Field and resonance parameters

Here we will not discuss these problems and the intriguing observation that am and strong correlation which is, however, difficult to explain (reviews Charton, 1981 Cook et al., 1989 Hansch et al., 1991). These questions were intensively studied in the 1970s and 1980s, leading gradually to the development of field and resonance parameters denoted by F and R respectively (after an original proposal of Swain and Lupton, 1968), which can be considered as independent of each other. The secondary parameters R + and R reflect the potential for an additional mesomeric donor-acceptor interaction (as in 7.7, and the opposite type with a donor instead of NQ2 and the reaction site as acceptor). 

Examples of the successful application of such dual substituent parameter (DSP) treatments with field and resonance parameters will be discussed in Sections 8.3 (hydroxy-de-diazoniation) and 10.5 (Sandmeyer reaction). 

Marriott and Topsom have recently developed theoretical scales of substituent field and resonance parameters. The former correspond to the traditional inductive parameters but these authors are firm believers in the field model of the so-called inductive effect and use the symbol The theoretical substituent field effect scale is based on ab initio molecular orbital calculations of energies or electron populations of simple molecular systems. The results of the calculations are well correlated with Op values for a small number of substituents whose Op values on the various experimental scales (gas-phase, non-polar solvents, polar solvents) are concordant, and the regression equations are the basis for theoretical Op values of about 50 substituents. These include SOMe and S02Me at 0.37 and 0.60 respectively, which agree well with inherent best values in the literature of 0.36 and 0.58. However, it should be noted that a, for SOMe is given as 0.50 by Ehrenson and coworkers . 

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). 

The F and R parameters are qualitatively analogous to the field and resonance parameters, 5 and SR, of Swain and Lupton19 that is, they measure the a and 7r-electronegativities, respectively, of substituents. However, the F and R values are more appropriate for correlating processes in which a localized positive charge develops than are the S and 91 values. Hence the F and R values correlate lone pair ionization potentials and proton affinities better than the corresponding and 91 values do. 

The revised version246 developed new scales of field and resonance parameters, the awkward symbols, T and 3i being replaced by the more straightforward F and R. Some of the criticism made of the earlier form of the treatment had been met by the modifications, but the critics were still not satisfied247-249. 

Fig. 22.4 Molecular properties can be divided into experimental (subdivided into biological and physicochemical) and in silico (subdivided into structural and substructural) properties, physicochemical and biological properties. Examples of experimental data are IC50 (binding affinity), MIC (antibacterial minimum inhibition concentration), LD50 (lethal dose), Vd (volume of distribution), F% (bioavailability), pKg (ionization constant), log P (partition coefficient from shake flask determination), log kn,(lipophilicity from HPLC measurement), A (hydrogen bond capability), solubility. Examples of calculated properties, either for whole molecule or for substituents or buildings blocks, are MW (molecular weight), MR (molar refractivity), molecular volume, PSA (polar surface area), HA (number of H-bond acceptors), HD (number of H-bond donors), CLOGP (calculated log P values), L (substituent length), B5 (substituent width), cr (Hammett constant), F, R (field and resonance parameters), TT (Hansch constant), f (hydrophobic fragmental constant).

We turn now to the part played by the ethynyl group in Topsom s papers on theoretical scales of substituent field and resonance parameters In the first of these " gr values... 

Electronic parameters, e.g. Hammett a constants, field and resonance parameters, parameters derived from spectroscopic data, charge transfer constants, dipole moments, and quantum-chemical parameters. 

Swain s treatments were a reaction against the proliferation of scales of polar substituent constants. He maintained that the polar effect of any given substituent could be adequately expressed in terms of just two basic characteristics a field constant and a fixed resonance constant, cf. the four resonance parameters continue to be applied by some workers and values are included in a recent compilation of substituent constants. ... 

A classical Hansch approach and an artificial neural networks approach were applied to a training set of 32 substituted phenylpiperazines characterized by their affinity for the 5-HTiA-R and the generic arAR [91]. The study was aimed at evaluating the structural requirements for the 5-HTiA/ai selectivity. Each chemical structure was described by six physicochemical parameters and three indicator variables. As electronic descriptors, the field and resonance constants of Swain and Lupton were used. Furthermore, the vdW volumes were employed as steric parameters. The hydrophobic effects exerted by the ortho- and meta-substituents were measured by using the Hansch 7t-ortho and n-meta constants [91]. The resulting models provided a significant correlation of electronic, steric and hydro-phobic parameters with the biological affinities. Moreover, it was inferred that the... 

The Hammett cr-values contain contributions from both inductive/field effects and the resonance effect. The cr-constant can be separated quantitatively into a resonance component R, which operates mainly in the para position, and an inductive component F, which is assumed to be equal in the meta and para positions. Hansch, Leo and Taft11 have calculated the F and R values of Me3Si to be 0.01 and —0.08, respectively, as quoted in Table 1. These values seem somewhat at odds with experimentally determined values12-18 for the inductive and resonance parameters, which give mean values of —0.08 and 0.06, respectively. These values confirm the generally accepted view that MesSi is electron-supplying by inductive effects and electron-withdrawing by resonance effects. 

