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The rate coefficients for the reaction with diazodiphenylmethane, in ethanol at 30.0°, of a number of substituted indole-2-carboxylic acids, indole-3-carboxylic acids, coumarin-3-carboxylic acids, coumarilic acids, and N-phenylglycines have been determined. The effect of substitution is assessed by use of adapted Hammett and Dewar–Grisdale relations. The relations give good correlations for oxygen-ring heterocyclic systems, and the relative ability of the systems to transmit π-electron effects has been determined. An anomalous perturbing effect appears to operate in the indole-carboxylic acid systems.

The rate coefficients for the reaction with diazodiphenylmethane in methanol, ethanol, isopropyl alcohol, t-butyl alcohol, 2-methoxyethanol, 2-n-butoxyethanol, and ethyl acetate at 30° and the pKa values in 80% 2-n-butoxyethanol–water of a series of 9-substituted 10-anthroic and 8-substituted 1-naphthoic acids have been determined. The effect of substitution has been analyzed by linear free energy relations. The variation in the susceptibilities of the systems to polar substituent effects with the medium are examined. The occurrence of reversed dipolar substituent effects in the reactions of the 1,8-naphthoic acids is detected. The implications of the results for the inductive and field effect models for the transmission of polar effects are discussed.

The transmission of polar effects by various groups is assessed by means of the reaction constants ρ or ρ″. The results are critically discussed in terms of the various polar, steric, and solvent effects. Conclusions are drawn as to the importance of the inductive and direct field effects.

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The pKa values of a series of ortho-substituted benzoic acids in 50% ethanol–water have been determined. The effect of ortho-substitution on the ionization of benzoic acid in this and other solvents has been correlated by a linear free energy relation. The reaction constants found are compared with those for the meta/para-substituted benzoic acids. While those for the former system are insensitive to changes in the medium, the latter vary considerably. It is suggested that this is due to transmission by the field effect passing almost entirely through the molecular cavity for ortho-substituents.

The stability constants K1 and K2 have been measured for the interaction of indium(III) with the ligands R•CO•CH2•CO•CF3 (R = 2-furyl, 2-thienyl, phenyl, 2-naphthyl, i-butyl, and (t-butyl). The pKa values for these compounds, and for R = 3-pyridyl and methyl, are also reported. A conventional potentiometric technique was used; the results refer to 46% aqueous acetone, at an ionic strength of approximately 0.1 M. The results are compared with published values for complexes of these ligands with divalent cations in other solvent systems.

A series of 9-substituted 10-triptoic acids have been prepared. Their pKa values in 80% 2-methoxy-ethanol–water and 50% ethanol–water at 25° and rate coefficients for esterification with diazodiphenyl-methane in five alcohols at 30° have been measured. The results have been analyzed by linear free energy relations. The π-inductive effect is shown to be unimportant in such systems, while the field effect model can account for the transmission.

The infrared spectra in the carbonyl-stretching region of certain arylaliphatic esters, RCOOkIe, have been examined. The stretching frequencies and absorption intensities are presented and are discussed in terms of polar and a-mass effects and thc occurrencc of conformational isomers. IXTKODCCTIOS As carbonyl vibrations are considered rarely to be perturbed by coupling with other vibrations, the corresponding absorption band and its variation with structure has been widely studied. Several factors may affect this vibration, of which the most important, for the present work, are polar, a-mass, and steric effects. Thompson and his co-worliers (I) have suggested that the force constant is primarily determined by the relative contributions of the canonical structures I, 11, 111, and IV to the structure of the carbonyl group. The relative importance of these structures is determined by the ability of X and Y either to interact with the carbonyl bond (cf. I11 and IV), or to alter the relative contributions of I and I1 by an electrostatic effect (i.e. inductive or direct field). Since the value of the frequency indicates the energy needed to produce a dipolar state, a reduction in the part played by structures 11, 111, and IV will increase the frequency. The effect on the frequency of increasing the irlass of a-substituents is significant for small masses but reaches a limit for group X or Y in XYC=O with higher masses (e.g., Halford (2) considers the effects to be constant above about 27 atomic weight units for X or Y). Substitution of deuterium for a-hydrogen atoms in esters or ketones has been found to give fairly large a-mass effects (3). A reduction in the X-C-Y intervalency angle in X-CO-Y will increase the frequency as has been observed for the carbonyl vibrations of strained ring ketones (4, cf, ref. 2). In the absence of any change in the steric environment of the motion, successful correlations have been obtained of the carbonyl frequencies of substituted ethyl benzoates and acetophenones with substituent constants of the Hammett type (5). Similar correlations involving the carbonyl-stretching frequencies of substituted aliphatic esters and ketones have been made with varying success. Correlations of doubtful value for intensities, due to the narrow range of intensities covered and the small number of substituents involved (B), have also been attempted. A number of investigators have observed the splitting of the carbonyl bands of ketones 'Present address: Depa~tnsent of Chemistry, Cniversity of British Columbia, Vancoztver 8, British Columbia.

