Chapter 6 Acid and Bases, Electrophiles and Nucleophile.ppt

1、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 l

2、ower 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 O

3、rganic Chemistry; 4th Ed.; March, J.; John Wiley 4th Ed.; March, J.; John Wiley 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

4、 + A2- HA2 + A1-,16,Calculation of pKa values:,17,18,Substituents stabilize conjugate base anion by resonance delocalization of negative charge.,B. Factors that Affect Carbon Acidity 1. Substituent Effects,19,pKa = 15,2. Aromaticity,pKa = 43,20,3. Stabilization by d-orbitals,CHCl3 + B: Cl2C-Cl Cl2C=

5、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

6、 N than C.,23,VI. Theories of Proton Transfer A. Eigen Model kd kp k-d,A-H + B (A-HB) (A-H-B+) A- + H-B+ k-d k-p kd kd = 4N(rAH + rB)(DAH + DB)e,24,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 re

7、verse 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 = equi

8、librium 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,DGp,Since DGp = lx2:,Therefore, when DGpo = 0: DGp DGint = l/4 and l = 4 DGint Position of the transition state: x = + DGpo/8 DGint,28,VII. Nuc

9、leophilicity and Electrophilicity A. Brnsted Linear Free Energy Relationship A formal similarity is noted between proton transfer and nucleophilic displacement or nucleophilic addition:,29,Brnsted equation for nucleophilic reactions: knuc = Gnuc Ka-nuc Taking the log transform: log knuc = bnucpKa +

10、log Gnuc = bnucpKa + C,30,B. Nucleophilic Brnsted 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,k3 k2 k3/k2 1 kobs = k1 log k

11、obs = 1pKa + C1,Special Cases: 1. k1 is rate-determining:,33,k3 k2 k3/k2 0 kobs = k1k3/k2 log kobs = (3+1-2)pKa + C123,2. k3 is rate-determining:,34,Slope = = 0.8 Reference: Bruce and Lipinski, J. Am. Chem. Soc. 1958, 80, 2265.,Example 1: reactivity of various imidazoles toward p-nitrophenyl acetate

12、,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:,Appreciable bond making,C,CH,3,O,O,N,O,2,N,N,H,Y,d,-,d,+,36,Castro and Castro, J. Org. Chem. 1981, 46, 2939-2943.,Example 2: Acetylati

13、on of Substituted Pyridines,37,The nonlinear Brnsted plot is proof of an intermediate: pKa 6 Formation of T is rate-determining. kobs = k1 obs = 1 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 non

14、linear Brnsted plot requires a mechanism with at least one intermediate. Caveat: The converse, that a linear Brnsted 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,T-,k3 = k

15、2 when pKa = 0,Prediction for a stepwise mechanism:,41,T -, if reaction is stepwise, Brnsted plot must have a break at pKanuc = 7.,42,C,H,3,C,O,O,C,6,H,4,N,O,2,O,C,6,H,4,Y,d,-,d,-,43,Ba-Saif, Luthra & Williams J. Am. Chem. Soc. 1987, 109, 6362-6368,What is observed?,44,For the equilibrium:,log Keq =

16、 C + eq pKanuc = 1.7 = nuc/eq = 0.44 is a measure of the position of the transition state on a More OFerrall-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 un

17、iversal: 1. Brnsted 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 inte

18、ractions 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. is

19、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 (electrophil

20、es),50,soft,hard,E. Quantitative Measures of Hardness and Softness Ionization potential measures EHOMO. Electron affinity measures ELUMO. Frontier Orbital Energies for Lewis Acids and Bases,51,Reactivity Trends: 1. Hg2+ (ELUMO = -448 kJ mol-1, soft electrophile) HS- CN- Br- Cl- HO- F- Reactivity par

21、allels EHOMO of nucleophile. 2. Ca2+ (ELUMO = 225 kJ mol-1, hard electrophile) HO- CN- HS- F- Cl- Br- I- Reactivity parallels pKa of conjugate acid of nucleophile.,52,n nucleophilicity parameter s = sensitivity of studied reaction (s = 1 for reaction in H2O),F. Structure-Nucleophilicity Correlations

22、 1. Swain-Scott LFER,log kNu/k0 = sn Reference reaction:,Nu:- + CH3Br NuCH3 + Br-,53,n values are for reactions in H2O. n0 values are for reactions in MeOH. More values in Table 6.10 Correlations best for nucleophilic displacements at saturated carbon.,54,2. Edwards “Oxybase” Equation log kNu/k0 = a

23、EN + bHN EN soft nucleophilicity (based on oxidation potentials) HN hard nucleophilicity (based on pKa values) k0 = rate constant for reaction with water EN and HN parameters are tabulated in Table 6.10. Examples:,Nu:- + CH3Br NuCH3 + Br- a = 2.50 b = 0.006,Nu:- + HO-OH NuOH + HO- a = 6.22 b = -0.43,55,3. Ritchie Nucleophilicity Parameters log kNu