The Analysis of Substituent Effects

In his work on the analysis of substituent effects in aliphatic ester reactions, Taft87,89 derived a values, from which 07 values may be calculated as follows NH2, 0.10 Me2N, 0.10 AcNH 0.28. Thus there are some discrepancies as between the results of Charton109 and of Taft87,89. 

A convenient tool for the analysis of substituent effects on the acid-base reactivity of homogeneous families of compounds is the comparison of their... 

For a reaction adequately described by just two configurations, reactant and product, the analysis of substituents effects is straightforward and was first treated by Horiuti and Polanyi (1935) almost 50 years ago. Subsequent contributions by Bell (1936) and Evans and Polanyi (1938) have led to these general ideas being jointly termed the Bell-Evans-Polanyi principle (Dewar, 1969). The treatment of multiconfiguration reactions is analogous and is illustrated in Fig. 12. Let us discuss this in detail. 

The analysis of substituent effects on RSE values does not only aid our understanding, but also holds a degree of predictive power, allowing one to design and select species with optimal radical stabilities for specific practical applications. Indeed, provided due attention is given to the effects of substituents on the other species involved, RSEs can even provide a qualitative guide to the thermodynamic stability of radicals in other types of chemical reaction, such as addition and beta-scission. In this section, some practical applications of RSE values are illustrated using some selected case studies from the literature. 

The difficulties encountered in using the analysis of substituent effects in solvolyses as a mechanistic probe mostly arise from the mechanistic involvement of the solvent (Shorter, 1978, 1982 Tsuno and Fujio, 1996). Consequently, the behaviour of benzylic carbocations in the gas phase should be the best model for the behaviour of the solvolysis intermediate in solution (Tsuno and Fujio, 1996). The intrinsic substituent effects on the benzylic cation stabilities in the gas phase have also been analysed by equation (2), and they will be compared here with the substituent effects on the benzylic solvolysis reaction. In our opinion, this provides convincing evidence for the concept of varying resonance demand in solvolysis. Finally, we shall analyse the mechanisms of a series of benzylic solvolysis reactions by using the concept of a continuous spectrum of varying resonance demand. 

Numerous solvolytic studies on diarylmethyl derivatives have been carried out under a variety of conditions. The analysis of substituent effects in the solvolysis of the monosubstituted chlorides [22] was reported earlier (Yukawa and Tsuno, 1959 Yukawa etal., 1966). The purpose of this analysis is to clarify the effect of a fixed substituent Y in one ring on the substituent effect of the variable substituents X on the second ring. Three extensive sets of kinetic data for the solvolysis of X, Y-disubstituted benzhydryl systems under fixed conditions have been reported one for the ethanolysis (Nishida, 1967), one for the chloride hydrolysis in 85% aqueous acetone at 0°C (Fox and Kohnstam, 1964) and one for the bromide hydrolysis (Mindl et al., 1972 Mindl and... 

Cherkasov, A.R., Jonsson, M. and Galkin, V.I. (1999) A novel approach to the analysis of substituent effects quantitative description of ionization energies and gas basicity of amines./. Mol Graph. Model., 17, 28 2. 

We have also discussed the use of the electrostatic potential for the analysis of substituent effects in aromatic systems. Substituent effects on gas phase and solution acidities of benzoic acids and phenols are dominantly determined by the relative stabilization of the negative charge in the ionized forms of these systems. The oxygen Vmin is an excellent tool for the analysis of this stabilization effect. On the other hand, we have found that the homol5dic O-H bond dissociation energy in phenols depends both on the substituent s ability to stabilize the parent molecule (the phenol) and the radical. The relative stabilization energies of the parent molecule and the radical can be estimated from their computed Vmin and surface maxima in the spin density, respectively. 

The analysis of substituent effects in metal complexes is one of the goals of electron transfer equilibrium studies. For example, alkyl substitution in metallocenes predictably decreases their lEs. At the same time it has been shown that the gas-phase EAs can be increased by a larger alkyl substituent in the hydrocarbon ligand (Figure 1). 

We have demonstrated that due to inhomogeneous distribution of both reaction partners in the micelles, the pseudophase model leads to erroneous estimates of the second-order rate Constantin the micellar pseudophase, so that conclusions regarding the medium of the reaction cannot be derived through this model. However, analysis of substituent effects and endo-exo ratios of the Diels-Alder adducts indicate that the reaction experiences a water-like medium. 

Increasing attention has been paid to the generation of quantitative stmcture—activity relationships in which the effects of molecular substitution on pharmacologic activity can be interpreted in terms of the physicochemical properties of the substituents. These approaches are based on the extrathermodynamic analysis of substituent effects (36) ... 

Analysis of substituent effects on tautomeric equilibria by the method of perturbed molecular orbitals Theoretical studies of heteroaromatic compounds (MNDO, 4-31G)... 

Analysis of substituent effects in the reaction revealed random correlations of rate with a values of substituents for the uncatalysed reaction, but for the acid-catalysed reaction, reasonable Hammett plots with p factors of —1.27 (HC104) and -1.12 (H3P04) were obtained (Table 253). 

Even if full potential energy surfaces are not calculated, simple EHT calculations, skilfully coupled with orbital symmetry considerations, can provide insight into complex reactivity problems. This is well exemplified by Hoffmann and Stohrer s analysis of substituent effects on the Cope rearrangement (28). 

The above theoretical analysis of substituent effects on orbital energies can be tested experimentally. Specifically, the energy of a given occupied MO in a closed shell system is equal to the negative of the corresponding ionization potential28 while the... 

