Hansch analysis Hammett constants

An effective QSAR parameter should correlate only to its specific property, be it electronics, lipophilicity, sterics, or something else, a- Values for R-groups in the meta and para positions have been found to account for only electronic effects. Substitution at the ortho position, however, is another story. Because ortho substituents are physically so close to the carboxylic acid, ortho R-groups affect the acid-base equilibrium through both electronic and steric effects. Therefore, the ortho tr-value (electronic parameter for QSAR studies. Despite their limitations, Hammett constants are by far the most commonly encountered electronic parameter in Hansch analysis. 

In 1962, Hansch, Maloney and Fujita [Hansch, Maloney et al, 1962] published their study on the structure-activity relationships of plant growth regulators and their dependency on Hammett constants and hydrophobidty. Using the octanol/water system, a whole series of partition coefficients was measured and, thus, a new hydrophobic scale was introduced for describing the inclination of molecules to move through environments characterized by different degrees of hydrophilicity such as blood and cellular membranes. The delineation of Hansch models led to explosive development in QSAR analysis and related approaches [Hansch and Leo, 1995]. This approach known with the name of Hansch analysis became and it still is a basic tool for QSAR modeling. 

Examining 18 substituted 3-phenylthio-1,1,1-trlfluoro-2-propanones, regression equations were obtained between the inhibitory activities and the Hammett (ct), Taft (E ) steric and Hansch (ir) hydrophobicity constants (H). In the fiope of increasing the significance of these equations and to better distinguish between the Importance of various substituent positions, several new compounds of the related structure were synthesized, a much larger set of substituent parameters was applied, and instead of the arbitrary choice of these values, the variables were selected into the equations by a more sophisticated tool, linear stepwise regression analysis. 

For substituted alcohols reacting with hydroxyl radicals, the least substituted alcohol, methanol, was used as a reference compound for Hammett correlation analysis. The o values were taken from Hansch et al. (1995) and rate constants were taken from the U.S. Department of Commerce (USDOC, 1977). These values are believed to be the most accurate rate constants in... 

These efforts were guided by the study of quantitative structure-activity relationships (QSAR) following the Hansch approach. In this method linear free-energy related and other electronic, hydrophobic, and steric substituent constants are used for a quantitative analysis of the possible ways in which substituents may modulate bioactivity in a congeneric series. In the QSAR studies of benzoylphenyl ureas the electronic Hammett a-constants and the hydro-phobic Hansch n-constants were used. To measure the steric influences, steric substituent constants of a new type (B1,B2,B3,B4, and L) were applied which had recently been introduced by us and which give improved correlations in comparison with the steric Es constants used in the literature hitherto (21, 22). The constants B- toBj are measures of the widths of substituents in four rectangular directions. The L-constant accounts for the length of a substituent ... 

Hansch constant — A measure of the capability of a solute for hydrophobic (lipophilic) interaction (see - hydrophobic effect) based on the partition coefficient, P, for distribution of the solute between octan-l-ol and water. The most general way of applying P in correlation analysis, etc. is as logP, but the behavior of substituted benzene derivatives maybe quantified by a substituent constant scale, n, which is defined in a way analogous to the Hammett a scale. There are various n scales, depending on the substrate series used as reference. See also - hy-drophilicity. 

The activity of 1,1jl-trifluoro 3-mercapto substituted phenyl propan-2-ones was not simply correlated with MR alone, therefore, a combination of Hammett a constant, Taft steric parameter (Eg) and Hansch hydrophobic constant (x) was included in the regression analysis. "Equation 36" was found to be of the best fit for compounds substituted in the meta and para positions. 

We have shown that the intrinsic electronic contribution to the Hammett substituent constant, cre(o>), may be obtained from a statistical analysis that follows from the comparison of the experimental <7p values and the electronic electrophilicity index co evaluated for isolated molecules.127 The analysis was performed for the electrophilicity of a series of substituted ethylenes, X-CH=CH2, and the crp values reported by Hansch et al.12S for a wide list of functional groups (FG), X-, commonly present in organic compounds. 

BR is the relative biologic activity under investigation, for example the molar EDr>o or the percent response at a given dose. Log P is the logarithm of the octanol-water partition coefficient, a is the approprite Hammett signa constant (electronic in nature), and Es is the Taft steric parameter. With the important demonstration by Hansch that the partition coefficient is often an additive constitutive property, all of the physical parameers may be obtained from the literature. A second important contribution by Hansch is the recognition that the use of statistical techniques is essential to the analysis of quantitative structure-activity relationships. To develop an equation such as that above, one feeds the... 

The study of structure-reactivity relationships by the organic chemist Hammett showed that there is often a quantitative relationship between the two-dimensional structure of organic molecules and their chemical reactivity. Specifically, he correlated the changes in chemical properties of a molecule that result from a small change in its chemical structure that is, the quantitative linear relationship between electron density at a certain part of a molecule and its tendency to undergo reactions of various types at that site. For example, there is a linear relationship between the effea of remote substituents on the equilibrium constant for the ionization of an acid with the effect of these substituents on the rate or equilibrium constant for many other types of chemical reaction. The relative value of Hammett substituent constants describes the similarity of molecules in terms of electronic properties. Taft expanded the method to include the steric hindrance of access of reagents to the reaction site by nearby substituents, a quantitation of three-dimensional similarity. In addition, Charton, Verloop, Austel, and others extended and refined these ideas. Finally, Hansch and Fujita showed that biological activity frequently is also quantitatively correlated with the hydrophobic character of the substituents. They coined the term QSAR, Quantitative Structure-Activity Relationships, for this type of analysis. 

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