Acetic acid inductive effects

With organic acids inductive effects and mesomeric effects affect the pA a values. A simple example is provided by the effect of replacing the hydrogen atoms in acetic acid by the more electronegative chlorine atom. The electron-withdrawing effect of the substituent makes ionisation easier, so successive pATa values decrease in the series 4.7, 2.8, 1.3 and 0.7 when 0,1, 2 or 3 chlorine atoms are present. The Hammett equation, provides a general expression for the effect of substituents. 

The greater positive character hence the increased acidity of the O—H proton of 2 2 2 tnfluoroethanol can be seen m the electrostatic potential maps displayed m Figure 1 8 Structural effects such as this that are transmitted through bonds are called indue tive effects A substituent induces a polarization m the bonds between it and some remote site A similar inductive effect is evident when comparing acetic acid and its trifluoro derivative Trifluoroacetic acid is more than 4 units stronger than acetic acid... 

Formic acid exhibits many of the typical chemical properties of the aHphatic carboxyHc acids, eg, esterification and amidation, but, as is common for the first member of an homologous series, there are distinctive differences in properties between formic acid and its higher homologues. The smaller inductive effect of hydrogen in comparison to an alkyl group leads, for example, to formic acid = 3.74) being a considerably stronger acid than acetic acid... 

The most frequently encountered hydrolysis reaction in drug instability is that of the ester, but curtain esters can be stable for many years when properly formulated. Substituents can have a dramatic effect on reaction rates. For example, the tert-butyl ester of acetic acid is about 120 times more stable than the methyl ester, which, in turn, is approximately 60 times more stable than the vinyl analog [16]. Structure-reactivity relationships are dealt with in the discipline of physical organic chemistry. Substituent groups may exert electronic (inductive and resonance), steric, and/or hydrogen-bonding effects that can drastically affect the stability of compounds. A detailed treatment of substituent effects can be found in a review by Hansch et al. [17] and in the classical reference text by Hammett [18]. 

The carbon atom of the carbonyl group of acetic acid bears a large positive charge, it adds its electron-withdrawing inductive effect to that of the oxygen atom of the hydroxyl group attached to it. 

The extra electron-withdrawing inductive effect of the electronegative chlorine atom is responsible for the greater acidity of chloroacetic acid by making the hydroxyl proton of chloroacetic acid even more positive than that of acetic acid. 

Quantitative determination of the products from Haworth methyla-tion of benzyl 4-0-methyl-/3-D-xylopyranoside gave277 the ratio of rate constants k2 k3 as 3.2 1. Satisfactory agreement between predicted and observed product-ratios was found if it was assumed that, after methylation of HO-2, the reactivity of HO-3 increases by a factor of 3, but that methylation of HO-3 does not alter the reactivity of HO-2. The greater reactivity at HO-2 is, presumably, a result of its greater acidity, resulting from the inductive effect of two acetal oxygen atoms on C-l. When this group is ionized, the acidity of HO-3 should be decreased, but methylation at HO-2 removes the effect. Methylation at HO-3 should not, however, similarly affect HO-2. 

A large inverse secondary deuterium KIE of 0.64 was observed in acetic acid at 25°C when the perdeutero (d2o) compound was the deuterated substrate. This large inverse deuterium KIE was attributed to the KIE for the rate-determining formation of the bromonium ion (62). Although a portion of this KIE is undoubtedly due to the inductive effect (deuterium is more electron-donating than hydrogen and the deuterated bromonium ion would... 

Further increase of the acid constant by substitution of electronegative atoms such as chlorine in the hydrocarbon chain (from Ka = 1.86 X 10 8 for acetic acid to 1.5 X 10-8 for chloroacetic acid, 5 X 10-2 for dichloroacetic acid, and 2 X lO-1 for trichloroacetic acid, for example) is attributed to the inductive effect, the effect of the electronegative atom being transmitted through the chain to the oxygen atom,88 and to electrostatic interactions. 

The result of this inductive effect is that the electron density on the carboxylate anion is reduced, the negative charge is distributed over more atoms, and the chloroacetate anion is stabilized relative to acetate. Because the chloroacetate anion is more stable than the acetate ion, its conjugate acid, chloroacetic acid, is a stronger acid than the conjugate acid of the acetate ion, acetic acid (Table 3.1). 

The oxidation of diols by quinolinium dichromate (QDC) shows a first-order dependence on QDC and acid.5 The oxidation of phenols to quinones by quinolinium dichromate in aqueous acetic acid is acid catalysed rate-determining formation of a cationic intermediate is indicated by a p value of —3.79 and further analysis shows the rates to be influenced equally by both inductive and resonance effects of the substituents.6... 

Another estimate seemed to support an inductive contribution to deuterium IEs on the acidity of carboxylic acids.37 This IE on acidity of some carboxylic acids was attributed to an inductive effect arising from the electrostatic interaction of the C-H or C-D dipole with the negative charge of the carboxylate, as expressed in Equation (31). The derivative dpK/dfi was estimated from the effect of a C-Cl dipole on acidity, using the difference in pATas of trichloroacetic acid (0.63) and acetic acid (4.75) and the difference between the dipole moments of t-butyl chloride (2.13 D) and isobutane (-0.13 D). Next Afj, was estimated as 0.0086 D, the difference between the dipole moments of (CH3)3CD and (CH3)3CH. Thus ApK was estimated as 0.005 per D, in excellent agreement with the observed 0.014 for acetic-d3 acid. Moreover, the IE of 0.002 per D in pivalic-J9 acid is consistent with a 2.8-fold falloff factor for inductive effects. Yet those estimates depend crucially on the difference between the dipole moments of isobutane and isobutane-d, which is unusually large, amounting to 6.5% of either s total dipole moment. 

The rapid fall in the reactivity of a CH bond, as its distance from the substituent X increases, indicates the importance of the inductive effect in hydrogen exchange with a base. This conclusion is reinforced by the fact that there is a linear relation (Fig. 3) between of and pKt for substituted acetic acids (CH2X.COOH) with the same substituent X... 

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