Chapter 6: Acid and Bases, Electrophiles and Nucleophiles

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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
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
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
Electron-withdrawing groups have a large effect
on the acidity of the OH function.
5
Acid pKa
-10
-7
-6.5
-7
-3.5
-2
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.

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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.
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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
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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
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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.
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HA 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
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Configuration diffusion of H3O and OH
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B. Nitrogen Bases
kR
R3N H2O R3NH HO-
kD
Kb kR/kD Ka Kw/Kb
pKa 14 - pKb
13
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.
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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-CHCH2 cyclopentadiene 50b 43b 15a
Alkenes H2CCH2 44b
Alkynes H-C ? C-H 25b
Aromatic Compounds 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,
3129-3141. d) Richard, J.P. Williams, G.
ODonoghue, A.C. Amyes, T.L. J. Am. Chem. Soc.
2002, 124, 2957-2968.
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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-
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Calculation of pKa values
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Medium pKa Range
H2O/HO- 1 14
CH3OH/CH3O- 14 16
CH3SOCH3/ CH3SOCH2- 13 28
18 32
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B. Factors that Affect Carbon Acidity
1. Substituent Effects
Carbon Acid pKa
CH3CN 25
CH2(CN)2 11
CH(CN)3 -5
CH3NO2 10
CH2(NO2)2 3.6
CH(NO2)3 0.1
20
12.6
Substituents stabilize conjugate base anion by
resonance delocalization of negative charge.
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2. Aromaticity

pKa 15
pKa 43
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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
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4. s-Character of Carbon Hybrid Orbitals
Carbon Acid s-Character pKa
H-C?C-H 50 25
H2CCH2 33 44
CH3CH3 25 50
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C. Nitrogen Acids
Acid pKa
NH3 40
C6H5NH2 30
CH3CONH2 26
(H2N)2CO 27
(H2N)2CS 21
N-H bond tends to be more acidic than C-H bond
due to higher electronegativity of N than C.
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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
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B. Marcus Theory

DG DGp WR
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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
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Derivation of the Marcus Theory Equation
DGp lx2 l(x-1)2 DGpo
lx2 l(x-1)2 DGpo
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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
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VII. Nucleophilicity and Electrophilicity A.
BrØnsted Linear Free Energy Relationship A
formal similarity is noted between proton
transfer and nucleophilic displacement or
nucleophilic addition
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BrØnsted equation for nucleophilic reactions
knuc Gnuc Ka-ßnuc Taking the log
transform log knuc bnucpKa log Gnuc
bnucpKa C
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B. Nucleophilic BrØnsted Plot for Stepwise
Mechanism
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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.
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Special Cases 1. k1 is rate-determining
k3 gtgt k2 k3/k2 gtgt 1 kobs k1 log kobs ß1pKa
C1
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2. k3 is rate-determining
k3 ltlt k2 k3/k2 0 kobs k1k3/k2 log kobs
(ß3ß1-ß2)pKa C123
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Example 1 reactivity of various imidazoles
toward p-nitrophenyl acetate
Slope ? 0.8 Reference Bruce and Lipinski, J.
Am. Chem. Soc. 1958, 80, 2265.
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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
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Example 2 Acetylation of Substituted Pyridines
Castro and Castro, J. Org. Chem. 1981, 46,
2939-2943.
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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.
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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.
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Example 3 An unambiguous test for
concertedness. Use nucleophiles of the same
structural class as the leaving group.
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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
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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
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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.

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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
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Bases (nucleophiles)
Type Species Examples
Hard small halide anions F-, Cl-
Hard oxygen nucleophiles H2O, ROH, HO-, RO-, ROR, MeCO2-, SO42-, PO43-
Hard amine nucleophiles RNH2, H2NNH2
Intermediate larger halide anions Br-
Intermediate nitrogen nucleophiles C6H5NH2, C5H5N, N3-
Intermediate oxygen nucleophiles NO2-, SO32--
Soft sulfur nucleophiles RSR, RSH, RS-
Soft phosphorus nucleophiles R3P, (RO)3P, R3As
Soft carbon nucleophiles CN-, CO, R-, C2H4, Ar
Soft others H-, I-
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Acids (electrophiles)
Type Species Examples
Hard high charge/radius cations H, Li, Mg2, Ca2, Al3, Cr3, Ti4, I5
Hard group II species Be(CH3)2
Hard group III species Al(CH3)3, BF3, B(OR)3
Hard H-bond donors ROH, HOH, RNH2, RNH3
Intermediate moderate charge/radius cations Fe2, Cu2, Zn2, Pb2, Sn2, Co2, Ni2
Intermediate carbocations (CH3)3C, ArH
Soft low charge/radius cations Cu, Ag, Au, Hg, Hg2, I, Br, RO
Soft carbon electrophiles RL, ArL (L nucleofuge)
Soft diatomic halogens I2, Br2, ICN
Soft radicals O, Cl, Br, I, RO ?
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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
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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.
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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-
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Nucleophile n n0
MeOH 0
H2O 0
AcO- 2.72 4.3
F- 2.7
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
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.
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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
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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.
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Ritchie Nucleophilicity Parameters
System N
H2O CH3OH 0.0 0.5
CN-/H2O CN-/CH3OH CN-/DMSO CN-/DMF 3.8 5.9 8.6 9.4
N3-/H2O N3-/CH3OH 5.4 8.5
PhS-/CH3OH PhS-/DMSO 10.7 13.1
HO-/H2O CH3O-/CH3OH 4.5 7.5
Conclusions Softer Lewis bases
(nucleophiles) are more reactive.
Hydroxylic solvents impede nucleophilic
reactivity.
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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
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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