Other papers in the series Chemometrical Analysis of Substituent Effects are on additivity of substituent effects in dissociation of 3,4-178 or 3,5-179disubstituted benzoic acids in organic solvents and on the ort/zo-effect180. In the last-mentioned, data for the dissociation of ortto-substituted benzoic acids in 23 solvents are combined with data on the reactions with DDM (Section IV.C) and with other rate and equilibrium data bearing on the behaviour of o/t/ o-substituents to form a matrix involving data for 69 processes and 29 substituents. 

The status of Exner s revised <7/ and or values has been debated for almost thirty years. A number of prominent workers in the field are rather critical of Exner s approach. For a fairly recent appraisal of the situation, see an article by the present author76. Exner has continued to propagate his view on this matter in his book published in 198877. Some of his papers in the past few years indicate that he is developing further criticisms of aspects of the traditional separation of inductive and resonance effects and of the ways in which correlation analysis of substituent effects is generally carried out138,240 -243. 

Most of the data in Table 12 come from the work of Shvo et al. (78). Careful band-shape analysis and solvent-effect studies permitted evaluation of the rate constants and AG values at 298 K, which renders the discussion of substituent effects more meaningful than usual. The authors obtained reasonably linear Hammett plots when correlating log km with Or (79) for X and Y, holding one of these substituents constant. They also found that the dihydropyridine system may act as an unusually efficient donor, giving a AG of 17.6 kcal/mol with X, Y = H, CN, the only barrier below 25 kcal/mol reported for any donor-substituted cyanoethylene. However, with other acceptor combinations the dihydropyridine moiety is not so outstanding, and this illustrates the difficulty of measuring donor and/or acceptor effects by rotational barriers alone (vide infra). 

Several attempts have been made to analyse the captodative effect through rotational barriers in free radicals. This approach seems to be well suited as it is concerned directly with the radical, i.e. peculiarities associated with bond-breaking processes do not apply. However, in these cases also one has to be aware that any influence of a substituent on the barrier height for rotation is the result of its action in the ground state of the molecule and in the transition structure for rotation. Stabilization as well as destabilization of the two states could be involved. Each case has to be looked at individually and it is clear that this will provide a trend analysis rather than an absolute determination of the magnitude of substituent effects. In this respect the analysis of rotational barriers bears similar drawbacks to all of the other methods. 

In spite of great effort, the analysis of structure effects on the dehydrogenation of alcohols on metals has not helped much toward an understanding of the mechanism. A broader range of substituents would be necessary in order to distinguish between the electronic and steric influences. 

An approach to the correlation analysis of substituent effects in chemical reactions and processes. In this treatment, there are two parameters, a field constant (F) and a resonance constant (R). The approach has received some criticism ... 

Veith, G.D., Mekenyan, O.G., Ankley G.T. and Call, D.J. (1995) A QSAR analysis of substituent effects on the photoinduced acute toxicity of PAHs. Chemosphere, 30, 2129-2142. 

A detailed analysis of substituent effects on the pKa values of imidazoles and tetrazoles as well as benzimidazoles and naphthimidazoles has been made.308 The ortho effect is shown to parallel that of 2-substituted pyridines and quinolines47 190 and application of the Hammett equation to the tautomerism of these systems is also considered. The equation also satisfies the effect of substituents on the basicity of the nitrogen in the 1-position for 1-pyrazolines.309... 

Wright JS, Johnson ER, DiLabio GA. 2001. Predicting the activity of phenolic antioxidants Theoretical methods, analysis of substituent effects, and application to major families of antioxidants, J Am Chem Soc 123 1173-1183. 

Since correct assignment of the protonation site for the enamine systems is essential, we believe that careful evaluation of the evidence in this context is in order. For this purpose, we shall consider such data as hydrogen affinities, analogies with saturated amines, theoretical calculations and the analysis of structural effects by using the Taft-Topsom substituent model13. 

For correlation analysis, the Y-T equation can be applied directly by least-squares analysis of the dual parameter relationship. However, improvement of the correlation is not of much interest since the increased number of parameters in the Y-T equation should inevitably improve the precision. Particularly in the investigation of reaction mechanisms, insufficient improvement could be more important for indicating the involvement of mechanistic complexity. The correlation will be frequently modified by various extraneous factors. We therefore illustrate the behaviour of substituent effects in several typical benzylic solvolyses in terms of the Y-T relationship. 

The utility of rate correlations such as (22) depends on the additivity of substituent effects. Whereas the correlation of /3-substituents requires a different p value, this may be treated as total effects of three a-substituents in the developing intermediate [36C ], R, R and -CHR R. In practice a rather good correlation covers 22 orders of magnitude in reactivity without any clear evidence of curvature. Thus Tidwell stated (Koshy et al., 1979) that the Y-T correlation was unnecessary for the analysis of a large body of hydration data. 

At present, the situation is not quite as bad as in the correlation analysis of substituent effects, where even more substituent parameters than common substituents seem to be known. It has been suggested that new solvent polarity scales should only be introduced into the literature if they exhibit significant advantages over existing solvent scales [235]. 

Electronic effects of substituents can affect organic molecules in diverse ways. Usually, loci near the substituent are most influenced, but often electron density is altered several bonds removed from the substituent. Aromatic organometallic tr-complexes provide fascinating systems for the study of substituent effects, for the three-dimensional nature of these complexes adds interesting complexities to the analysis of the distribution of electron density in such molecules. This chapter is intended to summarize homoannular, interannular, and metal-ring substituent effects in metallocene and similar systems with the idea of spurring additional research in the area. 

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