Chapter 6: Acid and Bases, Electrophiles and Nucleophiles I. Acid-Base Dissociation A. Water Acting as a Base

1. Chapter 6: Acid and Bases, Electrophiles and Nucleophiles I. Acid-Base Dissociation A. Water Acting as a Base Since for dilute solution the activity of water is constant:

2. B. Water Acting as An Acid Proceeding as before:

3. Since pKW = pH + pOH = 14 pKb = 14 - pKa Conclusion: stronger bases have lower pKb values, and their conjugate acids are weaker acids (higher pKa values).

4. II. Strengths of Oxygen and Nitrogen Acids Electron-withdrawing groups have a large effect on the acidity of the OH function.

5. Many important intermediates in organic reactions are strong acids. Reference: Advanced Organic Chemistry; 4th Ed.; March, J.; John Wiley & Sons: New York, 1992, pp. 250-252.

6. Ammonium ions are stronger acids, and therefore their conjugate bases weaker bases, than their oxygen analogs.

7. III. Leveling Effects of the Solvent The strongest acid that can exist in a solvent is the conjugate acid (lyonium species) of the solvent. H2SO4 + H2O H3O+ + HSO4- pKa ~ -4 pKa = -1.7 HCl + H2O H3O+ + Cl- pKa ~ -7

8. The strongest base that can exist in a solvent is the conjugatebase (lyoxide species) of the solvent. NH2- + H2O NH3 + OH- (iPr)2N- + H2O (iPr)2NH + OH- pKW = 14 pKa ~ 35-40 for neutral amines

9. IV. Rates of Proton Transfer A. Oxygen Acids kD HA + H2O A- + H3O+ kR Ka = kD/kR Rate constants for proton transfer from H3O+ to anionic bases are diffusion controlled. Values of kR are typically 1 to 5 x 1010 M-1 s-1.

11. Configuration diffusion of H3O+ and –OH:

12. B. Nitrogen Bases kR R3N + H2O R3NH+ + HO- kD Kb = kR/kD Ka = Kw/Kb pKa = 14 - pKb

13. Conclusion: Acid dissociation of ammonium ions is diffusion controlled.

14. V. Acidities of Carbon Acids a) Table 6.5, p 247 of book. b) Advanced Organic Chemistry; 4th Ed.; March, J.; John Wiley & Sons: New York, 1992, pp. 250-252. c) Amyes, T.L.; Richard, J.P. J. Am. Chem. Soc.1996, 118, 3129-3141. d) Richard, J.P.; Williams, G.; O’Donoghue, A.C.; Amyes, T.L. J. Am. Chem. Soc. 2002, 124, 2957-2968.

15. A. Measurement of Weak Acidity Make a solution of two weak acids and add a substoichiometric amount of a strong base. Measure the equilibrium concentrations: Keq HA1 + A2- HA2 + A1-

16. Calculation of pKa values:

18. B. Factors that Affect Carbon Acidity 1. Substituent Effects Substituents stabilize conjugate base anion by resonance delocalization of negative charge.

19. 2. Aromaticity pKa = 15 pKa = 43

20. 3. Stabilization by d-orbitals CHCl3 + B: Cl2C--Cl Cl2C=Cl- pKa = 25 R3P+-CH3 + B: R3P+-CH2- R3P=CH2 R2S+-CH3 + B: R2S+-CH2- R2S=CH2 pKa ~ 30 R3N+-CH3 + B: R3N+-CH2-+ BH pKa ~ 40 CH3-CH3 + B: CH3-CH2-+ BH pKa ~ 50

21. 4. s-Character of Carbon Hybrid Orbitals

22. C. Nitrogen Acids N-H bond tends to be more acidic than C-H bond due to higher electronegativity of N than C.

23. VI. Theories of Proton Transfer A. Eigen Model kd kp k-d A-H + B (A-HB) (A-H-B+) A- + H-B+ k-d k-p kd kd = 4N(rAH + rB)(DAH + DB)e

24. DGp‡ DG‡ B. Marcus Theory ‡ DG‡ = DGp‡+ WR

25. WR = work required to form encounter complex from reactants WP = work required to form the encounter complex in the reverse direction from products GR, GP = free energies of reactants and products, respectively, within the encounter complex G‡ = overall free energy of activation Gp‡ = free energy of activation for proton transfer within the encounter complex Go = overall equilibrium free energy of reaction Gpo = equilibrium free energy of reaction within the encounter complex

