Organic compounds free-energy relationships

Two approaches to quantify/fQ, i.e., to establish a quantitative relationship between the structural features of a compoimd and its properties, are described in this section quantitative structure-property relationships (QSPR) and linear free energy relationships (LFER) cf. Section 3.4.2.2). The LFER approach is important for historical reasons because it contributed the first attempt to predict the property of a compound from an analysis of its structure. LFERs can be established only for congeneric series of compounds, i.e., sets of compounds that share the same skeleton and only have variations in the substituents attached to this skeleton. As examples of a QSPR approach, currently available methods for the prediction of the octanol/water partition coefficient, log P, and of aqueous solubility, log S, of organic compoimds are described in Section 10.1.4 and Section 10.15, respectively. 

Goss, K.-U., and R. P. Schwarzenbach, Linear free energy relationships used to evaluate equilibrium partitioning of organic compounds , Environ. Sci. Technol., 35, 1-9 (2001). 

Helmer, F., K. Kiehs, and C. Hansch, The linear free-energy relationship between partition coefficients and the binding and conformational perturbation of macromolecules by small organic compounds , Biochemistry, 7, 2858-2863 (1965). 

Perhaps the most important feature of the linear free energy relationship is that the choice of compounds can be planned in advance and only those substances which offer most information about the system can be selected for further study. It is usually more useful to study a few compounds with widely differing substituent effects than a large number of compounds, the substituent constants of which differ only slightly. Consultation of a list of substituent constants can therefore be useful in choosing organic substances for a polarographic study. 

Grosjean, D., and E.L. Williams, n. 1992. Environmental persistence of organic compounds estimated from structure-reactivity and linear free-energy relationships. Unsaturated aliphatics. Atmos. Environ. 26A 1395-1405. 

The structure-reactivity relationship of acidic organophos-phorus compounds is well demonstrated by mono-esters of p-substi-tuted phenylphosphonic acids. The acidity of these organic acids increased as the polar nature of the substituents enhanced. A linear free energy relationship exists between the pKa value and the Hammett cr constants in acidic p-substituted phenylphospho-nates. When these structure parameters are plotted either against the t POO" asym. or against the 31p chemical shift of their dicyclo-hexylammonium salts straight lines resulted in both cases. 

Systematic studies of the effects of structure on the biological activities of organic compounds and the analysis of the results are comprised in the term Quantitative Structure-Activity Relationships (QSAR). Many of the treatments employed in the correlation analysis of data in this field closely resemble those used for linear free-energy relationships, e.g. the Hammett equation and extensions thereof, and so the study of the biological properties of organic compounds is often regarded as a part of physical organic chemistry. In recent years, some historical study of work in... 

The Hammett relationship is called a linear free energy relationship since it is based on—and reveals—the fact that a linear relationship exists between free energy change and the effect exerted by a substituent. Other linear free energy relationships arc known, which take into account steric as well as electronic effects, and which apply to ortho substituted phenyl compounds as well as meta and para, and tc aliphatic as well as aromatic compounds. Together they make up what is perhaps the greatest accomplishment of physical-organic chemistry. 

From the Hammett equation [Hammett, 1935, 1937], the seminal vork of Hammett gave rise to the a—p culture in the delineation of substituent effects on organic reactions, whose aim was to search for linear free energy relationships (LFER) [Hammett, 1938] steric, electronic, and hydrophobic constants were derived for several substituents and used in an additive model to estimate the biological activity of congeneric series of compounds. 

Zahradnik R. Correlation of the biological activity of organic compounds by means of the linear free energy relationships. Experientia 1962 18 534-536. 

G. J. Janz, Thermodynamic Properties of Organic Compounds, Academic Press, New York, 1967. Linear Free-Energy Relationships... 

V. Ventosa, J. Llibre, J. Torras, C. Rovira and J. Veciana, Modeling of the solubilities of organic compounds in supercritical fluids using the linear solvation free energy relationship theory... 

The history of quantitative structure-activity relationships dates back to the last century, when Crum-Brown and Fraser in 1865 postulated that there ought to be a relationship between physiological activities <1> and chemical structures C. Later, Richet correlated toxicities with aqueous solubility. Around 1900, Meyer and Overton found linear relationships between the narcotic potencies of organic compounds and their partitioning behavior. In the mid-1930s, Hammett defined a reaction constant p to describe the reactivity of aromatic systems R, expressed by rate constants k (or equilibrium constants K) and a parameter o to describe the electronic properties of aromatic substituents X (1 equation 1) (see Linear Free Energy Relationships (LFER)) ... 

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