Chapter 6: Acid and Bases, Electrophiles and Nucleophiles
I. Acid-Base Dissociation
A. Water Acting as a Base
H
Ka'
+
O
H A
H
Ka ' 
aA  aH O 
3
aHA aH 2O
H
O+
H
H
+
-
A
[A  ][H 3O  ] yA  yH3O


[HA][H 2 O] yHA yH 2O
Since for dilute solution the activity of water is constant:
K a  K a ' aH 2O
[A  ] y A 


a
H 3O 
[HA] y HA
[A  ]
pKa  pH  log
 pH  log I
[HA]
1
B. Water Acting as An Acid
Kb'
B
+
Kb'
H OH
aHO  aHB 
aB:aH 2O
+
B
H
+
-
HO
[HO ][HB ] yHO  yHB 


[B :][H 2 O]
yB: yH 2O
Proceeding as before:
K b  K b ' aH 2O
[HB ] y HB 


a
HO 
[B :]
y B:
[HB ]
pK b  pOH  log
 pOH  log I
[B :]
2
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).
3
II. Strengths of Oxygen and Nitrogen Acids
Acid
pKa
% Dissociation
in Water
H2SO4
-4
99.999
CH3CO-OH
4.76
1.3
Ph-OH
10.0
3.2 x 10-4
H-OH
14
1.8 x 10-7
Me-OH
16
3.2 x 10-7
Electronwithdrawing
groups have a
large effect on the
acidity of the OH
function.
4
Acid
+OH
R
C H
+OH
R
C
R
+OH
R
C OR'
+OH
R
C OH
+
R O
R'
pKa
-10
-7
-6.5
-7
-3.5
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.
H
+
R CH2OH2
-2
5
Acid
pKa
NH4+
9.2
CH3NH3+
10.6
(CH3)2NH2+
10.8
(CH3)3NH+
9.8
Pyridinium
5.2
4-Nitropyridinium
1.2
PhNH3+
4.6
Ammonium ions are
stronger acids, and
therefore their
conjugate bases
weaker bases, than
their oxygen analogs.
6
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
pKa ~ -4
HCl + H2O
H3O+ + HSO4-
pKa = -1.7
H3O+ + Cl-
pKa ~ -7
7
The strongest base that can exist in a solvent is the conjugate
base (lyoxide species) of the solvent.
NH2- + H2O
(iPr)2N- + H2O
NH3 + OH(iPr)2NH + OH-
pKW = 14
pKa ~ 35-40 for neutral amines
8
IV. Rates of Proton Transfer
A. Oxygen Acids
kD
A- + H3O+
HA + H2O
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.
9
pKa
kD (s-1)
kR (M-1 s-1)
H2O
15.7
2.5 x 10-5
1.4 x 1011
D2O
16.5
2.5 x 10-6
8.4 x 1010
HF
3.2
7.0 x 107
1.0 x 1011
CH3COOH
4.8
7.8 x 105
4.5 x 1010
C6H5COOH
4.2
2.2 x 106
3.5 x 1010
p-NO2C6H4OH
7.1
2.6 x 103
3.6 x 1010
HA
10
Configuration diffusion of H3O+ and –OH:
H
H
O H
H
+O
H
H
H
H
H
H
H O
O
O
H
O
O
H
H
+O H
H
H
H
H
H
H
O
O
H O
H
-
H
H
H
H
O
H
O
O
O
H
H
H
O
-
H
11
B. Nitrogen Bases
kR
R3NH+ + HO-
R3N + H2O
kD
Kb = kR/kD
Ka = Kw/Kb
pKa = 14 - pKb
12
R3N
pKB
pKa
kR (s-1)
kD (M-1 s-1)
NH3
4.8
9.2
6 x 105
3.4 x 1010
MeNH2
3.4
10.6
1.6 x 107
3.7 x 1010
Me2NH
3.2
10.8
1.9 x 107
3.1 x 1010
Me3N
4.2
9.8
1.4 x 106
2.1 x 1010
Conclusion: Acid dissociation of ammonium ions is
diffusion controlled.
13
V. Acidities of Carbon Acids
Compound Class
Example
pKa
Cyano Compounds
CH3CN
25a
Nitro Compounds
CH3NO2
10.2a
Sulphoxides
CH3SOCH3
28a
Ketones
CH3COCH3
20a
Esters
CH3COOCH2CH3
26c
Carboxylate Ions
CH3COO-
33d
Alkanes
CH3CH3
CH3-CH=CH2
cyclopentadiene
50b
43b
15a
Alkenes
H2C=CH2
44b
Alkynes
H-C  C-H
25b
Aromatic
Compounds
CH3
43b, 40b
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, 31293141. d) Richard,
J.P.; Williams, G.;
O’Donoghue, A.C.;
Amyes, T.L. J. Am.
Chem. Soc. 2002,
124, 2957-2968.
14
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-
15
Calculation of pKa values:
[HA2 ][A1 ] yHA 2 yA1 I 2
K eq 