26. Derivation of the Marcus Theory Equation: DGp‡=lx2 =l(x-1)2 +DGpo lx2 = l(x-1)2 + DGpo

27. Since DGp‡=lx2: DGp‡ Therefore, when DGpo = 0: DGp‡DG‡int = l/4 andl = 4 DG‡int Position of the transition state: x‡= ½ + DGpo/8 DG‡int

28. VII. Nucleophilicity and Electrophilicity A. BrØnsted Linear Free Energy Relationship A formal similarity is noted between proton transfer and nucleophilic displacement or nucleophilic addition:

29. BrØnsted equation for nucleophilic reactions: knuc = Gnuc Ka-βnuc Taking the log transform: log knuc =bnucpKa + log Gnuc = bnucpKa + C

30. B. Nucleophilic BrØnsted Plot for Stepwise Mechanism

31. Since ki = Gi Ka-bi: log kobs = (b3+b1-b2) pKa + C123 – log(1 + G23Kab2-b3) or log kobs = (b3+b1-b2) pKa + C123 – log(1 + G2310(b3-b2)pKa) The equation is nonlinear because of the last term.

32. Special Cases: 1. k1 is rate-determining: k3>> k2 k3/k2>> 1 kobs = k1 log kobs = β1pKa + C1

33. 2. k3 is rate-determining: k3<< k2 k3/k2~ 0 kobs = k1k3/k2 log kobs = (β3+β1-β2)pKa + C123

34. Example 1: reactivity of various imidazoles toward p-nitrophenyl acetate Slope =  = 0.8 Reference: Bruce and Lipinski, J. Am. Chem. Soc.1958, 80, 2265.

35. High sensitivity of rate constant to basicity of nucleophile is consistent with a late transition state with appreciable +-charge on bonding atom of nucleophile: ‡ Y CH 3 C O N O N + d 2 N H O - d Appreciable bond making

36. Example 2: Acetylation of Substituted Pyridines Castro and Castro, J. Org. Chem.1981, 46, 2939-2943.

37. The nonlinear BrØnsted plot is proof of an intermediate: pKa< 6 Breakdown of T± is rate-determining. kobs = k1k3/k2βobs = β3 + β1 - β2 pKa> 6 Formation of T± is rate-determining. kobs = k1 βobs = β1 pKa~ 6 Both k1 and k3 are rate-determining.

38. Leaving group abilities match for CH3CO2- (pKa = 4.8) and YPyr when pKa of YPyrH+ is 6.1. Conclusion: A nonlinear BrØnsted plot requires a mechanism with at least one intermediate. Caveat: The converse, that a linear BrØnsted plot requires a concerted mechanism, is not true.

39. Example 3: An unambiguous test for concertedness. Use nucleophiles of the same structural class as the leaving group.

40. Prediction for a stepwise mechanism: T- k3 = k2 when pKa = 0

41. , ifreaction is stepwise, BrØnsted plot must have a break at pKanuc = 7. T-

42. - d O - d C H C O C H N O 3 6 4 2 O C H Y 6 4

43. What is observed? Ba-Saif, Luthra & Williams J. Am. Chem. Soc.1987, 109, 6362-6368

44. For the equilibrium: log Keq = C + βeq pKanucβ = 1.7 α = βnuc/βeq = 0.44 α is a measure of the position of the transition state on a More O’Ferrall-Jencks diagram:

45. ‡ ‡

46. C. Hard and Soft Acids and Bases • Various observations indicate that the correlation of nucleophilicity with basicity, as measured by conjugate acid pKa values, is not universal: • 1. BrØnsted analysis degrades when nucleophiles of different structural classes • are used.2. HI is a very strong acid (pKa = -9) whose conjugate base is nonetheless a strong nucleophile: • 3. I- is an example of a soft Lewis base, and methyl is an example of a soft Lewis acid. • 4. Hard-hard interactions and soft-soft interactions are stronger than hard-soft interactions.

47. D. Energetics of Nucleophile-Electrophile Interactions qn and qe are charges on nucleophile and electrophile, respectively. cn and ce are orbital coefficients of nucleophile HOMO and electrophile LUMO, respectively. β is the resonance integral. EHOMO = energy of nucleophile HOMO ELUMO = energy of electrophile LUMO Electrostatic term: important for interactions of hard acids with hard bases Orbital interaction term: important for interactions of soft acids with soft bases

48. Bases (nucleophiles)

49. Acids (electrophiles)

50. E. Quantitative Measures of Hardness and Softness Ionization potential measures EHOMO. Electron affinity measures ELUMO. Frontier Orbital Energies for Lewis Acids and Bases soft hard