Resonance and inductive effects

Let us consider the a value for 4-methoxybenzoic acid the transmission of charge to the carhoxyl group is by inductive and resonance pathways (Eqn. 48). 

We may make the assumption that is the sum of inductive and resonance effects (cj, + aR = ap). To a near approximation = a, because with the meta substituent there can be no through resonance. Special a values have been defined (a°, a , a ) where through resonance is absent values are usually derived from side-chain reactions insulated from the aromatic ring by one or two methylene groups. Values of a are from ordinary a values where a p value is obtained for a reaction using substituents free of resonance interaction. Values of a may then be calculated from the basic Hammett regression line. Values of a were defined from the rates of alkaline hydrolysis of ethyl arylacetates. 

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Electrophilic substitution of a disubstituted benzene ring is governed by the same resonance and inductive effects that affect monosubstituted rings. The only difference is that it s now necessary to consider the additive effects of two different groups. Tn practice, this isn t as difficult as it sounds three rules are usually sufficient. 

Another important site of structural variation in cephalosporins is C(3) (Table 5.4.J). Electron-withdrawing substituents at C(3) such as a Cl-atom or a MeO group increase base-catalyzed hydrolysis of cephalosporins by both resonance and inductive effects [92], For cephalosporins carrying 3-methylene-linked substituents with leaving group ability (e.g., acetate, thiol, or pyridine), it has been postulated that a concerted expulsion of the substituent facilitates the nucleophilic attack on the /3-lactam carbonyl group [104][105]. However, there are also arguments for a stepwise process in which the ex-... 

Problem 19.13 In terms of resonance and inductive effects, account for the following relative acidities. 

The DSP approach nicely answers the controversial question about which substituent parameters should be employed to correlate pKa data for 4-substituted pyridinium ions. Statistically, the best correlation is given by Eq. (9), which has values to measure the resonance contribution of a substituent, a result in keeping with chemical intuition. This correlation is statistically superior to a Hammett treatment, where both resonance and inductive effects of a group are combined into a single parameter, p or ap.53,54 Moreover, now it is possible to rationalize why a simple Hammett treatment using ap works so well. Equation (9) reveals that the protonation equilibrium is much more sensitive to an inductive effect (p, — 5.15) than to a resonance effect (p = 2.69). Hence, substituent parameters, such as erp, which are derived from a consideration of the dissociation constants for benzoic acids where resonance contributions are small serve as a useful approximation. The inductive effect is said to have a larger influence on pKa values for pyridinium ions than for benzoic acids because the distance between the substituent and the reactive site is shorter in the pyridine series.53... 

A discussion in terms of resonance and inductive effects of a heteroatom on the acidities of protonated azole rings is available.120 A... 

The Bronsted correlation for five-membered rings shows that effects of structure on reactivity and on acidity are related. Variations in rate constants for quaternization and in pKa values (Table III) are understandable in terms of resonance and inductive effects of the heteroatom X.120 The effects on the energy of a transition state leading to quaternized product are similar but smaller than those on the energy of protonated material. The following considers in more detail the influence of benzo-fusion. 

In aromatic compounds carbon-13 shifts are largely determined by mesomeric (resonance) and inductive effects. Field effects arising from through-space polarization of the n system by the electric field of a substituent, and the influences of steric (y) effects on the ortho carbon nuclei should also be considered. Substituted carbon (C-l) shifts are further influenced by the anisotropy effect of triple bonds (alkynyl and cyano groups) and by heavy atom shielding. 

SCHEME 12.2 Resonance and inductive effects in substituted benzoic acids... 

Tuning of selectivity in the metallation of m-anisic acid has been realized by an appropriate choice of base.67 The results obtained with LTMP have indicated that the regiochemistry of the lithiation of m-anisic acid is thermodynamically controlled. Resonance and inductive effects favour removal of the H(2) proton. In contrast, superbases such as n-BuLi-r-BuOK are not significantly influenced by or//m-directing groups and preferentially attack H(4), the inductively activated aromatic position next to the most electronegative heteroatom and/or the most acidic position available. 

It is now evident why the formation of the alkylvanadates is insensitive to the pKa of the parent alcohol. The electron density about vanadate is close to optimal, so small changes arising from variation in the ability of the ligand to donate or withdraw electrons are relatively unimportant components of complexation of the alcohols. It would be expected, and is also observed, that both resonance and inductive effects are small for the reaction of vanadate with phenols [4], Considering that the pKa values of the various substituted phenols are considerably lower than 15, an approximately linear relationship (Figure 9.3) between the pKa of the aryl-vanadate and the pKa of the ligand would be expected and can be predicted from the observations of alkylvanadates. There are only minor differences that arise because of resonance electron donation and withdrawal. 

For cyclohexane rrans-fused hydrazone analogs of 37 (R1 = H, R2 = Ar, R3 = Me, CH2Ph), the presence of only the open-chain form was observed. The C = N 13C-chemical shifts of hydrazones were analyzed for the first time in terms of separate resonance and inductive effects by using the dual-substituent-parameter approach (94JOC5895). 

Amines and amides are very weak acids and they only react with very strong bases. The pKa values for ethanamide and ethylamine are 15 and 40, respectively, which means that ethanamide has the more acidic proton (Fig.A). This can be explained by making use of resonance and inductive effects (Fig.B). 

Now let s address the reactivity of these compounds—that is, how the rate and the position of the equilibrium for the reaction are affected by the structure of the compound. The first step, attack of the nucleophile, is usually the rate-determining step. Because this step is the same as the first step in the mechanism for additions to aldehydes and ketones, steric, resonance, and inductive effects control the rate of this reaction in exactly the same manner as was described in Sections 18.3 and 18.4. These effects can be summarized as follows ... 

Strongly associated with resonance and inductive effects are the correlations with the Hammett equation which have been extended to mass-spectrometric processes and are discussed later (Section VIIB). 

A frequently encountered problem in chemistry concerns the effect of a substituent on the properties of a parent molecule. Perhaps the most important, and certainly the most studied (.6), class of substituents are alkyl groups. The highest-lying occupied TV orbitals of molecules such as ethylene, formaldehyde, and benzene are well known to be destabilized by alkyl substitution. The situation for the n orbitals is much less clear. From our ETS studies (4, T, 8) we have found that alkyl substitution destabilizes the LUMO of ethylene and formaldehyde but slightly stabilizes that of benzene, toluene, and t-butylbenzene. This result is particularly significant because the conventional picture of resonance and inductive effects leads one to expect that alkyl substitution should also destabilize the benzene tv orbitals Csee Figure 1). 

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