Benzoic electronic parameters

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 ... 

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 ... 

CoMFA and related 3D QSAR approaches have been applied to correlate various physicochemical properties. Equilibrium constants of the hydration of carbonyl groups could be explained by a combination of C=0 bond order, steric, and electrostatic fields [1005]. 3D QSAR studies that correlate a, inductive, and resonance parameters of benzoic acids [1015, 1016] as well as pKg values ofclonidine analogs [1017] show that a H " field precisely describes such electronic parameters, e.g. (Jm.p of benzoic acids (n = 49 rpir = 0.976 snr = 0.082 Spress = 0.093). Steric parameters of benzoic acids, like surface area and van der Waals volume can be described by a steric field alone, while values of acetic acid methyl esters need a combination of both steric and electrostatic fields (n = 21 rpix = 0.984 Sfit = 0.133 SpREss = 0.209) [1016]. 

By introducing reasonable values (about 2 for nitrogen, 4 for oxygen) for the electron affinity parameter relative to carbon, 8, and for the induced electron affinity for adjacent atoms (32/8i = Vio), we have shown that the calculated permanent charge distributions for pyridine, toluene, phenyltrimethylammonium ion, nitrobenzene, benzoic acid, benzaldehyde, acetophenone, benzo-nitrile, furan, thiophene, pyrrole, aniline, and phenol can be satisfactorily correlated qualitatively with the observed positions and rates of substitution. For naphthalene and the halogen benzenes this calculation does not lead to results... 

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. 

The electronic demand parameter r), characteristic of a given process, is equal to the ratio of the coefficients R/D and has been shown to depend on the nature of the active site, skeletal group and medium. Contrary to the general view, electronic demand is roughly the same in magnitude for ar (based on benzoic acid ionization) and o f, scales, but is positive for the former and negative for the latter. 

Hence, the Pi ligand parameter reflects, in an overall way, the combined a- and Tt -electronic properties of the coordination M—L bond. It is noteworthy to mention that it relates to the variation of the free-energy difference of the redox processes (consider the known expression AG = —nFE, in which n is the number of electrons transferred and F is the Faraday constant). It has analogies with the Hammett Up constant [11, 12] defined as og[Kx/Kh), that is, log Kx - log K, in which Kx and ATh are the acidic constants of the p-substituted benzoic acid HOOCCg H4X-4 and of benzoic acid itself, respectively [13] (consider also the known relationship AG = —RT nK). 

HA compounds is not necessary for the formation of a polyester. Nevertheless, an acceleration effect of HA compounds on the rate of copolymerization was detected later 36 57 74), even for systems in which proton donors are directly bound to monomers 67). This effect is not the sum of the contributions from the tertiary amine and the proton donor but even stronger. Hence, proton donors display a cocatalytic effect. Concerning the effect of HA compounds Tanaka and Kakiuchi 36) established a linear correlation between Hammett s ct constants and the logarithm of the gelation time for various substituted derivatives of benzoic acid, benzyl alcohol and phenol, and positive reaction parameters q were found in all cases. This means that electron-withdrawing substituents increase the effect of HA compounds, or their effect becomes more pronounced with increasing hydrogen atom acidity. 

The slope of line p (called the reaction constant) is a measurement of the sensitivity of such a reaction to the electronic effect of the substituents nevertheless, it can be explained as a proportionality constant pertaining to a given equilibrium (i.e., it depends on the reaction and the solvent), ft relates the effect of substituents on that equilibrium to the effect of those substituents on the benzoic acid equilibrium. That is, if the effect of substituents is proportionally greater than that on the benzoic acid equilibrium, then p > 1 if the effect is less than that on the benzoic acid equilibrium, then p < 1. By definition, for benzoic acid the parameter p is equal to 1 in water at 25°C. Many organic reactions proceed via a series of steps, each of which might have a different reaction constant p hence, to achieve a successful correlation, p must be at least roughly additive. 

Hammett s success in treating the electronic effect of substituents on the equilibria rates of organic reactions led Taft to apply the same principles to steric, inductive, and resonance effects. The Hammett o constants appear to be made up primarily of two electronic vectors field-inductive effect and resonance effect. For substituents on saturated systems, such as aliphatic compounds, the resonance effect is rarely a factor, so the o form the benzoic acid systems is not applicable. Taft extended Hammett s idea to aliphatics by introducing a steric parameter ( .). He assumed that for the hydrolysis of esters, steric and resonance effects will be the same whether the hydrolysis is catalyzed by acid or base. Rate differences would be caused only by the field-inductive effects of R and R in esters of the general formula (XCOOR), where X is the substituent being evaluated and R is held constant. Field effects of substituents X could be determined by measuring the rates of acid and base catalysis of a series XCOOR. From these rate constants, a value a could be determined by Equation (5.9) ... 

Hammett decided not to use the pJCas themselves for his correlation but defined a new parameter, which he called o. This O shows how electron-donating or -withdrawing a group is relative to H as a ratio of the logics or the difference of the piCas between the substituent and benzoic acid itself. If the acid required to determine a for a new substituent was not available, o could be determined by correlation with other reactions. Here are the equations and the table of o values for the most important substituents. A different value of a for any given substituent was needed for the meta and the para positions and these are called om and op, respectively. 

The intrinsic delocalized (resonance) electrical-effect parameter. It represents the delocalized electrical effect in a system with zero electronic demand. cTg The electronic demand sensitivity parameter. It adjusts the delocalized effect of a group to meet the electronic demand of the system. cTj) A composite delocalized electrical-effect parameter which is a function of and cTg.Examples of constants are the ctr and ctr constants.The ctr constants, where k designates the value of the electronic demand rj, are also examples of Ojy constants. ctr a composite delocalized electrical-effect parameter of the ctd type with rj equal to 0.380. It is derived from 4-substituted benzoic acid pK values. 

In 1962, Hansen [14] derived a first Hammett-type relationship between the toxicities of substituted benzoic acids and the electronic a constants of their substituents. However, later, it turned out that this was a chance correlation that only resulted from a close interrelationship between the Hammett a parameter and the lipophilicity constant % (Sec. 4 Eqs. (42) and (43)). In the same year, for the very first time, a nonlinear multiparameter equation (Eq. 6) [15] was used to describe biological activity values ... 

The Hammett LFER relates the dissodation constants of substituted benzoic acids to that of benzoic acid itself. Described in 1937, the original relationship was developed to explain the electronic effects of substituents on the strengths of m- and p-substituted benzoic acids. Then, the parameter cr was defined for m- and p-substituted acids as... 

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