The effects of substituents on acidity

The actual pKa of phenolic compounds depends upon the overall structure of the molecule and the nature of the substituents on the aromatic ring(s). The compound 2,4,6-trinitrophenol (2.6) has a pKa value 0.71, equivalent to that of a strong acid. This low pKa-value is the result of the electron-pulling N02 substituents. The presence of these groups stabilizes the anion that results after the proton is removed. 

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It is possible to break down the effect of substituents on acidity or basicity into the effect on the charged species on the one hand and on the corresponding neutral species on the other. For example, the effect of substituents on the acidity of aniline (reaction 4) is given by the difference between the interaction energies for the appropriate substituted anilide ion (reaction 7) ... 

The effect of substituents on the rate of the reaction catalysed by different metal ions has also been studied Correlation with resulted in perfectly linear Hammett plots. Now the p-values for the four Lewis-acids are of comparable magnitude and do not follow the Irving-Williams order. Note tlrat the substituents have opposing effects on complexation, which is favoured by electron donating substituents, and reactivity, which is increased by electron withdrawirg substituents. The effect on the reactivity is clearly more pronounced than the effect on the complexation equilibrium. 

The effect of structure on acidity was introduced m Section 1 15 where we developed the generalization that electronegative substituents near an lomzable hydrogen increase Its acidity Substituent effects on the acidity of carboxylic acids have been extensively studied... 

The triarylmethyl cations are particularly stable because of the conjugation with the aryl groups, which delocalizes the positive charge. Because of their stability and ease of generation, the triarylmethyl cations have been the subject of studies aimed at determining the effect of substituents on carbocation stability. Many of these studies used the characteristic UV absorption spectra of the cations to determine their concentration. In acidic solution, equilibrium is established between triarylearbinols and the corresponding carbocations. 

A general method for malting Camps precursors has been developed/ Treatment of an anthranilic acid 15 with an acid anhydride or chloride in the usual way results in the corresponding benzoxazinone (16). Subsequent treatment with the dianion of an N-substituted acetamide furnishes P-keto amide 17. The reactions were run with crude 16, yields typically 50-80% overall. The effect of substituents on the reaction has not been extensively investigated. 

THE EFFECT OF SUBSTITUENTS ON THE ABSORPTION SPECTRUM OF BENZOIC ACID... 

The hyponitrites (16), esters of hyponitrous acid (HO N=N OH), are low temperature sources of alkoxy or acyloxy radicals. A detailed study of the effect of substituents on k4 for the hyponitrite esters has been reported by Quinga and Mendenhall,114... 

The reaction is less selective than the related benzoylation reaction (/pMe = 30.2, cf. 626), thereby indicating a greater charge on the electrophile this is in complete agreement with the greater ease of nuclophilic substitution of sulphonic acids and derivatives compared to carboxylic acids and derivatives and may be rationalized from a consideration of resonance structures. The effect of substituents on the reactivity of the sulphonyl chloride follows from the effect of stabilizing the aryl-sulphonium ion formed in the ionisation step (81) or from the effect on the preequilibrium step (79). 

Hammond postulate has been used to explain the effect of substituents on the rate of benzilic acid rearrangements, mechanism of electrophillic aromatic substitution reactions and reactions involving highly reactive intermediates such as carbonium ions and carbon ions. 

To improve DPP-4 activity as well as pharmacokinetic properties, the effects of substituents on triazolopiperazine moieties were examined (Table 17.7) [48], Aryl and heteroaryl substituents were found to be as effective as alkyl substituents at improving DPP-4 activity. Unlike most ofthe previous (1-amino acid amide analogues in this series, these analogues (e.g. 43 and 44) exhibited unacceptable DPP-8 and hERG activities (IC50 S — 1-4 pM). The effects of perfluoroalkyl substituents were... 

More important and more widely applicable criteria of protonation sites are available in the effects of more distant substituents, in particular meta and para in benzene derivatives, which are as a rule purely electronic in origin. Exceptionally, they may be complicated by steric effects (e.g., in polysubstituted derivatives). The most widely useful approach is that of Hammett (1940), who suggested that the effects of substituents on the ionization constants of benzoic acid may be taken as a measure of their effectiveness in other systems involving other reaction centres and in reactions other than acid-base equilibria. He thus defined substituent constants, a, by the equation... 

The effect of substituents on h+ for the C— bond cleavage of orthoesters and hemiorthoesters derived from benzoic acid... 

