Chapter 6: Acid and Bases, Electrophiles and Nucleophiles

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.
10
(No Transcript)
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.
ODonoghue, 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
17
(No Transcript)
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
Cl2CCl- pKa 25
R3P-CH3 B R3P-CH2-
R3PCH2
R2S-CH3 B R2S-CH2-
R2SCH2 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
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??
DGint l/4 and l 4 DGint Position
of the transition state x
½ DGpo/8 DGint
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-ßnuc 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 (b3b1-b2) pKa C123 log(1
G23Kab2-b3) or log kobs (b3b1-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 gtgt k2 k3/k2 gtgt 1 kobs k1 log kobs ß1pKa
C1
33
2. k3 is rate-determining
k3 ltlt k2 k3/k2 0 kobs k1k3/k2 log kobs
(ß3ß1-ß2)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 lt 6 Breakdown of T
is rate-determining. kobs
k1k3/k2 ? ßobs ß3 ß1 - ß2 pKa gt
6 Formation of T is rate-determining.
kobs k1 ? ßobs ß1 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

?, if reaction 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 ßeq pKanuc ß
1.7 a
ßnuc/ßeq 0.44 a 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
  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. ß 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
51
Reactivity Trends 1. Hg2 (ELUMO -448 kJ
mol-1, soft electrophile) HS- gt CN- gt
Br- gt Cl- gt HO- gt F- Reactivity
parallels EHOMO of nucleophile. 2. Ca2 (ELUMO
225 kJ mol-1, hard electrophile) HO- gt
CN- gt HS- gt F- gt Cl- gt Br- gt I- Reactivity
parallels pKa of conjugate acid of nucleophile.
52
F. Structure-Nucleophilicity Correlations
1. Swain-Scott LFER
n ? nucleophilicity parameter s
sensitivity of studied reaction (s
1 for reaction in H2O)
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 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. 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/k0 N
Features ? Not a LFER.
? Provides a scale of nucleophilicities for
anion/solvent systems.
? Reference system is H2O. ?
Works for reactions with carbocation and carbonyl
carbons.
56
Ritchie Nucleophilicity Parameters
Conclusions Softer Lewis bases
(nucleophiles) are more reactive.
Hydroxylic solvents impede nucleophilic
reactivity.
57
G. Relationship Between Nucleophilicity and
Nucleofugacity
105 k2 (M-1 s-1) Ratio
I- EtI EtI I-
6000 1440
Pyr EtI EtPyr I-
4.17
I- EtBr EtI Br-
195 269
Pyr EtBr EtPyr Br-
0.725
58
(No Transcript)
59
H. a-Effect Nucleophiles

• ? Hydrazines, hydroxylamines, peroxide anions
• ? Unusually strong nucleophiles in relation to
  their weak basicity
• ? Lone-pair repulsions raise EHOMO.
• Example

kHOO-/kHO- 20 pKa of H2O 15.7
pKa of H2O2 11.6