I1
[HA1 ][A 2 ] yHA1 yA 
2
pKa (HA1 )  pH  log
pKa (HA2 )  pH  log
[A1 ] yA 
1
[HA1 ] yHA 1
[A 2 ] yA 
2
[HA2 ] yHA 2
 pH  log I1
 pH  log I 2
16
log K eq
I2
 pKa ( HA2 )  pKa ( HA1 )  log
I1
pKa
Keq  10
where
pKa  pKa ( HA2 )  pKa ( HA1 )
Medium
pKa Range
H2O/HO-
1 – 14
CH3OH/CH3O-
14 – 16
CH3SOCH3/ CH3SOCH2-
13 – 28
/
NH2
-
+
NH Cs
18 – 32
17
B. Factors that Affect Carbon Acidity
1. Substituent Effects
Carbon Acid
pKa
CH3CN
25
11
-5
CH2(CN)2
CH(CN)3
CH3NO2
CH2(NO2)2
CH(NO2)3
O
CH3
CH3
C
10
3.6
0.1
20
Substituents
stabilize conjugate
base anion by
resonance
delocalization of
negative charge.
CH3
O
O
C
C
CH2
12.6
CH3
18
2. Aromaticity
H
H
-
+ B:
+ BH
+
pKa = 15
CH3 CH CH2 + B:
[CH2 CH CH2 ] - + BH+
pKa = 43
19
3. Stabilization by d-orbitals
CHCl3 + B:
Cl2C--Cl
Cl2C=Cl-
pKa = 25
R3P+-CH3 + B:
R3P=CH2
R2S+-CH3 + B:
R2S=CH2
R3P+-CH2R2S+-CH2-
pKa ~ 30
R3N+-CH3 + B:
R3N+-CH2- + BH
pKa ~ 40
CH3-CH3 + B:
CH3-CH2- + BH
pKa ~ 50
20
4. s-Character of Carbon Hybrid Orbitals
Carbon Acid
% s-Character
pKa
H-CC-H
50
25
H2C=CH2
33
44
CH3CH3
25
50
21
C. Nitrogen Acids
Acid
NH3
pKa
~ 40
C6H5NH2
30
CH3CONH2
26
(H2N)2C=O
27
(H2N)2C=S
21
N-H bond tends
to be more
acidic than C-H
bond due to
higher
electronegativity
of N than C.
22
VI. Theories of Proton Transfer
A. Eigen Model
kd
A-H + B
k-d
(A-HB)
kp
(A-H-B+)
k-p
k-d
A- + H-B+
kd
kd = 4N(rAH + rB)(DAH + DB)e
23
B. Marcus Theory
GP
Free Energy
GR
Gp‡
G‡
WP
WR
} G
o
p
} G
o
Reaction Progress
G‡
= Gp + WR
‡
2

 
 W
G  1 
R


4



‡
G op
24
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
25
Derivation of the Marcus Theory Equation:
Gp‡ = x2 = (x-1)2 + Gpo
x2 = (x-1)2 + Gpo
o

1  G p
x  1
2






26
Since Gp‡ = x2:
Gp‡

 


1
4
 


G op
2
Therefore, when Gpo = 0:
Gp‡ G‡int = /4
and
 = 4 G‡int
Position of the transition state:
x‡ = ½ + Gpo/8 G‡int
27
VII. Nucleophilicity and Electrophilicity
A. BrØnsted Linear Free Energy Relationship
A formal similarity is noted between proton transfer and
nucleophilic displacement or nucleophilic addition:
CH3CH2NH2 + H
CH3CH2NH2 + CH3
+
-
CH3CH2N H3 + I
I
I
+
CH3CH2NH2CH3 + I
28
O
CH3CH2NH2 +
H
O
C
+
CH3CH2N H2
-
C
H
BrØnsted equation for nucleophilic reactions:
knuc = Gnuc Ka-βnuc
Taking the log transform:
log knuc = bnucpKa + log Gnuc = bnucpKa + C
29
B. Nucleophilic BrØnsted Plot for Stepwise Mechanism
k obs
k 1k 3
k 1k 3 / k 2