The rate coefficients for the esterification with diazodiphenylmethane in ethanol at 30° and the pKa values at 25° of a number of ortho-substituted trans-cinnamic, phenoxyacetic, 3-phenylpropionic, ortho-, meta-, and para-substituted cis-trans-α-phenylcinnamic acids have been determined. The effects of substitution have been assessed by a Hammett-type correlation. A comparison of the transmission of the polar effects of ortho and meta/para substituents indicates the prime importance of the field effect, augmented where possible by a π-inductive effect. A reversed dipolar substituent field effect has been detected for the cis-ortho-substituted cinnamic acids.

The equilibrium constants for ring–chain tautomerism in a series of 8-aroyl-1-naphthoic acids in dioxan have been determined by an i.r. spectroscopic method and have been correlated with the substituent constants σ1 and σR0 using a modified Hammett equation. The observed pKa values, which have been measured in 80%(w/w) 2-methoxyethanol–water, have been corrected for these tautomeric equilibria to give the true pKaT value. The effect of substitution on the latter values have been assessed using the Hammett equation. The equilibrium constants for ring–chain tautomerism in a series of 8-acyl-1-naphthoic acids have been determined by using the observed pKa and estimated true pKaT values in 80%(w/w) 2-methoxyethanol–water. These equilibria constants have been correlated with steric substituent constants Es. The ‘cis’ and ‘trans’ conformers of methyl 8-aroyl- and 8-acyl-1-naphthoates has been detected by i.r. spectroscopy and the carbonyl stretching frequencies of the ester carbonyl groups have been assigned. The results are related to the polar, resonance, and steric effects of the substituents.

Rate coefficients have been determined for the reactions in ethanol at 30° of diazodiphenylmethane with several groups of carboxylic acids. Each group included the parent acid and three nuclear substituted acids. The parent acids were: benzoic, phenylacetic, β-phenylpropionic, phenoxyacetic, and trans-cinnamic acid. The reactions of 3-fluoro- (or chloro-) or 4-methyl-biphenyl-4′-carboxylic, and of 9-X-10-anthroic acids (X = Me, Cl, or Br) were also studied similarly. The Hammett polar susceptibility constant, ρ, has been calculated for each set of reactions. The values of ρ are discussed in terms of transmission of electronic effects through the side-chain by a field effect, and for side-chains conjugated with the ring, by a π-electron effect, both of which are inversely proportional to the first power of the distance of the carbonyl group from the ring.

The rate coefficients for the reaction with diazodiphenylmethane in ethanol at 30° and the acid-catalyzed esterification with methanol at 60° of a number of arylaliphatic carboxylic acids and their pKa values in 80% 2-methoxyethanol–water have been measured. Rate coefficients have also been measured for the alkaline hydrolysis in 70% dioxan–water of their 2-diethylaminoethyl esters at 45°. The pKa values and diazodiphenylmethane esterification rate coefficients were also measured for a series of 2-substituted fluorene-9-carboxylic acids. The latter results have been correlated by Hammett equations and the transmission of polar effects in fluorene is discussed. Polar and steric substituent constants are evaluated for the arylaliphatic systems. These values are used to successfully correlate the hydrolysis and ionization reactions using the Taft–Ingold equation.

