SUBSTITUENTS EFFECTS AND LINEAR FREE-ENERGY RELATIONSHIPS

1. SUBSTITUENTS EFFECTS AND LINEAR FREE-ENERGY RELATIONSHIPS • It is known that different substuents exert a different effect on e.g. the acid strength of acetic acids. In particular the presence of groups more electronegative than hydrogen increases the strength of the acid with respect to acetic acid. • Many detailed relationships between substituent groups and chemical properties have been identified, which, in many cases, can be expressed quantitatively and are useful for both interpreting reaction mechanisms and for predicting reaction rates and equilibria. substituent groups chemical properties

2. The most widely applied of these relationships is the Hammett equation, which relates rates and equilibria of many reactions of compounds containing substituted phenyl groups. • It was noted in the 1930’s that there is a relationship between the acid strengths of substituted benzoic acids and the rates of many other chemical reactions, for instance the rates of hydrolysis of substituted ethyl benzoates.

3. k and k0 are the rate constants of the hydrolysis of substituted or simple ethyl benzoate: • PhCOOEt + OH- → PhCOOH + EtOH -2.0 p-NO2 m-NO2 8.0 p-Cl 0 H p-Me -0.4 • K and K0 are the acid dissociation constants of the corresponding benzoic acids: PhCOOH → PhCOO- + H+ m-NH2 p-OMe -1.2 p-NH2 -2.0 -0.8 -0.4 0 0.4 0.8 1.2 The correlation is illustrated in this graph, where log k/k0 is plotted against log K/K0. log k/k0 log K/K0

4. Neither the principles of thermodynamics nor theories of reaction rates require that there have to be such linear relationships. There are, in fact, numerous reaction series that fail to show such correlations. • The origin of these correlations can be explained considering the relationships between the equation of correlation and the free energy changes involved in the two processes. The line depicted in the graph has this equation: in which m is the slope of the line that is m (log K – log K0) = (log k – log k0)

5. Let us try to substitute the equilibrium constants K and the rate constants k with the corresponding free energies: • The linear correlation therefore indicates that the change in free energy of activation on the introduction of a series of substituent groups is directly proportional to the change in the free energy of ionization that is caused by the same series of substituents on benzoic acid. • The various correlations arising from such directly proportional changes in free energies are called linear free energy relationships.

6. for equilibrium constants for rate constants SinceDG and DG‡ are combinations of enthalpy and entropy terms, a linear free-energy relationship between two reaction series can result from one of three circumstances: • DH is constant and the DS terms are proportional for the two series • DH is proportional for the two series and DS is constant • DH and DS are linearly related The Hammett correlation of free energy can also be expressed in this way:

7. substituent constant s reaction constant r • The numerical values of terms s and r are defined by specifying the ionization of benzoic acids as the standard reaction to which the reaction constant r = 1 is assigned. • The substituent constant s can be determined for a series of substituent groups by measurements of the acid dissociation constant of the substituted benzoic acids. • The s values so defined are used in the correlation of other reaction series, and the r values of the reactions are thus determined.

8. and 1 For standard reaction, in which r =1 : The relationship between the two equations is evident when the Hammett equation is expressed in terms of free energy. Thus, substituting into equation 1:

9. The value of s reflects the effects that the substituent group has on the free energy of ionization of substituted benzoic acids. The effect of the substituent results from a combination of factors. • A group can cause the polarization of electron density around the ring through the p system in both the reactant and the product. This affects the position of the equilibrium. • In the case of a reaction rate the relative effect on the reactant and on the transition state will determine the effect on the energy of activation.

10. The effect of substituent results from a combination of factors. A substituent can exert three different effects: • Resonance effect • it is an effect of polarization and redistribution of the charge through the p system of the molecule:

11. 2) Field effect It is an effect caused by the dipoles of the bonds between groups with different electronegativity and results from the through-space electrostatic interaction. Substituents more electronegative than aromatic carbon atom generate a positive charge on the substituted carbon atom, while substituents less electronegative than the aromatic carbon atom will have the opposite effect. The resulting dipoles can perturb the electronic situation in two ways. The presence of the charge separation will influence the energy associated with development of charge elsewhere in the molecule:

12. 3) Inductive effect The presence of the charge separation will influence the energy associated with development of charge elsewhere in the molecule. This is transmission of bond dipoles through the intervening bonds by successive polarizations of each bond: The Hammett equation does not take in exam steric effects, because it is applied only to meta and para substituents, that do not interact sterically with the reaction centre.

