Effects of Conjugation on Reactivity

In addition to steric effects, there are other important substituent effects which determine both the rate and mechanism of nucleophilic substitution reactions. It was 

Substitution reactions by the ionization mechanism proceed very slowly on a-halo derivatives of ketones, aldehydes, acids, esters, nitriles, and related compounds. As discussed on p. 284, such substituents destabilize a carbocation intermediate. Substitution by the direct displacement mechanism, however, proceed especially readily in these systems. Table S.IS indicates some representative relative rate accelerations. Steric effects be responsible for part of the observed acceleration, since an sfp- caibon, such as in a carbonyl group, will provide less steric resistance to tiie incoming nucleophile than an alkyl group. The major effect is believed to be electronic. The adjacent n-LUMO of the carbonyl group can interact with the electnai density that is built up at the pentacoordinate carbon. This can be described in resonance terminology as a contribution flom an enolate-like stmeture to tiie transition state. In MO terminology,.the low-lying LUMO has a 

It should be noted that not all electron-attracting groups enhance reactivity. The sulfonyl and trifluoro groups, which cannot participate in diis type of n conjugation, retard the rate of substitution at an adjacent caibon.  

Studies of the stereochemical course of rmcleophilic substitution reactions are a powerful tool for investigation of the mechanisms of these reactions. Bimolecular direct displacement reactions by the limSj.j2 meohanism are expected to result in 100% inversion of configuration. The stereochemical outcome of the lirnSj l ionization mechanism is less predictable because it depends on whether reaction occurs via one of the ion-pair intermediates or through a completely dissociated ion. Borderline mechanisms may also show variable stereochemistry, depending upon the lifetime of the intermediates and the extent of internal return. It is important to dissect the overall stereochemical outcome into the various steps of such reactions. 

Neopentyl (2,2-dimethylpropyl) systems are resistant to nucleo diilic substitution reactions. They are primary and do not form caibocation intermediates, but the /-butyl substituent efiTectively hinders back-side attack. The rate of reaction of neopent i bromide with iodide ion is 470 times slower than that of n-butyl bromide. Usually, tiie ner rentyl system reacts with rearrangement to the /-pentyl system, aldiough use of good nucleophiles in polar aprotic solvents permits direct displacement to occur. Entry 2 shows that such a reaction with azide ion as the nucleophile proceeds with complete inversion of configuration. The primary beiuyl system in entry 3 exhibits high, but not complete, inversiotL This is attributed to racemization of the reactant by ionization and internal return. 

In addition to steric effects, there are other important substituent effects that influence both the rate and mechanism of nucleophilic substitution reactions. As we discussed on p. 302, the benzylic and allylic cations are stabilized by electron delocalization. It is therefore easy to understand why substitution reactions of the ionization type proceed more rapidly in these systems than in alkyl systems. Direct displacement reactions also take place particularly rapidly in benzylic and allylic systems for example, allyl chloride is 33 times more reactive than ethyl chloride toward iodide ion in acetone. These enhanced rates reflect stabilization of the Sjv2 TS through overlap of the /2-type orbital that develops at carbon. The tt systems of the allylic and benzylic groups provide extended conjugation. This conjugation can stabilize the TS, whether the substitution site has carbocation character and is electron poor or is electron rich as a result of a concerted Sjv2 mechanism. 

Adjacent carbonyl groups also affect reactivity. Substitution by the ionization mechanism proceeds slowly on a-halo derivatives of ketones, aldehydes, acids, esters, nitriles, and related compounds. As discussed on p. 304, such substituents destabilize a carbocation intermediate, but substitution by the direct displacement mechanism proceeds especially readily in these systems. Table 4.10 indicates some representative relative rate accelerations. 

MO representation of stabilization of substitution transition state through interaction with C=0 k orbital 

The extent of the rate enhancement of adjacent substituents is dependent on the nature of the TS. The most important factor is the nature of the TT-type orbital that develops at the trigonal bipyramidal carbon in the TS. If the carbon is cationic in character, electron donation from adjacent substituents becomes stabilizing. If bond formation at the TS is advanced, resulting in charge buildup at carbon, electron 

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It is in this area of dienone photochemistry that the effect of structure on reactivities of excited states seems to be especially complex. For example, Kropp has shown that the presence of the 4-methyl group in santonin is responsible for preferential formation of the fused 5,7 ring system in photosantonic lactone.403 An analogous cross-conjugated dienone with a 2-methyl substituent yields only a spiro compound in acidic media,404 while a dienone with neither 2- nor 4-substituents yields mixtures of the two types of products.409... 

