Hammett electronic parameter

The next step in the development of the extrathermodynamic approach was to find a suitable expression for the equilibrium constant in terms of physicochemical and conformational (steric) properties of the drug. Use was made of a physicochemical interpretation of the dissociation constants of substituted aromatic acids in terms of the electronic properties of the substituents. This approach had already been introduced by Hammett in 1940 [14]. The Hammett equation relates the dissociation constant of a substituted benzoic acid (e.g. meta-chlorobenzoic acid) to the so-called Hammett electronic parameter a ... 

Lipophilicity (log P), Hammett electronic parameter (a) and inhibitory concentration (ICj,) for oxidative phosphorylation of 11 doubly substituted salicylanilides [17], The two substitution positions are labeled A and B. 

Five new pyridazinones were synthesized with substitutions in the two-position of the phenyl ring as given in Table II. Using the Hansch approach, correlations were made between the experimentally determined 18 2/18 3 ratios and the values and a,a values taken out of the data collection of Hansch and Leo (15) (Table II and Equations 1-3). The hydrophobic parameter is derived from the 1-octanol/water partition coefficient and o is the Hammett electronic parameter. 

A positive correlation was also established with the Hammett electronic parameters for positions C7 and C2, but the negative correlation with the I, term shows that presence of a substituent at the 6 position decreases binding affinity. 

Substituent effects in diorganyl sulfones, 3- and trans-3,4-substituted thiolane 1,1-dioxides and 4-substituted 2-thiolene 1,1-dioxides have been investigated and correlations with and in analogous compounds as well as with Taft (Hammett) electronic parameters have been reported. Stereochemical effects on S shielding have been studied such as the stereomeric sulfones [4] and [5]. 

In this exercise, we compare MLR and SVMR QSAR models for the benzodiazepine receptor affinity of 52 2-aryl(heteroaryl)-2,5-dihydropyrazo-lo[4,3-c]quinolin-3-(3H)-ones (Figure 53). Both models were developed with five structural descriptors, namely the Hammett electronic parameter Qr, the molar refractivity MRrs, the Sterimol parameter Lr<4<, an indicator variable 7 (1 or 0) for 7-substituted compounds, and the Sterimol parameter The MLR model has a calibration correlation coefficient of 0.798 and fairly good prediction ability ... 

The Hammett substituent parameter was used by Hansch as a concise measure of th electronic characteristics of the molecules. Hammett and others (such as Taft) showed the... 

C-nmr data have been recorded and assigned for a great number of hydantoin derivatives (24). As in the case of H-nmr, useful correlations between chemical shifts and electronic parameters have been found. For example, Hammett constants of substituents in the aromatic portion of the molecule correlate weU to chemical shifts of C-5 and C-a in 5-arylmethylenehydantoins (23). Comparison between C-nmr spectra of hydantoins and those of their conjugate bases has been used for the calculation of their piC values (12,25). N-nmr spectra of hydantoins and their thio analogues have been studied (26). The N -nmr chemical shifts show a linear correlation with the frequencies of the N—H stretching vibrations in the infrared spectra. 

A table of correlations between seven physicochemical substituent parameters for 90 chemical substituent groups has been reported by Hansch et al. [39]. The parameters include lipophilicity (log P), molar refractivity MR), molecular weight MW), Hammett s electronic parameters (a and o ), and the field and resonance parameters of Swain and Lupton F and R). 

Physicochemical and biological parameters obtained from 6 oxazepine (X = O) and 6 thiazepine (X = S) neuroleptics. These include Hammett s electronic parameter (o ), lipophilicity (log P) and its squared value, and the activities (log l/EDjn) in two pharmacological tests in rats [41]. 

The rate of the Schmidt reaction of para-substituted benzoic acids is governed by the electron-releasing character of the substituent, the value of the Hammett p parameter being the same as that needed to correlate product ratios in the related reaction of 1,1-diarylethylenes.807 The latter reaction is believed to go by a similar mechanism. 

For the tautomeric equilibria of perhydro-l,3-oxazines and their benzo derivatives bearing an X-substituted phenyl group at position 2, the proportion of the ring-closed forms has been found to be strongly dependent on the electronic character of the substituent X on the phenyl ring. For these compounds, a linear correlation (Equation 1) has been found between the log values of the equilibria (Xx= [ring]/[chain]) and the Hammett-Brown parameters of the substituents X on the 2-aryl group ... 

Rates of oxidation of para-substituted arylphosphines with singlet oxygen show good correlation with the Hammett a parameter (p = —1.53) and with the Tolman electronic parameter. The only products are the corresponding phosphine oxides. However, for ortho-substituted phosphines with electron-donating substituents, there are two products, namely a phosphinate formed by intramolecular insertion and phosphine oxide. Kinetic analyses demonstrated that both products are formed from the same intermediate, a phosphadioxirane. VT NMR experiments showed that perox-idic intermediates can only be detected for highly hindered and very electron-rich arylphosphines 243... 

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. 

The approach of Hansch is fully analogous to the methodology that Hammett used to develop his electronic parameter. In both cases, the substituent parameter is defined as the logarithm of the ratio of two equilibrium constants (Equations 12.9 and 12.13). 

The distribution of electrons within a molecule depends on the nature of the electron withdrawing and donating groups found in that structure. Hammett used this concept to calculate what are now known as Hammett constants (try) for a variety of monosubstituted benzoic acids (Equation (4.5)). He used these constants to calculate equilibrium and rate constants for chemical reactions. However, they are now used as electronic parameters in QSAR relationships. Hammett constants (crx) are defined as ... 

The cathodic process (reduction) has been studied in different experimental conditions being the potential of the one-electron reaction correlated with other structural parameters, i.e., with the reduced-product lowest vacant orbital energy [86], with the substituent Hammett a parameter [87], or with the biological activity (see below). Table 4 shows reduction potentials for some QDO and PDO derivatives in different experimental conditions [88,89]. 

Evaluation of steric effects can also be made by separating electronic from steric effects with the help of linear free energy relationship and appropriate parameters. Applications of the Hammett equation to heterocycles have been reviewed (64AHC(3)209 76AHC(20)1) and the influence of substituent effects on the basicity and N-alkylation of pyridines, which have been by far the most widely studied, shows the difficulties in this approach. Jaffe and Jones (64AHC(3)209) reported a good correlation between pKA of 3- and 4-substituted pyridines and Hammett a parameters ([Pg.179]

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