Reaction resonance effect

Let us illustrate this with the example of the bromination of monosubstituted benzene derivatives. Observations on the product distributions and relative reaction rates compared with unsubstituted benzene led chemists to conceive the notion of inductive and resonance effects that made it possible to explain" the experimental observations. On an even more quantitative basis, linear free energy relationships of the form of the Hammett equation allowed the estimation of relative rates. It has to be emphasized that inductive and resonance effects were conceived, not from theoretical calculations, but as constructs to order observations. The explanation" is built on analogy, not on any theoretical method. 

This work already showed that substituent constants of one reaction can only be transferred to another reaction when similar effects are operating and when they are operating to the same extent. In order to find a broader basis for the transfer-ability of substituent constants, they were split into substituent constants for the resonance effect and those for the inductive effect. 

Clearly, the nex.t step will be to investigate the physicochemical effects, such as charge distribution and inductive and resonance effects, at the reaction center to obtain a deeper insight into the mechanisms of these biochemical reactions and the finer details of similar reactions. Here, it should be emphasized that biochemical reactions arc ruled and driven basically by the same effects as organic reactions. Figure 10.3-22 compares the Claisen condensation of acetic esters to acctoacctic esters with the analogous biochemical reaction in the human body. 

There were two schools of thought concerning attempts to extend Hammett s treatment of substituent effects to electrophilic substitutions. It was felt by some that the effects of substituents in electrophilic aromatic substitutions were particularly susceptible to the specific demands of the reagent, and that the variability of the polarizibility effects, or direct resonance interactions, would render impossible any attempted correlation using a two-parameter equation. - o This view was not universally accepted, for Pearson, Baxter and Martin suggested that, by choosing a different model reaction, in which the direct resonance effects of substituents participated, an equation, formally similar to Hammett s equation, might be devised to correlate the rates of electrophilic aromatic and electrophilic side chain reactions. We shall now consider attempts which have been made to do this. 

The quatemization reaction of the thiazole nitrogen has been used to evaluate the steric effect of substituents in heterocyclic compounds since thiazole and its alkyl derivatives are good models for such study. In fact, substituents in the 2- and 4-positions of the ring only interact through their steric effects (inductive and resonance effects were constant in the studied series). The thiazole ring is planar, and the geometries of the ground and transition states are identical. Finally, the 2- and 4-positions have been shown to be different (259. 260). 

Resonance stabilization energies are generally assessed from thermodynamic data. If we define to be the resonance stabilization energy of species i, then the heat of formation of that species will be less by an amount ej than for an otherwise equivalent molecule without resonance. Likewise, the AH for a reaction which is influenced by resonance effects is less by an amount Ae (A is the usual difference products minus reactants) than the AH for a reaction which is otherwise identical except for resonance effects ... 

The way out of this dilemma is easily stated, although not easily acted upon. It is not adequate to consider any one of these approaches for the explanation of something as complicated as these reactions. Polarity effects and resonance are both operative, and, if these still fall short of explaining all observations, there is another old standby to fall back on steric effects. 

Resonance effects are the primary influence on orientation and reactivity in electrophilic substitution. The common activating groups in electrophilic aromatic substitution, in approximate order of decreasing effectiveness, are —NR2, —NHR, —NH2, —OH, —OR, —NO, —NHCOR, —OCOR, alkyls, —F, —Cl, —Br, —1, aryls, —CH2COOH, and —CH=CH—COOH. Activating groups are ortho- and para-directing. Mixtures of ortho- and para-isomers are frequently produced the exact proportions are usually a function of steric effects and reaction conditions. 

In general, the dissection of substituertt effects need not be limited to resonance and polar components, vdiich are of special prominence in reactions of aromatic compounds.. ny 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 interactioa For example, it has been suggested that electronegativity and polarizability can be treated as substituent effects separate from polar and resonance effects. This gives rise to the equation... 

In the El cb mechanism, the direction of elimination is governed by the kinetic acidity of the individual p protons, which, in turn, is determined by the polar and resonance effects of nearby substituents and by the degree of steric hindrance to approach of base to the proton. Alkyl substituents will tend to retard proton abstraction both electronically and sterically. Preferential proton abstraction from less substituted positions leads to the formation of the less substituted alkene. This regiochemistry is opposite to that of the El reaction. 

If the two interaction mechanisms maintain the same relative importance throughout the reaction series, that is, if the ratio pj/pi is constant, Eq. (7-26) becomes identical in form with Eq. (7-24). This in fact appears to be the usual situation in Hammett correlations, PP- and the two interaction mechanisms are commonly discussed in terms of the inductive and resonance effects of electronic displacement. 

A further complication arises with Ingold s suggestion" that both the inductive and resonance effects are composed of initial state equilibrium displacements that reveal themselves in equilibrium properties like dipole moments and equilibrium constants and of time-dependent displacements produced during reaction by the approach of an attacking reagent, observed rate effects being resultants of both types of electronic effects. Hammett, however, claims that it is not necessary or possible to make this distinction. 