k 2  k3 1 k3 / k2
30
Since
ki = Gi Ka-bi:
k obs 
G123 K ba 2 b1 b3
1  G 23 K ba 2 b3
and
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.
31
Special Cases:
1. k1 is rate-determining:
k3 >> k2
k3/k2 >> 1
T-
kobs = k1
G
log kobs = β1pKa + C1
A + Nu
P
Reaction Progress
32
2. k3 is rate-determining:
k3 << k2
k3/k2 ~ 0
-
T
G
kobs = k1k3/k2
log kobs = (β3+β1-β2)pKa + C123
A + Nu
P
Reaction Progress
33
Example 1: reactivity of various imidazoles toward
p-nitrophenyl acetate
2
Slope = b = 0.8
Reference:
Bruce and
Lipinski, J. Am.
Chem. Soc.
1958, 80, 2265.
1
log k1
0
-1
-2
3
4
5
6
7
8
9
pKa
34
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
H
CH3
+N
d
N
C O
NO2
Od
Appreciable bond making
35
Example 2: Acetylation of Substituted Pyridines
Y
+
N
CH3
O
O
C
C
O
k1
CH3
k2
+
N
log kN (M-1 s-1)
-
C OAc
Y
CH3
T
4
O
+
O
+
N CCH3
k3
Y
-
+ CH 3CO2
b = 0.2
Castro and
Castro, J. Org.
Chem. 1981,
46, 2939-2943.
2
b = 1.0
0
-2
2
4
6
pKa
8
10
36
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.
k obs
k1k 3

k 2  k3
37
O
+
N
-
C O CCH3
Y
CH3
T
O
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.
38
Example 3: An unambiguous test for concertedness.
Use nucleophiles of the same structural class as the leaving group.
O
O
-
O
OCCH3
OCCH3
+
Y
O
+
O2N
Y
O2N
39
-
Prediction for a stepwise mechanism:
O
O
O
-
OCCH3
+
Y
O2N
O
k1
Y
-
C CH3
O
k2
TNO2
k3
k3 = k2 when
pKa = 0
O
O
-
OCCH3
+
O2N
Y
40
O
O2N
O
-
C CH3
O
OH
pKa of
is 6.98
O2N
, if reaction is stepwise,
BrØnsted plot must have a
break at pKanuc = 7.
TNO2
41
pKa = 0
-
log knuc
Od
CH3
C
OC 6H4NO2
- OC 6H4Y
d
-
d
O
CH3
d-
C
OC 6 H4 NO 2
OC 6 H4 Y
5
6
7
8
9
10
pKa
42
What is observed?
log kArO- (M-1 s-1)
1
0
Ba-Saif,
Luthra &
Williams
J. Am.
Chem. Soc.
1987, 109,
6362-6368
pKa = 0
-1
-2
b = 0.75
-3
-4
5
6
7
8
9
10
11
pKa(ArOH)
43
For the equilibrium:
O
O
-
OCCH3
O
OCCH3
Keq
+
Y
O
+
O2N
O2N
Y
log Keq = C + βeq pKanuc
β = 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:
44
-
O
-
YArO
O
OAr
MeCOArY
+ ArO
Me
‡
O
O
-
+ YArO
+ ArO
C
MeCOAr
+ YArO
O2N
+
Me
‡
d-
CH3
O
C
O
0.44
O
0.44
d-
NO2
45
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. 1. BrØnsted analysis degrades when nucleophiles of different structural classes
2.
are used.
2. HI is a very strong acid (pKa = -9) whose conjugate base is nonetheless a
strong nucleophile:
O CH3
+
H
I
+
O
CH3
+
I
-
H
OH
+ CH 3I
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.
46
D. Energetics of Nucleophile-Electrophile Interactions
qn qe
2(c n ceb)2
E 

