CATALYSIS BY ACIDS AND BASES

1. CATALYSIS BY ACIDS AND BASES • A detailed comprehension of reaction mechanisms requests to know the role played by the catalyst in the reaction. • Catalysts do not influence the position of the equilibrium of the reaction, but they increase the rate of one or more steps of the reaction mechanism, offering a reaction pathway at lower energy. • The more populated family of catalyic processes is the proton transfer. Many reactions that start from neutral reagents are strongly catalyzed by proton donors or acceptors, that is by Brønsted acids or bases. • Catalysis takes place when the conjugated basis or the conjugated acid of the substrate are more reactive than the neutral specie.

2. more electrophile • For example the reactions of nucleophilic attack to carbonyl are often accelerated by acids. This kind of catalysis takes place because the conjugated acid of the compound is more electrophile than the neutral molecule

3. more nucleophile • On the other hand many important organic reactions involve nucleophile carbon atoms (carbanions), but the majority of C-H bonds is poorly acid and does not ionize spontaneously. • The reactions are then performed in the presence of a base that can generate the intermediate carbanion, more reactive. Base catalyzed condensations of carbonyl compounds belong to this category of reactions.

4. The role played by acid or basic catalysts can be explained and quantitatively studied through kinetic methods. • Two kinds of acid (or basic) catalysis exist: • SPECIFIC ACID (OR BASIC) CATALYSIS • GENERAL ACID (OR BASIC) CATALYSIS

5. The term “SPECIFIC” is used when the rate of the raction depends on the equilibrium for protonation of the reagent. • This kind of catalysis is independent by the concentration and by the specificstructureof the different proton donors in the solution. • Specific acid catalysis is governed by the concentration of the H+ ion in solution (pH). • When the nature and the concentration of the proton donors in solution influence the rate of the reaction, the catalysis is defined “GENERAL”. • General acid catalysis is governed by the concentration of each source of H+ion in solution.

6. Consequently also the kinetic equations that describe these two different situations are different: • Specific acid catalysis is well described by an equation that contains the term of the concentration of the H+ ion. v = k[H+][X][Y] [X][Y] → reagents concentration • General acid catalysis is described by an equation that contains a the term for every protons source that may act as catalyst. v = k [H+][X][Y] + k2 [HA1][X][Y] + k3 [HA2][X][Y]… [X][Y] → reagents concentration HA1, HA2…→ significative proton donors

7. SPECIFIC GENERAL The rate of the reaction depends on the protonation equilibrium of the reagent; proton transfer is not rate determining The reagent is involved in a rate determining proton transfer equilibrium The catalytic effect depends on the concentration of the different proton donors present in the reaction mixture • The catalytic effect is independent • of the concentration • of the specific structure • of the different proton donors in the reaction mixture The function of reaction rate contains a term for every proton donors present in the reactive system: V = k [H+][X][Y]+k2[HA1][X][Y]+k3[HA2][X][Y]+…. The reaction rate is pH dependent: V = k [H+][X][Y] ACID OR BASE CATALYSIS

8. From an experimental point of view general acid catalysis is detected with rate measurements at constant pH, in buffer solution of different concentration. • In these conditions [H+] remains constant, but the terms due to the weak acid (HA1, HA2, …) change and the observation of a change in rate is evidence of general acid catalysis. • If the rate remains constant, the reaction exibits specific acid catalysis. • In the same way the rate of reactions with a general base catalysis depends on the the concentration and the components of a buffer solution.

9. Specific acid catalysis is observed when a reaction proceeeds only through a protonated intermedium, which is in equilibrium with its conjugated base. The position of equilibrium is a function of the concentration of solvated protons. This is the reason because in the kinetic expression appears only one term depending on [H+]. • For example in a two step reaction in which a reagent reacts with the conjugated acid of the other in the rate determining step, the kinetic law will be: kobs

10. General acid catalysis can be observed in several situations. For example it can be the result of the formation of an hydrogen bond between the reagent R and the proton donor D-H, to form a reactive complex {D-H…R} that then reacts with a substance Z: • In this situation every potential hydrogen donor D-H will bring a particular contribute to the total reaction rate: v = k [H+][X][Y] + k2 [HA1][X][Y] + k3 [HA2][X][Y]… [X][Y] → reagents concentration HA1, HA2…→ significative proton donors

11. General acid catalysis is observed also when a rate determining (slow) proton transfer takes places, by acids different from solvated proton:

12. Specific acid catalysis describes a situation in which the reagent is in equilibrium with respect to the proton transfer and, in turn, proton transfer is not rate determining. fast reagent reagent-H+ • On the other hand, every time that a general acid catalysis is observed, proton transfer takes place in the rate determining step. slow reagent reagent-H+ • Owing to these differences, the study of the reaction rate as a function of pH and of the concentration of buffer solutions allows conclusions on the nature of the proton transfer and on its relation with the rate determining step

13. As it can be expected, there is a relationship between the efficacy of general acid catalysis and the acidity of a proton donor, as it is stated by the acid dissociation constant, expressed by Brønsted Catalysis Law (a similar one for bases exists): log kcat = a log Ka + b • This equation requests that the free energies of activation for the catalytic step for a serie of acids are directly proportional to the free energies of dissociation for the same serie of acids (another correlation betrween kinetic and thermodynamic parameters).

14. The value of the constant of proportionality a indicates the sensitivity of the catalytic step to structural changes, correlated to the effect of the same changes on acid dissociation. Often it was found that a single a value is valid only for structurally very similar acids and that each kind of acid presents a values of different magnitude. • For example, the reaction of hydrolysis of an enolether, for which the Bronsted law graphic was traced, in which the catalytic force of several carboxylic acids was correlated to their dissociation constant.

15. log kHA/p 1 0 -1 The constant correlates the sensitivity of the proton transfer to the one of the acid dissociation. -2 -3 In this particular case the constant d = 0.79 -4 -5 -6 -5 -4 -3 -2 log qKHA/p Frequently it is assumend that it can be used as indicator of the structure of the transition state, but this interpretation in some cases suffers of evident limits.

16. The details of the proton transfer process can be ascertained also studyng solvent isotopic effects, for example comparing the rate of the reaction in H2O and in D2O. • The isotopic effect of the solvent can be normal or inverse depending on the nature of the proton transfer in the reaction mechanism. D3O+ is a stronger acid with respect to H3O+ and consequently ragents in D2O are more protonated than in water, at the same acid concentration. • A reaction that passes through a fast protonation equilibrium proceeds more quickly in D2O than in water, because the protonated reagent is present at higher concentration in the reaction system.

17. On the other hand, if the proton transfer takes part in the rate determining step, the reaction will be quicker in water than in D2O, because of the primary isotopic effect just known (remember that deuterium has twice the mass of the proton). • The interpretation of isotopic effects can be made more complex by the big number of secondary isotopic effects that can be expected when the solvent is the site of the isotopic substitution and sometimes can be a problem of difficult solution.