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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:. B. Water Acting as An Acid. Proceeding as before:. Since pK W = pH + pOH = 14
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I. Acid-Base Dissociation
A. Water Acting as a Base
Since for dilute solution the activity of water is constant:
Proceeding as before:
pKb = 14 - pKa
Conclusion: stronger bases have lower pKb values,
and their conjugate acids are weaker
acids (higher pKa values).
Electron-withdrawing groups have a large effect on the acidity of the OH function.
Advanced Organic Chemistry; 4th Ed.; March, J.; John Wiley & Sons: New York, 1992, pp. 250-252.
Ammonium ions are stronger acids, and therefore their conjugate bases weaker bases, than their oxygen analogs.
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
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
A. Oxygen Acids
HA + H2O A- + H3O+
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.
R3N + H2O R3NH+ + HO-
Kb = kR/kD Ka = Kw/Kb
pKa = 14 - pKb
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.
Make a solution of two weak acids and add
a substoichiometric amount of a strong base. Measure the
HA1 + A2- HA2 + A1-
1. Substituent Effects
Substituents stabilize conjugate base anion by resonance delocalization of negative charge.
pKa = 15
pKa = 43
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
N-H bond tends to be more acidic than C-H bond due to higher electronegativity of N than C.
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
B. Marcus Theory
DG‡ = DGp‡+ WR
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
DGp‡=lx2 =l(x-1)2 +DGpo
lx2 = l(x-1)2 + DGpo
Therefore, when DGpo = 0:
DGp‡DG‡int = l/4 andl = 4 DG‡int
Position of the transition state:
x‡= ½ + DGpo/8 DG‡int
A. BrØnsted Linear Free Energy Relationship
A formal similarity is noted between proton transfer and
nucleophilic displacement or nucleophilic addition:
knuc = Gnuc Ka-βnuc
Taking the log transform:
log knuc =bnucpKa + log Gnuc = bnucpKa + C
log kobs = (b3+b1-b2) pKa + C123 – log(1 + G23Kab2-b3)
log kobs = (b3+b1-b2) pKa + C123 – log(1 + G2310(b3-b2)pKa)
The equation is nonlinear because of the last term.
1. k1 is rate-determining:
kobs = k1
log kobs = β1pKa + C1
kobs = k1k3/k2
log kobs = (β3+β1-β2)pKa + C123
Slope = = 0.8
Bruce and Lipinski, J. Am. Chem. Soc.1958, 80, 2265.
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
Castro and Castro, J. Org. Chem.1981, 46, 2939-2943.
pKa< 6 Breakdown of T± is rate-determining.
kobs = k1k3/k2βobs = β3 + β1 - β2
pKa> 6 Formation of T± is rate-determining.
kobs = k1 βobs = β1
pKa~ 6 Both k1 and k3 are rate-determining.
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.
Use nucleophiles of the same structural class as the leaving group.
k3 = k2 when
pKa = 0
BrØnsted plot must have a
break at pKanuc = 7.
Ba-Saif, Luthra & Williams
J. Am. Chem. Soc.1987, 109, 6362-6368
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:
qn and qe are charges on nucleophile and electrophile, respectively.
cn and ce are orbital coefficients of nucleophile HOMO and electrophile
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
Ionization potential measures EHOMO.
Electron affinity measures ELUMO.
Frontier Orbital Energies for Lewis Acids and Bases
1. Hg2+ (ELUMO = -448 kJ mol-1, soft electrophile)
HS-> CN-> Br-> Cl-> HO-> F-
Reactivity parallels 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.
1. Swain-Scott LFER
s = sensitivity of studied
reaction (s = 1 for
reaction in H2O)
log kNu/k0 = sn
Nu:- + CH3Br NuCH3 + Br-
n0 values are for reactions in MeOH.
More values in Table 6.10
Correlations best for nucleophilic displacements at saturated carbon.
log kNu/k0 = aEN + 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.
Nu:- + CH3Br NuCH3 + Br-a = 2.50 b = 0.006
Nu:- + HO-OH NuOH + HO-a = 6.22 b = -0.43
log kNu/k0 = N+
● Not a LFER.
● Provides a scale of nucleophilicities for anion/solvent systems.
● Reference system is H2O.
● Works for reactions with carbocation and carbonyl carbons.
Softer Lewis bases (nucleophiles) are more reactive.
Hydroxylic solvents impede nucleophilic reactivity.
105 k2 (M-1 s-1) Ratio
I- + EtI* EtI + I*-6000
Pyr + EtI EtPyr+ + I-4.17
I- + EtBr EtI + Br- 195
Pyr + EtBr EtPyr+ + Br- 0.725
kHOO-/kHO- = 20
pKa of H2O = 15.7 pKa of H2O2 = 11.6