Chapter 3: Nucleophilic catalysis

1. Chapter 3: Nucleophilic catalysis Principle: reaction rate is enhanced by a nucleophilic compound that forms a low-energy intermediate. Of course, the nucleophile does not end up in the reaction product. Criteria for a nucleophilic catalyst: 1. The catalyst Nu– has to react faster with the substrate R-X than the nucleophilic particle Y–; 2. The intermediate R-Nu has to react faster with Y– than the starting material R-X. This means that the catalyst has to be both a very effective nucleophileand a good leaving group! Or, to say the latter in other words, the intermediate complex has to be very susceptible to nucleophilic attack.

2. Example: Both reaction steps are faster than the direct interaction of the p-nitrophenyl acetate with water. Furthermore, imidazole is recovered unchanged after the reaction, so imidazole is a real nucleophilic catalyst

3. Nucleophilic power There is no simple correlation between chemical structure and nucleophilic power. Nucleophilicity, among others, depends on: - the solvation energy of the nucleophile (which is influenced by the solvent); - the strength of the chemical bond to the electrophile (the C-Nu bond); - the size (steric hindrance); - the electronegativity and the polarisability of the nucleophilic atom in the nucleophile The effects of the latter factors have been quantified by Edwards:

4. Edwards equation: Nucleophilic power = - k0 is the rate constant of the reaction with a standard nucleophile (H2O) - P = polarisability, related to the refractive index: (RNu = refractive index of the nucleophile) - H = basicity, related to the pKa: H = pKa + 1.74 - a and b are dependent on the reaction (usually a >> b) a and b can be determined by performing a reaction of a substrate with a set of nucleophiles, like:

5. P mainly depends on the nature of the nucleophilic atom. So, when the nucleophilic atoms are identical and the nucleophiles are structurally similar, P hardly changes, so we can write:  similar to the Brønsted equation (log kHA = a log KHA + a constant) A change of the nucleophilic atom has a dramatic effect on the nucleophilicity! This is caused by a change in polarisability. Polarisability decreases from left to right in the periodic system: OH- > F- SH- > Cl- and increases top-down in the periodic system: F- < Cl- < Br- < I- OH- < SH-

6. Some factors are not included in the Edwards equation, like: 1. The influence of the solvent (solvation) For instance: CN- is in DMF 106 a more powerful nucleophile than in water 2. The a-effect A nucleophile that has one or more free electron pairs on the atom immediatelynext to the nucleophilic atom is much more reactive than one without electron pairs. Examples of such nucleophiles are: CH3O-NH2, HO-O–, Cl-O–, H2N-O–, H2N-NH2, etc. Reason: repelling effect by the free electron pairs. For this reason, ClO- is a much more reactive than OH-, although it is a weaker base.

7. Relation between nucleophilic power and substrate: the HSAB theory HSAB = Hard and Soft Acids and Bases Edwards: a and b: susceptibility constants P = polarisability, large for “soft” nucleophiles H = pKa, large for “hard” nucleophiles

8. Examples of hard electrophiles (Lewis acids): hardly polarisable Soft electrophiles: strongly polarisable Examples of hard nucleophiles (Lewis bases): hardly polarisable, relatively strong bases Soft electrophiles: strongly polarisable, relatively weak bases

9. Example: reactions of 3 electrophiles with a set of nucleophiles Nucleophile pKa k (1) k (2) Nucleophile k (3) HOO–11.5 2 x 103 1 x 105 SCN– 3.2 x 10-5 OH– 15.7 9 x 102 1.6 x 103 NO2– 1.8 x 10-5 PhO– 10.0 1 x 102 3.4 x 101 I– 1.2 x 10-5 ClO– 7.2 1.6 x 103 7 x 102 CN– 1 x 10-5 NH2OH 6.0 1 x 102 1.3 SO32- 2.3 x 10-6 NH3 9.2 1 x 101 – OH– 1.2 x 10-6 PhS– 6.4 – 7.4 x 10-3 Br– 5 x 10-7 pyridine 5.4 1 x 10-1 – NH3 2.2 x 10-7 acetate 4.8 5 x 10-6 – pyridine 9 x 10-8 H2O –1.7 6 x 10-7 1 x 10-6 H2O 1 x 10-10 Esters (1 and 2) are relatively hard electrophiles: order of reactivity of nucleophiles is mainly determined by the pKa. However: a effect gives higher reactivity; N-nucleophiles are more reactive than O-nucleophiles. CH3Cl (3) is a relatively soft electrophile, order of reactivity is determined by the polarisability of the nucleophile; pKa plays a minor role.

10. Use of the HSAB theory 1) To choose a catalyst: you need a hard nucleophile (= nucleophilic catalyst) if you want to react at a hard reaction centre (electrophile) 2) Predict where a nucleophile will react in case there are more possibilities:

11. General base catalysis or nucleophilic catalysis? Consider the following reaction: Does Et3N act as a nculeophilic or a general base catalyst? Mechanism for Et3N as a nucleophilic catalyst:

12. Mechanism for Et3N as a general base catalyst:

13. How to distinguish between nucleophilic catalysis and general base catalysis? 1. “Common ion effect” Add anions that are identical to the leaving group in the reaction (assuming that the pKb of the leaving group is such that the group effectively acts as a base) and determine the reaction rate: - faster: general base catalysis, since addition of the leaving group increases the concentration of base in solution and n = S[Bi][S]. - slower: nucleophilic catalysis, addition of extra leaving group drives the reaction equilibria back from product to the covalent intermediate.

14. Example: General base catalysis would involve an intermediate like: Mechanism of nucleophilic catalysis: A rate enhancement was found upon addition of F- general base catalysis

15. 2.Detection of a covalent intermediate is a proof for nucleophilic catalysis. The existence of the intermediate can be proven by: - isolation - spectroscopic detection:

16. - trapping, i.e. the in situ modification of the intermediate by a “trapping agent” that is deliberately added to the reaction mixture. With caution, the failure to detect an intermediate can be used as a proof for the occurrence of general base catalysis, e.g.:

17. o x o o x log k x x o pKa (cat.) 3. Nonlinearity of the Brønsted plot: In general base catalysis there is a good correlation, data points (x) are on a straight line; in nucleophilic catalysis there are sometimes strong deviations (o). Reasons for deviations in the Brønsted plot: a) A difference in polarisability at the same pKa. Substrate kim/phosphate kOH-/im type of catalysis (~same pKa) (~same nucleophilicity) ethyl acetate 0.25 910 000 general base catalysis ethyl dichloroacetate 1.9 650 000 general base catalysis p-nitrophenyl acetate 4700 16 nucleophilic catalysis acetic anhydride 860 7.2 nucleophilic catalysis im = imidazole

18. b) Steric hindrance Not important for base catalysis (H-transfer), but very important in nucleophilic catalysis, e.g.: This reaction is not catalysed by sterically hindered bases like: c) The a-effect.

19. 4. Determine the solvent isotope effect (H2O vs. D2O): The rate determining step in general base catalysis = cleavage of a O-H (O-D) bond, which is not the case in nucleophilic catalysis. E.g.: Substrate kH/D type of catalysis ethyl dichloroacetate 3 general base catalysis p-nitrophenyl acetate 1 nucleophilic catalysis N.B.: the isotope effect can be obscured by solvation effects!