Basicity and hydrogen bonding

Kenny followed the approach of Murray and Politzer and investigated correlations between the electrostatic potential and hydrogen bond basicity for a set of 23 heterocycles with nitrogen as the acceptor [69]. A very good linear relationship (R = 0.981) was found between the HF/6-31G computed Vmin and log Khb for formation of 1 1 complexes with 4-nitrophenol in 1,1,1-trichloroethane. It was pointed out that the Vmin versus log Khb relationship is significantly better than the correlations between aqueous basicity and hydrogen bond basicity (pKa versus log K) for the same types of system. The predictive capability of the relationship was further demonstrated for a set of five heterocycles in which all molecules contains two or more non-equivalent nitrogen donors. Four of the predictions are within 0.30 units of the experimental values, while the fifth, tetrazole, is overestimated by 0.51 units. 

Meot-Ner M (1979) Ion thermochemistry of low-volatility compounds in the gas phase. 2. Intrinsic basicities and hydrogen-bonded dimers of nitrogen heterocyclics and nucleic bases. J Am Chem Soc 101 2396-2403. doi 10.1021/ja00503a027... 

Figure 1 Depiction of the relationship between molecular structure and therapeutic effect of a medicine. Underlying all the other properties a compound can exhibit arc its 3D disposition of atomic nuclei and the electronic distribution around the nuclei. These inanimate particles of physics determine the chemistry the compound can undergo (reactivity) and its physical properties (density, index of refraction, dipole moment, etc.). The properties, in turn, determine how that molecule will interact with other molecules. The interactions determine solubility, lipophilicity, association, and stability, which affect how well a compound, if administered to a patient, will be transported to its site of action. These interactions will also determine how well the compound will attach to the receptor by first being recognized as complementary to the receptor structure in shape and electronic structure (acidic, basic, and hydrogen bonding groups). The affinity between the compound and the receptor will determine how well a biochemical or conformational change in the receptor will be induced. The latter change must then lead to a cascade of biochemical events that will eventually be observable in the patient in terms of therapeutic response to the drug...

The extensive researches of Gerrard and his co-workers on the solubility of HCl in various solvents include a number of alcohols (121,123-127,129,130). The meanii of this combined measurement of basicity and hydrogen bonding factors is probably made even more obscure for the alcohols than for other solvents since the hy-droxylic solvents can serve not only as hydrogen bond acceptors from the protonic end of the HCl dipole but can also donate a hydrogen bond to stabilize anions or the anionic ends of dipoles (348). It is found that these results for the alcohols form an orderly picture that is readily interpretable in terms of inductive and steric factors. 

The theory has been extended to polar solvents by including dispersion 5, permanent dipole orientation 5q, dipole induction 8ind> and hydrogen-bonding interactions 5ii such as acidic 5 and basic 8i,. In this case the solubihty parameter 5j is given by Equation 4.5 ... 

Abraham s solute descriptors to yield a predictive regression equation. Further, the solute dipolarity/polarizability, hydrogen bond acidity, and hydrogen bond basicity were found to favor blood and solute size favor brain. 

High lipophilicity and van der Waals surface area of basic atoms facilitates a compound s BBB permeability, whereas high polarity and hydrogen-bonding potential have a negative impact on the BBB permeability. 

A number of 7V-carboxyalkyl and A-phosphonoalkyl substituted substrate analogue inhibitors have been examined [161,204-208]. These derivatives contain both the acidic carboxylate (or phosphonate) and basic amine functionalities in the vicinity of the scissile bond. Thus, they are capable both of electrostatic interaction with the active site Zn(II) and hydrogen bonding interactions with other active site residues. They are, however, only moderately potent collagenase inhibitors Table 8.18). The stereochemistry at the carbon atom to which the carboxylate moiety is bonded markedly influences the inhibitory potency of these derivatives ((197) vs. (198)). The phosphonate analogues of this class of derivatives have also been evaluated Table 8.18), but are not substantially better inhibitors than the carboxyl-ates. 

Nishi has found that chondroitin sulfate A and C are more effective in the resolution of basic drugs than dextran or dextrin and even dextran sulfate because of additional ionic interactions with sulfate or carboxylic groups. The small ionic character of chondroitin sulfate C leads to large enantiose-lectivity under acidic conditions, whereas heparin was not so effective. Using neutral polysaccharides, only hydrophobic interactions and hydrogen bonding may occur (117). 

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