Modification of Chemical Structure of Drug The use of a Hammett linear free-energy relationship to investigate the effects of substituents on the rates of aromatic side-chain reactions such as hydrolysis of esters has been alluded to earlier vis-a-vis attainment of optimum stability [9,10]. Degradation of erythromycin under acidic pH conditions is inhibited by substituting a methoxy group for the C-6 hydroxyl as found for the acid stability of clathromycin, which is 340 times greater than that of erythromycin [70]. 

If the nucleophilic site (HOMO) involves a nonbonded pair of electrons (path a), a stable covalently bonded complex will form. If the HOMO is a a bond, direct reaction is unlikely unless the bond is high in energy and sterically exposed, as in a three-membered ring, but if the bond is to H, hydride abstraction may occur (path b, steps 1 and 2) or a hydride bridge may form (path 6, step 1). The last two possibilities are discussed further in Chapter 10. If the HOMO is a n bond, a n complex may result (path c, step 1), or, more commonly, donation of the n electrons results in the formation of a a bond at the end where the n electron density was higher, the other end becoming Lewis acidic in the process (path c, steps 1 and 2). The effects of substituents on olefin reactivity were discussed in Chapter 6. 

In summary, the most important factors influencing the pKa of a given acid or base function are inductive, resonance, and steric effects. The impact of a substituent on the pK3 depends critically on where the substituent is located in the molecule relative to the acid or base group. In one place, a given substituent may have only one of the mentioned effects, while in another location, all effects may play a role. It is quite difficult, therefore, to establish simple general rules for quantifying the effect(s) of structural entities on the pK3 of an acid or base function. Nevertheless, in certain restricted cases, a quantification of the effects of substituents on the pKa value is possible by using LFERs. In the next section, we discuss one example of such an approach, the Hammett correlation for aromatic compounds. First, however, a few comments on the availability of experimental pKiz values are necessary. 

Recently, Noyce and Pollack306 have found kinetic evidence for a changeover from acyl to alkyl-oxygen cleavage in the hydrolysis of a-acetoxystyrenes. At low acidities (1 M H2S04) compounds with electron-withdrawing substituents are hydrolyzed in a reaction which behaves as expected for the Aac2 mechanism. The solvent deuterium isotope effect, kH/kD = 0.75, and the effect of substituents on the rate is small. As the acidity of the medium is increased... 

This would have both a solvent effect and a mass law effect on the rate of ester formation. The error is systematic, since it is most serious for the slower ester formation reactions, and consequently the p value calculated by Jaffe144 from the data of Hartman and Borders142 is not accurate. Later workers allowed for this side-reaction 46 or used aromatic sulphonic acids rather than HC1 as the catalyst145147. However, whatever the exact p values, it is quite clear that the polar effects of substituents on acid-catalyzed ester hydrolysis and formation are small. 

Sw m1,M>1, has discussed the effect of substituents on tin Susceptibility of olefins to peroxy acid attack, on the basis of kinetic... 

Complex formation of nickel(II) with a variety of hydroxy acids has been investigated. It has been reported that in aqueous solution in the pH range 6-7.2 at 25 °C, a 1 1 neutral complex is formed between nickel(II) and the salicylato monoanion, HOCsH Oj (Keq —1.4 x 10 6), or its 5-substituted analogue, with the further release of a proton.1789,1790 The effects of substituents on the stability constants of nickel complexes with various 4- and 5-substituted salicylic acids were also studied.1791,1792... 

The reaction of silver(I) ions with amino acids has received considerable attention.397 A number of studies have attempted to analyze the effects of substituents on the stability of the silver(I) complexes. When a series of a>-amino adds NHJ(CH2) C02 (n = 1-5) were examined, it was found that lengthening of the aliphatic side chain increased the overall stability of the complex.398,399... 

Quantitative application of electrostatic theory to the effect of substituents on the ionizations of carboxylic acids, such as chloroethanoic acid, is rendered... 

We have discussed the influence of substituents on acid strengths of simple carboxylic acids as though the full electrostatic effect of the substituent were exerted solely on the A// of ionization. However, careful thermodynamic analysis of acidities in aqueous solution show that entropy effects (Section 4-4B) are very important. This may seem surprising because entropy effects ought to be small for relative acid strengths, which can be assessed by the constants for simple equilibria such as Equation 18-3, in which (1) there are the same number of molecules on each side of the equation, and (2) the constraints on the species involved hardly seem different from one side of the equation to the other ... 

If we now examine the effect of substituents on another reaction, for example acid dissociation of phenylacetic acids (Equation 2.10), we can anticipate that the... 

Rate constants for the hydrolysis of 2-exo-norbomyl phenyl ether and several metaox /> ra-substituted derivatives have been measured in concentrated perchloric acid solutions.17 The effect of substituents on the rate constant and activation parameters is small. The mechanism appears to be of the A-1 type. 

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