er
E HOMO  E LUMO
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
47
Bases (nucleophiles)
Type
Hard
Intermediate
Soft
Species
Examples
small halide anions
F-, Cl-
oxygen nucleophiles
H2O, ROH, HO-, RO-,
ROR, MeCO2-, SO42-,
PO43-
amine nucleophiles
RNH2, H2NNH2
larger halide anions
Br-
nitrogen nucleophiles
C6H5NH2, C5H5N, N3-
oxygen nucleophiles
NO2-, SO32--
sulfur nucleophiles
RSR, RSH, RS-
phosphorus
nucleophiles
R3P, (RO)3P, R3As
carbon nucleophiles
CN-, CO, R-, C2H4, Ar
others
H -, I 48
Acids (electrophiles)
Type
Hard
Intermediate
Soft
Species
Examples
high charge/radius
cations
H+, Li+, Mg2+, Ca2+, Al3+,
Cr3+, Ti4+, I5+
group II species
Be(CH3)2
group III species
Al(CH3)3, BF3, B(OR)3
H-bond donors
ROH, HOH, RNH2,
RNH3+
moderate charge/radius
cations
Fe2+, Cu2+, Zn2+, Pb2+,
Sn2+, Co2+, Ni2+
carbocations
(CH3)3C+, ArH+
low charge/radius
cations
Cu+, Ag+, Au+, Hg+, Hg2+,
I+, Br+, RO+
carbon electrophiles
RL, ArL (L = nucleofuge)
diatomic halogens
I2, Br2, ICN
radicals
O, Cl, Br, I, RO 
49
E. Quantitative Measures of Hardness and Softness
Ionization potential measures EHOMO.
Electron affinity measures ELUMO.
Frontier Orbital Energies for Lewis Acids and Bases
Base
EHOMO (kJ)
Acid
ELUMO (kJ)
H-
-711
Hg2+
-448
I-
-801
Ag+
-272
SH-
-829
Na+
0
CN-
-847
H+
40.5
Br-
-889
Li+
47.3
Cl-
-959
Fe3+
66.5
HO-
-1008
Ca2+
225
H2O
-1032
F-
-1175
soft
hard
50
Reactivity Trends:
1. Hg2+ (ELUMO = -448 kJ mol-1, soft electrophile)
HS- > CN- > Br- > Cl- > HO- > FReactivity parallels EHOMO of nucleophile.
2. Ca2+ (ELUMO = 225 kJ mol-1, hard electrophile)
HO- > CN- > HS- > F- > Cl- > Br- > IReactivity parallels pKa of conjugate acid of nucleophile.
51
F. Structure-Nucleophilicity Correlations
1. Swain-Scott LFER
log kNu/k0 = sn
n  nucleophilicity
parameter
s = sensitivity of studied
reaction (s = 1 for
reaction in H2O)
Reference reaction:
Nu:- + CH3Br
NuCH3 + Br52
Nucleophile
n
MeOH
n0
0
H2 O
0
AcO-
2.72
F-
n values are for reactions in
H2O.
4.3
2.7
n0 values are for reactions
in MeOH.
More values in Table 6.10
Cl-
3.04
4.33
Br-
3.89
5.79
I-
5.04
7.42
SCN-
4.77
6.7
C6H5NH2
4.49
5.7
Correlations best for
nucleophilic displacements
at saturated carbon.
53
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
Nu:- + HO-OH
NuCH3 + BrNuOH + HO-
a = 2.50
b = 0.006
a = 6.22
b = -0.43
54
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.
55
Ritchie Nucleophilicity Parameters
System
N+
H2O
CH3OH
0.0
0.5
Conclusions:
CN-/H2O
CN-/CH3OH
CN-/DMSO
CN-/DMF
3.8
5.9
8.6
9.4
Softer Lewis bases
(nucleophiles) are more
reactive.
N3-/H2O
N3-/CH3OH
5.4
8.5
PhS-/CH3OH
PhS-/DMSO
10.7
13.1
HO-/H2O
CH3O-/CH3OH
4.5
7.5
Hydroxylic solvents
impede nucleophilic
reactivity.
56
G. Relationship Between Nucleophilicity and Nucleofugacity
105 k2 (M-1 s-1)
I- + EtI*
EtI + I*-
Ratio
6000
1440
Pyr + EtI
EtPyr+ + I-
4.17
I- + EtBr
EtI + Br-
195
269
Pyr + EtBr
EtPyr+ + Br-
0.725
57
CH3
Nu C
H
-
X
H
1
1
BCX
CH3CH2Nu
0
1
BCNu
+ X
-
BCNu
0
1
Nu: +
CH3CH2X
0
0
BCX
-
Nu: + X
+
CH 3CH2
58
H. α-Effect Nucleophiles

●
Hydrazines, hydroxylamines, peroxide anions

●
Unusually strong nucleophiles in relation to their weak
basicity

●
Lone-pair repulsions raise EHOMO.
Example:
HOO
-
+ -O2CCH2
Br
-
O2CCH2
OOH + Br
-
+ -O2CCH2
Br
-
O2CCH2
OH + Br
HO
-
-
kHOO-/kHO- = 20
pKa of H2O = 15.7
pKa of H2O2 = 11.6
59