Six-membered rings are considered before five-membered ones because they have been studied in greater detail and consequently their reactions are better understood. Because rate constants for quater-nization reactions have been correlated with values pertaining to the conjugate acids of heteroaromatic nucleophiles, substituent effects on acidities will be discussed prior to kinetic results. Acidity investigations suffer from fewer complications than N-alkylation and therefore provide results that offer considerable insight into the electronic effects of substituents on reactivity. Our review mentions only incidentally such related reactions, as oxidation - and acylation at an annular nitrogen atom. 

The effects of substituents on the form of the substrate reacting is nicely shown by comparison of the rate profiles for 9.27 and 9.33. 4-Pyri-done (9.27) exchanges as the free base even at H0 -10, whereas for its 2,6-dimethyl derivative (9.33), the reaction takes place mainly via the conjugate acid at // -— 3.5. 1,2,6-Trimethyl-4-pyridone (9.35) shows the changeover at even lower acidity (H0 -— 2.7). At high acidity, 9.33, 9.35, and 4-methoxy-2,6-dimethylpyridine (9.36) all react at similar rates and show similar dependence of rate upon acidity. This indicates that all react as the conjugate acids of type 9.37, and excludes the unlikely alternative 9.38. [In [68JCS(B)866], curve C of Fig. 3 refers to 4-methoxy-2,6-dimeth-ylpyridine, and not as stated]. At lower acidity the similarity in rate persists for 9.33 and 9.35, but 9.36 is much less reactive. Hence, the 4-pyridone 9.33 reacts as such and not as the 4-hydroxypyridine tautomer. 

The NPA electron distribution can be related to the VB concept of resonance structures. The orbitals corresponding to localized structures and those representing delocalization can be weighted. For example, Scheme 1.5 shows the relative weighting of the most important resonance structures for 1,3-butadiene, benzene, the benzyl cation, formamide, and the formate anion. These molecules are commonly used examples of the effect of conjugation and resonance on structure and reactivity. 

Braude ei al. studied the dependence of rates of acid-catalyzed isomerization of of-ethynyl-y-methylallyl alcohoF and a-phenyl-y-methylallyl alcohol on the composition of mixed solvents such as aqueous ethanol and aqueous dioxane. If allowance is made for the effect of solvent on the concentration of the reactive conjugate acid of the alcohol, these data show that the rate of isomerization of the conjugate acid is nearly independent of solvent composi-tion as would be expected for a unimolecular rate-limiting dissociation of the conjugate acid to a solvated carbonium ion, Kwart and Herbig reached a... 

The stability of phenoxy radicals is determined by the effect of conjugation of the unpaired electron with the system of the remaining bonds and by steric effects. The introduction of such voluminous substituents as tertiary butyl and phenyl, which shield the reaction centers of the radicals, sharply increases their stability. Radicals of imsubstituted or incompletely substituted phenols readily recombine or disproportionate, and do not accumulate in significant concentrations [4]. There is no direct and distinct relationship between the stability of the radical and the effectiveness of the corresponding phenol as an inhibitor, since the effectiveness depends not only on the reactivity of the OH-bond, but also on a number of other factors. However, there is a general correspondence between the stability of the radical and the effectiveness of the corresponding phenol. 

Shirai, M., Kawai, Y, Yamanishi, R., Kinoshita, T., Chiunan, H. Terao, J. (2006). Effect of conjugated quercetin metaboUtes, quercetin-3-glucuronide, on hpid hydroperoxide-dependent formation of reactive oxygen species in differentiated PC-12 cells. Free Radical Research, 40,1047-1053. 

Diphenylmethane is the conjugate acid of the diphenylmethyl carbanion, and the equilibrium acidity constants (Ka) have been measured both directly and indirectly in the gas phase and in solution [3]. The most extensive investigations of the effect of structure on acidity for carbon acids have been carried out in DMSO using a carbon indicator method to determine relative acidities and this scale was anchored with potentiometric measurements to provide an absolute scale of acidities [3, 43]. A summary of relevant pKg values for various carbon acids is shown in Table 2. The data in Table 2 are especially relevant for considering the reactivity of 1,1-diphenylmethyl carbanionic species as initiators in anionic polymerization. In general, an appropriate initiator for a given monomer is an anionic species that has a reactivity (stability) similar... 

A familiar feature of the electronic theory is the classification of substituents, in terms of the inductive and conjugative or resonance effects, which it provides. Examples from substituents discussed in this book are given in table 7.2. The effects upon orientation and reactivity indicated are only the dominant ones, and one of our tasks is to examine in closer detail how descriptions of substituent effects of this kind meet the facts of nitration. In general, such descriptions find wide acceptance, the more so since they are now known to correspond to parallel descriptions in terms of molecular orbital theory ( 7.2.2, 7.2.3). Only in respect of the interpretation to be placed upon the inductive effect is there still serious disagreement. It will be seen that recent results of nitration studies have produced evidence on this point ( 9.1.1). 

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