The chemical shifts of the ring protons in a series of monosubstituted mesitylenes and durenes, and of the 10-protons of a series of 9-substituted triptycenes and anthracenes have been measured in dimethyl sulfoxide, acetone, 2-methoxyethanol, and carbon tetrachloride. The solvent dependence of the substituent chemical shifts has been analyzed by linear free energy relations. The systems all show similar dependence which increases with increasing dielectric constant of the solvent. This does not result from the field effect being transmitted through the medium, but appears to arise from the formation of a hydrogen-bonded interaction between the solvent and the hydrogen of the solute. The substituent chemical shifts appear to arise from contributions from substituent field, resonance, magnetic anisotropy, and solvent effects.

The rate coefficients for the acid-catalyzed esterification in methanol at 35.0° of fourteen 3-substituted acrylic acids have been determined. Rate coefficients have also been determined for the alkaline hydrolysis in 70% v/v dioxin–water at 18.8° of 13 methyl esters and the carbonyl-stretching frequencies of the esters have been examined. The effect of trans-substitution is assessed by use of the Hammett equation. In the alkaline hydrolysis, the transmission of polar effects is approximately 1.9 that of the meta- and para-substituted benzoates. An analysis of the steric effects in the cis-isomers in both reactions shows that the steric effects of the halogeno-substituents in the two reactions differ and an explanation is offered. The application of the Taft–Ingold equation to ortho-substituted benzoates is criticized. The carbonyl-stretching frequencies of the cis-halogeno-esters exhibit a shift of +8 cm−1 compared with the trans-isomers; this shift is attributed to an electrostatic effect.

The rate coefficients for the reaction with diazodiphenylmethane in methanol, ethanol, isopropyl alcohol,t-butyl alcohol, 2-methoxyethanol, 2-n-butoxyethanol, dimethyl sulfoxide, ethyl acetate, and toluene at 30° and the pKa values in water, 50% ethanol–water, and 80% 2-methoxyethanol–water of 18 substituted acetic and propionic acids have been determined. A further 14 acids have been studied to a more limited extent. The effect of substitution has been estimated by linear free energy relations. The reaction constants for the ionization reaction are almost independent of the medium. This is interpreted as being due to the field effect of the proximate polar substituents passing through the molecular cavity almost alone. The occurrence of steric inhibition of solvation causing acid weakening for bulky multi-substitution is confirmed. The reaction constants for the esterification reaction are affected by the solvent. This is attributed to dependence on solvation of the transition state.

A correlation of the bronchodilator activity of a series of substituted 6-thioxanthines has been made with partition parameters and/or the steric “bulk” of the 1- and 3-substituents. The 3-substituted series are correlated by a Hansch relation involving partition factors alone. Steric factors appear to be important for substitution at the 1-position. In general, an increase in activity is observed on introduction of “bulky” substituents at both these positions. The significance of these results is discussed.

The rate coefficients for the reaction with diazodiphenylmethane in ethanol, t-butyl alcohol, and ethyl acetate at 30° and the pKa values in water at 25° of fourteen 3-substituted acrylic acids have been determined. The effect of substitution is assessed by use of linear free energy relations. A definite incremental acid-strengthening effect solely due to cis-substitution is confirmed. This is not a "bulk" steric effect and is due solely to the orientation of substitution. The polar effect of a substituent is found to be approximately the same from the cis- or trans-position. An attempt is made to test the suggested mechanisms for the transmission of the polar effect. In the reactions studied the transmission of the polar effect in 3-substituted acrylic acid and ortho-substituted benzoic acids is approximately twice that of the meta- or para-substituted benzoic acids. This appears to be reasonably accommodated by a significant field effect.

Evidence from model systems for enzyme catalysis is discussed. These models involve neighboring group participation by carbonyl or carbon-acid groups, and indicate the important roles of proximity, strain, and orientation as potential sources of the special catalytic power of enzymes.

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