A (h,x,s)> AE(h,x,0) and A (o,s) can be analyzed in terms of the Taft-Topsom formalism88 wherein these effects are decomposed into electronegativity, polarizability, field and resonance contributions, respectively measured by the descriptors ax, aa, Linear combinations of ax and or lead to a reasonably good description of the AE values indicated above. The main semiquantitative conclusions of such an analysis are as follows ... 

The electronic properties of amino acid side chains are summarized in Table 3, and they represent a wide spectrum of measures. The NMR data are derived experimentally (37). The dipole (38), C mull, inductive, field, and resonance effects were derived from QM calculations (15). The VHSE5 (39) and Z3 (25) scales were developed for use in quantitative structure-activity relationship analysis of the biologic activity of natural and synthetic peptides. Both were derived from principal components analysis of assorted physico-chemical properties, which included NMR chemical shift data, electron-ion interaction potentials, charges, and isoelectric points. Therefore, these scales are composites rather than primary measures of electronic effects. The validity of these measures is indicated by their lack of overlap with hydrophobicity and steric parameters and by their ability to predict biologic activity of synthetic peptide analogs (25, 39). Finally, coefficients of electrostatic screening by amino acid side chains (ylocal and Ynon-local) were derived from an empirical data set (40), and they represent a composite of electronic effects. 

Jones and co-workers used regression analyses to study the effects of field constants and resonance parameters (110) of some carbamate derivatives on their penetration and detoxication with some success (111). Similar studies have also been made by Fukuto and co-workers using selected oximes and their anticholinesterase activities (112). Kakeya et al. used chemical shifts and valence force constants in addition to other thermodynamic parameters in the structure-activity study of a series of sulfonamide carbonic anhydrase inhibitors (113). 

Zollinger examined the empirical correlation equation for Wcxy ( q- 4) in the context of dual substituent parameter equations for a number of other, unrelated reactions (e.g., the loss of nitrogen from ArN2 ). [78] Eq. 4 was thus shown to be one of a family of equations that can be derived to separate the influences of substituent resonance and field (inductive) effects on chemical reactivity. These equations trace back to Taft s formulation, Eq. 7, in which separate p and a terms are used to represent the field and resonance electronic properties of substituents. [79] Zollinger points out that our Wcxy version of this expression is one of few dual substituent parameter equations in which the signs of the resonance and field terms are opposed (cf, Eq. 4, where the coefficients are -1.10 and +0.53, respectively). We have discussed the meaning of this opposition in Section 1.2, above. 

In 1968 Swain and Lupton [298] tried to stop the proliferation of a scales. They defined field and resonance components and by assuming that any set of g values can be expressed by a weighted cohibination + h, that there is no resonance contribution in the case of 4-substituted bicyclo[2.2.2]octane-carboxylic acids (b = 0), and that there is no resonance contribution of a N (CH3)3 substituent ( = 0). They were able to correlate 43 different electronic parameters with linear combinations of these two parameters (many r values being larger than 0.98), e.g. eqs. 40 and 41. 

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]. 

The successful decomposition of a values into field and resonance components could eliminate the need for several sets of o values. The Swain-Lupton system must treat meta- and para-substituted compounds as separate reaction series, with differing values for r and / for a meta versus para placement of the substituent. The reason is that resonance interactions are usually stronger in the para series. There must also be an additional parameter for each reaction, since the relative sensitivity to resonance and field effects differs from reaction to reaction. Swain and Lupton have observed satisfactory correlation for over forty reaction series using and This treatment also provides an indication of the relative importance of resonance and field interactions. The mathematical manipulations are, of course, more complex than in the simple Hammett equation. The Swain-Lupton correlations are carried out by a computer program that provides a best-fit correlation in terms of /, r, and The computation also yields percent resonance by comparing the magnitude of/ andr. 

In general, the dissection of substituent effects need not be limited to resonance and field components, which are of special prominence in reactions of aromatic compounds. Any type of substituent interaction with a reaction center could be characterized by a substituent constant characteristic of the particular type of interaction and a reaction parameter indicating the sensitivity of the reaction series to that particular type of interaction. For example, it has been suggested that electronegativity and polarizability can be treated as substituent effects separate from field and resonance effects. This gives rise to the equation... 

In addition to the log P, other physico-chemical parameters were investigated as to their relationship with the observed toxicities of both the subgroups and the entire set of 1,4-di-substituted benzene derivatives. Parameters so used include w for each of the subset functional groups (R = NO2, NHj, Cl, OH, NMOj), and the substituents (X) molar refractivity (AMR), cTp, and field and resonance contributions, as listed by Hansch and Leo (1979). While some of the correlation coefficients improved and slightly lower s values were obtained, all these derived equations fail to satisfy the demand for an explanation of all the data with an acceptable standard error of, say, s = 0.3 to 0.4 log units. It can be concluded then, that one or more of the following conditions prevail ... 

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