Linear Free Energy Relationships

Among the most commonly observed characteristics of reactions are their rates and their equilibrium constants (if observable). In this respect, the influence of substituents on reactivity often provides information about a reaction mechanism , and has been the subject of extensive study. For example, the acidity constants for some substituted benzoic acids range from 3.4 * 105 for the para-methoxy compound to 6.7 * 103 for the ortho-nitro compound. A similar, but not identical, increase in the rate of base catalyzed ester hydrolysis has been noted, with the para-nitro compound reacting over 103 times faster than the para-methoxy compound. Now these differences in reactivity may be attributed to perturbations of G and/or G by a combination of inductive, resonance and steric effects. If the same factors are responsible for the substituent effects in various different reactions, the rates and or equilibria should change in a proportional manner. Indeed, the exponential relationship of free energy to rate or equilibrium constants, as shown on the right, suggests that logarithmic plots should demonstrate this proportionality. To investigate this possibility, logarithms of the rate and equilibrium constants noted above for substituted benzoic acids and their ethyl esters were graphed as shown below. The data points are represented by small circles. It is immediately apparent that the rates and equilibria of the meta and para substituted compounds correlate well (the green line), but the ortho substituted compounds do not. This is not entirely unexpected, since the ortho substituents lie close to the reaction site and each may interact with different intermediates or transition states in many different ways. An analysis of factors that influence the acidity of ortho-substituted benzoic acids is presented elsewhere.

Linear free energy plots of the kind shown here are called Hammett Plots in recognition of Louis Hammett (Columbia University), who first employed this analysis of organic reactions. Hammett selected the Ka's of substituted benzoic acids as a reference system, and defined a substituent constant :, based on the log of the ratio of a substituted benzoic acid's acidity (K) to that of benzoic acid itself (Ko).

= log(K/Ko)
A table of these : constants for different substituents at meta and para locations on a benzene ring is provided here. An examination of the sign and magnitude of these substituent constants is instructive, particularly in context with the influence they have on electrophilic aromatic substitution. Electron withdrawing substituents increase the acidity of benzoic acid (K > Ko) and will therefore have positive constants. Electron donating substituents will decrease the acidity, resulting in a negative . Inductive and resonance effects do not necessarily act in the same direction, so many values are small. Many of the substituent groups listed in the section on the left have negative constants and are electron donating. The hydroxy and methoxy substituents change sign depending on their location, illustrating the inductive withdrawal of electrons (meta) and strong resonance electron donation (para). The substituent groups listed in the right hand section are all strongly electron withdrawing, both by inductive and resonance influence. When there is strong resonance interaction between a substituent group and the reaction site, deviations from a Hammett equation plot may occur. For example, the acidity of phenols or anilinium cations is enhanced by para-nitro, cyano and carbonyl substituents to a greater degree than predicted by their values. Likewise, electron donating parasubstituents such as NH2 and OR facilitate benzyl cation formation to an exceptional degree. These deviations have led to the formulation of specialized constants ( e.g. and + among others ) for specific applications. These will not be discussed here.

Hammett Substituent Constants

Substituent meta para H 0 0 CH3 -0.07 -0.17 C2H5 -0.07 -0.15 (CH3)3C -0.10 -0.20 C6H5 +0.06 -0.01 (CH3)3Si -0.04 -0.07 OCH3 +0.12 -0.27 OH +0.12 -0.37 NH2 -0.16 -0.66 O() -0.71 -1.00 Substituent meta para F +0.34 +0.06 Cl +0.37 +0.23 Br +0.39 +0.23 I +0.35 +0.28 OCOCH3 +0.39 +0.31 NHCOCH3 +0.21 0.00 SH +0.25 +0.15 SCH3 +0.15 +0.00 CO2() -0.10 0.00 SO3() +0.05 +0.09 Substituent meta para CF3 +0.43 +0.54 CO2H +0.36 +0.41 CO2CH3 +0.32 +0.39 COCH3 +0.38 +0.50 SO2CH3 +0.60 +0.72 CN +0.56 +0.66 NO2 +0.71 +0.78 (+) (CH3)2S +1.00 +0.92 (CH3)3N(+) +0.88 +0.82 N2(+) +1.76 +1.91

Since the substituent constants are a logarithmic function of benzoic acid K as, the previous log-log plot of ethyl benzoate hydrolysis rates can be reproduced as a plot of rates against . Such a plot is shown below, and the slope of the best fitting correlation line is a characteristic of the specific reaction (and its conditions) for which rate or equilibrium data has been determined. Hammett called this slope the reaction constant, .

Reaction constants for a large group of reactions involving substituted benzyl or benzoyl functions have been measured. Since the acidity of benzoic acids serves as a reference, the for this reaction is 1.00. Some additional reaction constants are listed in the following table.

Hammett Reaction Constants

Equilibrium or Rate Acidity of phenols. (water, 25 C) Equilibrium Acidity of anilinium cations. (water, 25 C) Equilibrium Acidity of cinnamic acids (water, 25 C) Equilibrium Cyanohydrin formation from benzaldehydes. (water, 25 C) Rate Base-catalyzed hydrolysis of ethyl benzoates. (85% ethanol, 25 C) Rate Acid-catalyzed hydrolysis of benzamides. (water, 100 C) Rate Esterification of benzoic acids. (methanol, acid, 25 C) Rate Dimethylanilines + CH3I. (90% acetone/water, 35 C) Rate Hydrolysis of benzyl chlorides - SN1 (50% acetone, 30 C) Rate Reaction of benzyl chlorides with iodide anion- SN2 (acetone, 20 C) Rate Alkylation of phenolate anions by ethyl iodide- SN2 (ethanol, 42 C) Rate Reaction 2.11 2.77 0.47 1.83 2.54 0.12 0.23 3.30 1.82 0.79 0.99

The following diagram shows rate or equilibrium plots against for three different reactions. The slope of each best-fit line provides the for that reaction. These relationships have been consolidated by a simple mathematical formula, known as the Hammett Equation. If the and Ko (or ko) of a reaction are known, then the K (or k) for a substituted analog is easily calculated from the for the substituent.
log(K/Ko) or log(k/ko) =

Reaction constants are useful indicators of the electron demands at the reaction site. Anilinium ion acidity, shown by the green line above, has a large positive , indicating enhancement by electron withdrawing substituents. Phenolate anion alkylation, shown by the blue plot has a moderate negative and is retarded by electron withdrawing substituents, but accelerated by electron donation. A near zero, as in the acid -catalyzed benzamide hydrolysis reported in the table, indicates a reaction that is relatively insensitive to meta or para ring substitution. Care must be taken to recognize all reaction variables, since values are sensitive to both solvent and temperature changes. Thus, the for anilinium acidity increases from 2.77 in pure water to 3.57 in 70% aqueous dioxane, both at 25 C. Saponification of ethyl benzoate in 85% ethanol at 25 C has a = 2.54, which drops to 2.32 at 50 C in the same solvent. Interestingly, acid-catalyzed hydrolysis of this ester in 60% acetone at 100 C has a rather small = 0.11, similar to that for acid-catalyzed benzamide hydrolysis. Base-catalyzed benzamide hydrolysis in water at 100 C has a = 1.1. The near zero for acid-catalyzed ester and amide hydrolysis probably reflects the intermediacy of a conjugate acid species, the concentration of which would be increased by para-electron donating substituents.