Hydrolysis rate constants, QSAR

L.A. (2005) Estimation of phosphate ester hydrolysis rate constants. I. Alkaline hydrolysis. QSAR Comb. Sci., 25 (2), 123-133. 

Equation (30) represents a QSAR for the base-mediated hydrolysis of formates and acetates. The correlation is between the second-order alkaline hydrolysis rate constants and the linear combination of the shifts of the vC=0 and vC-O stretching peaks for 12 of the 41 compounds in Table 13.3. 

Methods to predict the hydrolysis rates of organic compounds for use in the environmental assessment of pollutants have not advanced significantly since the first edition of the Lyman Handbook (Lyman et al., 1982). Two approaches have been used extensively to obtain estimates of hydrolytic rate constants for use in environmental systems. The first and potentially more precise method is to apply quantitative structure/activity relationships (QSARs). To develop such predictive methods, one needs a set of rate constants for a series of compounds that have systematic variations in structure and a database of molecular descriptors related to the substituents on the reactant molecule. The second and more widely used method is to compare the target compound with an analogous compound or compounds containing similar functional groups and structure, to obtain a less quantitative estimate of the rate constant. 

Quantitative structure/activity relationships (QSARs) for hydrolysis are based on the application of linear free energy relationships (LFERs) (Well, 1968). An LFER is an empirical correlation between the standard free energy of reaction (AG0), or activation energy (Ea) for a series of compounds undergoing the same type of reaction by the same mechanism, and the reaction rate constant. The rate constants vary in a way that molecular descriptors can correlate. 

The use of a Hammett substituent constants in QSAR analyses has been prominent since the early studies by Hansch and Fujita (1964) in medicinal chemistry. The electron-withdrawing/releasing potency of substituents on an aromatic system has been formalized by the Hammett equation (Hammett, 1940). The relative reactivities among homologous series of compounds under defined conditions - for example, the logarithms of the rate and equilibrium constants for the hydrolysis of substituted benzoic acid esters (rate constant k) and the ionization constants (K) of the corresponding acids, were found to be linearly related ... 

Hein and Nieman, the substrates of the general type NH-CHR COR bind to three rather hydrophobic sites of the enzyme. We choose as leading example, for NTD-mapping of receptor sites, correlations of A =log (bimolecular rate constant) for hydrolysis of esters with NTD and also other parameters. We choose this area, because of the wealth of experimental data, because there is also other QSAR work for comparison, and because the orientation of the molecules in the receptor site of the enzyme will be well-defined, especially for molecules RCDNH-CHR -CQR of peptidic type, were RCONH will enter the p.-site... 

Numerical values for the structural parameters of QSAR are obtained from an evaluation of the effect of the substituent on the properties (e.g., the rate or equilibrium constants) of a model reaction. The classification of these parameters is therefore model dependent. The model reactions are chosen to represent the most pervasive types of physicochemical phenomena (e.g., dissociation reactions, hydrolysis, substitution reactions, partition between solvents). 

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