13. In addition to sm and sp, other values of s are reported in the tables, in particular s+ an s- that reflect a recognition that the extent of resonance can vary for different reactions. s+ → values used for reactions in which there is direct resonance interaction between an electron-donor substituent and a cationic reaction centre s- → values used for reactions in which there is direct resonance interaction between the substituent and an an electron-rich reaction site.

14. large r reaction with a large resonance component r goes to zero original Hammett equation One approach is to correct for the added resonance interaction. This is done in a modification of the Hammett equation known as the Yukawa-Tsuno equation: The additonal parameter r is adjusted from reaction to reaction: it reflects the extent of the additional resonance component. A large r corresponds to a reaction with a large resonance component, whereas when r goes to zero, the equation is identical to the original Hammett equation. When there is direct conjugation with an electronic rich reaction center, an equation analogous to the previous can be employed, using s- instead of s+.

15. Tables of s values for many substituents have been collected; some values are given in this table, but substituents constants are available for a much wider range of substituents. The s value for any substituent reflects the interactions of the substituent with the reacting site by a combination of resonance and field interactions.

16. This table shows a number of r values. The r value reflects the sensitivity of the particular reaction to substituent effects

17. electron-withdrawing groups s > 0 electron-releasing groups s < 0 reactions favoured by electron-withdrawing groups r > 0 reactions favoured byelectron-releasing groups r < 0 Let us now consider how linear free-energy relationships can provide insight into reaction mechanism. • The choice of benzoic acid ionization as the reference raction for the Hammett reaction leads to s > 0 for electron-withdrawing groups and s < 0 for electron-releasing groups, since electron-withdrawing groups favour the ionization of the acid and electron-releasing groups have the opposite effect. • From a r point of view: r will be positive for all reactions favored by electron releasing groups and negative for all reactions favored by electron releasing groups. • If the rates of a reaction serie show a satisfactory correlation, both the sign and magnitude of r provide information about the transition state for the reaction.

18. For example: the r value for the saponification of substituted methyl benzoates is +2.38. This indicated that electron-withdrawing groups facilitate the reaction and that the reaction is somewhat more sensitive to substituent effects than the ionization of benzoic acids. • The observation that the reaction is favored by electron withdrawing substituents is in agreement with the accerted mechanism for ester saponification: the tetrahedral intermediate is negatively charged and its formation should therefore be favored by electron-withdrawing substituents that can stabilize the developing charge. • There is also a ground state effect working in the same direction: electron-withdrawing substituents will tendo to make the carbonyl group more electrophilic and favor the addition of hydroxide ion.

19. The solvolysis of aryl methyl chlorides in ethanol shows a r value of -5.0, indicating that electron-releasing groups greatly increase the reaction rate and supporting a mechanism involving ionization as the rate-determining step. Electron-releasing groups can facilitate the ionization by a stabilizing interaction with the electron-deficient carbocation that develops as ionization proceeds. • The relatively large r shows that the reaction is very sensitive to substituents effects and implies that there is a large redistribution of charge in the transition state.

20. Not all the reactions can be fitted by the Hammet equations or the multiparameter variants. There can be several reasons for this. The most common is that the mechanism of the reaction depends on the nature of the substituent. In a multistep reaction, for example, one step may be rate-determining in the case of electron-withdrawing substituents, but a different step may become rate-limiting when the substituent is electron-releasing. • The rate of semicarbazone formation of benzaldehydes shows a nonlinear Hammet plot with r of about 3.5 for electron-withdrawing groups. The change in r is believed to be the result of a change in the rate-limiting step. Any reaction which shows a major shift in transition-state structure over the substituent series would be expected to give a nonlinear Hammet plot, since a variation in the extent of resonance participation would then be expected.

21. By comparing s+, s- and sI, individual substituents can be separated into three groups. • Alkyl groups are electron-releasing by both resonance and polar effects. • Substituents such as alkoxy, hydroxy and amino, which can act as resonance donors, have negative sp and s+ values, but when polar effects are dominant, these substituents acts as electron attracting groups, as illustrated by the sm and sI values. • A third group of substituents are electron-withdrawing by both resonance and polar interactions. These include carbonyl groups in aldehydes, ketones, esters and amides, as well as cyano, nitro and sulfonyl substituents.

22. -M -I -M +I +M +I Me, Et, But -NH2, OH- -Br, -Cl, -F MeO-, EtO- Ph -CF3 Me3N+