Although cTi estimates by different methods or from different data sets may disagree, it is generally held that the inductive effect of a substituent is essentially independent of the nature of the reaction. It is otherwise with the resonance effect, and Ehrenson et al. have defined four different ctr values for a substituent, depending upon the electronic nature of the reaction site. An alternative approach is to add a third term, sometimes interpreted as a polarizability factor, and to estimate the inductive and resonance contribution statistically with the added parameter the resonance effect appears to be substantially independent of reaction site. " " ... 

A more quantitative formulation of the varying resonance effects in electrophilic nuclear substitution reactions has been suggested by Tsuno, who has proposed to use Eq. (2), where Aa+ is a resonance exaltation term, and r is a susceptibility constant. 

Few other reactions of series of substituted pyridines have been investigated extensively. Dondoni, Modena, and Todesco have measured the rate of N-oxidation of a limited series of pyridines and found a good correlation with normal u-values with a p-value of — 2.23. The A-alkylation of pyridines with alkyl iodides in nitrobenzene has been studied by Brown and Cahn and by Clarke and Rothwell. Unfortunately, the only data available are for the parent compound and for alkyl derivatives, and, since the a-values for the various alkyl groups in a given position are substantially constant, this leaves a correlation of only three independent points. However, the rates of A-alkylation of the j8- and y-alkyl derivatives are so nearly equal that it appears as if no correlation existed. Clarke and Rothwell have also studied the alkylation with allyl bromide in nitromethane at various temperatures, and in this case a more extensive series is available. The authors state that no overall Hammett correlation is obtained however, the j8-substituted derivatives fall on one straight line and the y-derivatives on another one with a different slope. The data are shown in Fig. 2. The line for the j8-compounds, p = — 2.53 0.31, r = 0.95, is seen not to be very good the line for the y-derivatives, p = — 1.42 0.06, r = 0.99, is much more satisfactory. It does not seem likely that the discrepancy is due to the intervention of resonance effects, since in this case one would expect the correlation for the y-derivatives to be poorer than that for the j8-analogs. More extensive studies with a wider variety of substituents would seem very desirable. 

The least squares value for the p constant obtained by this procedure is +6.2 it wiU be obviously subject to change as more meta and epi substituents become available. Only the cata-NO group was excluded from the above plot because it causes a strongly enhanced resonance effect in nucleophilic substitution (Section IV,C, l,a) and an anomalous effect of uncertain origin in the dissociation of carboxylic acids. It can be assumed that the reaction constant for 4-chloro-... 

Meta-directing deactivators, such as —CHO, act through a combination of electron-withdrawing inductive and resonance effects that reinforce each other and are felt most strongly at the ortho and para positions. As a result, the ortho and para intermediates are less stable so reaction with an electrophile occurs at the meta position (Figure 16.16). 

One further comparison aromatic aldehydes, such as benzaldehyde, are less reactive in nucleophilic addition reactions than aliphatic aldehydes because the electron-donating resonance effect of the aromatic ring makes the carbonyl group less electrophilic. Comparing electrostatic potential maps of formaldehyde and benzaldehyde, for example, shows that the carbonyl carbon atom is less positive (less blue) in the aromatic aldehyde. 

Haloalkane,. see Alkyl halide Haloform reaction, 854-855 Halogen, inductive effect of, 562 resonance effect of, 563 Halogenation, aldehydes and, 846-848... 

In common with a number of heterocyclic iodinations, kinetic effects are found in the iodination of indole and 2-methylindole [68AC(R)1435], When the substituent effects for the reaction are examined it is clear that any resonance effects from the fused benzene ring are only poorly relayed to the reactive 3-position, and the rates appear to be controlled by inductive effects. A 5-methyl group was more activating than 5-methoxy [69AC(R)799]. 

However, the duality of substituent constants and the attempt to deal with crossconjugation by selecting cr+, a or a in any given case is somewhat artificial. The contribution of the resonance effect of a substituent relative to its inductive effect must in principle vary continuously as the electron-demanding quality of the reaction center is varied, i.e. whether it is electron-rich or electron-poor. A sliding scale of substituent constants would be expected for each substituent having a resonance effect and not just a pair of discrete values a and a for — R, or o and a for + R substituents55. 

Taft, following Ingold," assumed that for the hydrolysis of carboxylic esters, steric, and resonance effects will be the same whether the hydrolysis is catalyzed by acid or base (see the discussion of ester-hydrolysis mechanisms. Reaction 10-10). Rate differences would therefore be caused only by the field effects of R and R in RCOOR. This is presumably a good system to use for this purpose because the transition state for acid-catalyzed hydrolysis (7) has a greater positive charge (and is hence destabilized by —I and stabilized by +1 substituents) than the starting ester. 

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