in this chapter will focus on the use of the electrostatic potential as a means to understanding and predicting chemical interactions. First, we will examine some of its properties and important features. Next, we will discuss methodology. Finally we will review some recent applications of the electrostatic potential in areas such as hydrogen bonding, molecular recognition, and understanding and prediction of a variety of physio-chemical properties related to molecular interactions. Our intent has not been to provide a complete survey of the ways in which the potential has been used, many of which are described elsewhere (Politzer and Daiker 1981 Politzer, Laurence, and Jayasuriya 1985 Politzer and Murray 1990 Politzer and Murray 1991 Politzer and Truhlar 1981 Scrocco and Tomasi 1973), but rather to focus on some diverse examples. 

Murray, J. S., S. Ranganathan, and P. Politzer. 1991. Correlations Between the Solvent Hydrogen Bond Acceptor Parameter (3 and the Calculated Molecular Electrostatic Potential. J. Org. Chem. 56, 3734. 

Ghafourian, T. and J. C. Dearden. 2004. The use of molecular electrostatic potentials as hydrogen-bonding-donor parameters for QSAR studidsarmaco59 473-479. 

Although X-ray crystallography has mainly been used for structure determination in the past, the diffraction data, especially if measured carefully and to high orders, contain information about the total electron density distribution in the crystal. This may be analyzed to provide essential information about the chemical properties of molecules, in particular the characterization of covalent and hydrogen bonds, both from the point of view of the valence electron density, the Laplacian of the density and derived energy density distribution. In addition, calculation of the molecular electrostatic potential indicates direction of chemical attack as well as how molecules can interact with their environment. 

V s.min and Vs,max are the most negative and positive values of the molecular electrostatic potential on the molecular surface the maximum reflects the tendency for long-range attraction of nucleophiles at a specific site, while the minimum reflects the tendency for long-range attraction of electrophiles at a specific site. Vs.imu and V"5, ,ax for a large variety of molecules correlate with hydrogen-bond basicity and acidity, respectively [Murray and Politzer, 1998]. 

Improvements of the Pohtzer hydrophobic model were later proposed using additional quantum-chemical descriptors derived from the molecular electrostatic potential, dipole moment, and ionization energies. These descriptors were searched for to give the best estimations of the cavity term, polarity/dipolarizability term, and hydrogen-bond parameters defined in -> linear solvation energy relationships [Haeberlein and Brinck, 1997]. 

M. D. Ryan, Effect of hydrogen bonding on molecular electrostatic potentials. In Modeling the Hydrogen Bond, edited by D. A. Smith (American Chemical Society, Washington, 1994), ACS Symposium Series 569, Chapter 4. 

Murray, J.S., Ranganathan, S. and Politzer, P. (1991) Correlations between the solvent hydrogen bond acceptor parameter p and the calculated molecular electrostatic potential./. Org. Chcm., 56,3734—3737. 

One of the early applications of molecular electrostatic potentials was in relation to hydrogen bonding. The Fm n (most negative potentials) were found to be effective in identifying sites at which hydrogen bonds would be accepted [16,89-91]. Furthermore, Kollman et al. [89] showed that the calculated energy of the interaction between hydrogen fluoride and a series of acceptors correlates well with the value of V(r) at a fixed distance from the latter. 

Kollman PA. The role of the electrostatic potential in modeling hydrogen bonding and other non-covalent interactions. In Politzer P, Truhlar DG, eds. Chemical Applications of Atomic and Molecular Electrostatic Potentials. New York Plenum, 1981 243-255. 

In light of the known importance of electrostatic effects in hydrogen bonding, it is not surprising that the molecular electrostatic potential has been used to provide some useful guidelines concerning such interactions. These... 

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