Phenylacetic acid, ionization

Hammett plots. For phenylacetic acid ionization constants and for benzoic acid in ethanol. Data to generate these plots were taken from Bright W. L., and Briscoe, H. T. "The Acidity of Organic Acids in Methyl and Ethyl Alcohols." J. Phys. Chem., 37,787 (1933), and Dippy, J. F., and Williams, F. R. "Chemical Composition and Dissociation Constants of Mono-Carboxylic Acids. Part I. Some Substituted Phenylacetic Acids." /. Chem. Soc., 161 (1934). 

The Hammett equation is the best-known and most widely studied of the various linear free energy relations for correlating reaction rate and equilibrium constant data. It was first proposed to correlate the rate constants and equilibrium constants for the side chain reactions of para and meta substituted benzene derivatives. Hammett (37-39) noted that for a large number of reactions of these compounds plots of log k (or log K) for one reaction versus log k (or log K) for a second reaction of the corresponding member of a series of such derivatives was reasonably linear. Figure 7.5 is a plot of this type involving the ionization constants for phenylacetic acid derivatives and for benzoic acid derivatives. The point labeled p-Cl has for its ordinate log Ka for p-chlorophenylacetic acid and for its abscissa log Ka for p-chloroben-zoic acid. The points approximate a straight line, which can be expressed as... 

It was mentioned in Section II.B that the ionization of benzoic acids is not regarded as an entirely satisfactory standard process, since in the case of —R substituents, such as OMe, it is subject to some slight effect of cross-conjugation (see structure 16). Consideration of insulated series , not subject to this effect, e.g. the ionization of phenylacetic acids, is used as the basis of the cr° scale. For the sake of uniformity cr° values for +R substituents have also been based on such systems. Wepster and colleagues124,125, however, have criticized the use of systems in which the substituent is insulated by methylene groups from the reaction centre for its tendency to lead to slightly exalted values of cr° for +R substituents, i.e. the supposed insulation is not 100% effective. They see an analogy to the very pronounced exaltations that occur in the effects of +R substituents on the... 

There are at least three possibile ways in which the inhibitor can bind to the active site (1) formation of a sulfide bond to a cysteine residue, with elimination of hydrogen bromide [Eq. (10)], (2) formation of a thiol ester bond with a cysteine residue at the active site [Eq. (11)], and (3) formation of a salt between the carboxyl group of the inhibitor and some basic side chain of the enzyme [Eq. (12)]. To distinguish between these three possibilities, the mass numbers of the enzyme and enzyme-inhibitor complex were measured with matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI). The mass number of the native AMDase was observed as 24766, which is in good agreement with the calculated value, 24734. An aqueous solution of a-bromo-phenylacetic acid was added to the enzyme solution, and the mass spectrum of the complex was measured after 10 minutes. The peak is observed at mass number 24967. If the inhibitor and the enzyme bind to form a sulfide with elimination of HBr, the mass number should be 24868, which is smaller by about one... 

The five parent compounds in Table III are arranged in order of increasing pKa of their ionizable protonic groups. For phenoxyacetic acid (pKa = 3.17) and phenylacetic acid (pKa = 4.31), the primary ionization is that of the carboxylic acid side chain. The acidity of the TFMS parent compound (pKa = 4.45) is attributable to the loss of the relatively labile proton from the parent side chain (< -NH-SOo-CF3 < -N -S02-CF3 -f- H+). For aniline, the process with pKa = 4.63 is associated with protonic ionization of the anilinium cation. The pKa = 9.89 process in phenol refers to the formation of phenolate anion. 

The effect of the 4-Cl substituent on the ionization of 4-Cl phenylacetic acid (PA) was found to be proportional to its effect on the ionization of 4-Cl benzoic acid (BA). 

One shortcoming of the benzoic acid system is the extent of coupling between the car-bo l group and certain lone-pair donors. Insertion of a methylene group between the core (benzene ring) and the functional group (COOH moiety) leads to phenylacetic acids and the establishment of scale from the ionization of X-phenylacetic acids. A flexible method of dealing with the variability of the resonance contribution to the overall electronic demand of a reaction is embodied in the Yukawa-Tsuno equation (86). It includes nor-nial d enhanced resonance contributions to an LFER. 

The relation between the constant of the para acid and that of the ortho or meta acid varies with the nature of the substituent. While p-nitrobenzoic acid is a slightly stronger acid than m-nitro-benzoic acid, the constant of p-chlorobenzoic acid is only about one-half that of the meta acid. The case of p-hydroxybenzoic acid is a striking one while o-hydroxybenzoic acid and m-hy-droxybenzoic acid are more highly ionized than benzoic acid, the constant of the para acid is less than half that of benzoic acid. A satisfactory explanation of such facts as these would, no doubt, materially advance organic chemistry. The effect of a phenyl radical on a carboxyl group in a side-chain, is shown by the constants for phenylacetic acid, hydrocinnamic acid, and cinnamic acid. 

Figure 7.5 Log-log plot of ionization constants of benzoic and phenylacetic acids in water at 25°C. (From J. S. Hine, Physical Organic Chemistry. Copyright 1962. Used with permission of McGraw-HiU Book Company.)...

Aromatic tt or / values derived from meta and para substituents tend to be identical, but ortho substituents often give outlying values, e.g., when they permit internal hydrogen-bonding, lipophilicity is increased. Nevertheless, by much more complicated calculations, Fujita and Nishioka (1975) have made a special table for ortho substituents that integrate well with the meta and para values. Apart from this, these tt and / values are very sensitive to polar environments. For example, tt for chlorine substituted in benzene is 0.71, but this becomes (insertion is in all cases, meta) 0.61 in nitrobenzene, 0.68 in phenylacetic acid, 0.83 in benzoic acid (all ionizable substances are corrected for ionization), 0.98 in aniline, and 1.04 in phenol. This difference of 0.43 between extremes is increased to 0.90 when nitro-group replaces chlorine in the... 

A solvent isotope effect is observed when the rate constant or the equilibrium constant for a process changes when a solvent is replaced with an isotopically substituted solvent. Most often solvent isotope effect studies involve a hydroxylic solvent in which the OH group is replaced with an OD group. For example, the value of Kh/Kd for ionization of phenylacetic add in H2O versus ionization of phenylacetic acid-O-d in D2O is 3. " Schowen has indicated three ways for solvent isotope effects to occur ... 

Several attempts have been made to define <7 values for reactions in which only field effects could be important. These have involved the ionization of phenylacetic acids to generate a series of acetic acids to generate cti values/ or other reactions in which resonance was considered unimportant to generate tr" values. ... 

Figure 8.11, for example, shows a plot of the log of ionization constants of substituted phenylacetic acids in water, and the ionization of substituted benzoic adds in ethanol. Thep for phenylacetic acid derivatives is 0.56, while that for benzoic acid derivatives in ethanol is... 

Very often the magnitude of p is used as a guide to the amount of charge that has developed in a transition state or in the product. Such an interpretation must be made with caution, because p really only relates the sensitivity of ionization to the substituents. In the examples just discussed, the amount of charge on the products is the same in all three reactions (phenylacetic acid, and benzoic acid in ethanol or water), but the p values are significantly different. 

We can contrast primary and secondary isotope effects on equilibria, if we consider the ionization of phenylacetic acid. Carboxylic acids deutcrated in the hydroxyl group are characteristically less dissociated in water than the parent acids. Thus, for the two reactions ... 

Let us consider a thermodynamic secondary isotope effect like that on the ionization constant of phenylacetic acid (I-l, 1-3). A general formulation of such an effect would be ... 

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