Chem 215 F11 Notes – Dr. Masato Koreeda - Page 1 of 6.
Date: October 14, 2011
Chapter 16-1, 3-5: Acidity and Basicity; Enolization/Enolate Formation
I. Solvation, Inductive, and Resonance Effects in Acidity and Basicity
(1) Solvation effect: More effective solvation on the conjugate base increases the acidity of
the original acid.
Alcohols:
R OH
+
R O
H3C OH
pKa
CH3CH2 OH
15.5
(CH3)3C OH
17.0
19.2
O
R
R
OH
O
H
pKa
(CH3)2CH OH
15.9
O
Carboxylic acids:
H
O
+
H
O
OH
H 3C
3.75
O
OH
CH3CH2
4.76
O
O
OH
(CH3)2CH
4.88
(CH3)3C
OH
4.85
5.05
(2) Hybridization effect on R-C(=O)OH - Inductive effect by the α-carbon
electronegativity
2.48
electronegativity
2.78
O
CH3CH2
O
OH
CH2=CH
4.88
4.20
α-C:
sp3 C
sp2 C
O
O
OH
pKa
electronegativity
3.07
electronegativity
2.71
C
OH
H
~4.2
C
C
OH
1.84
sp2 C
sp C
(3) Halogenated Carboxylic Acids
pKa
H
C
H
H
Cl
C
H
H
Cl
Cl
C
H
Cl
Cl
C
Cl
O
C
O
C
O
C
O
C
O
O
O
H
H
H
pKa
Examples of
the Inductive Effect
4.8
2.8
Cl closer
to the
C(=O)OH
more
Cl atoms
Cl
4.05
H
C
H H
O
1.3
O
F
H
C
C
O
F
F
0.64 stronger
0.23
H
R
O
C
O
H
electrons are withdrawn more
to the O atom of the O-H
bond by the halogen atom(s)
O
H H
C
O
C
C
C
H H Cl H
stronger
acid
acid
C
H H
O
C
H
Cl H O
C H
C
O
C
C
H H H H
2.86
H
H H
C
4.52
R
O
C
O
O
+
charge more stabilized
by the presence of the
halogen atom(s)
H
H
OH
Chem 215 F11 Notes – Dr. Masato Koreeda - Page 2 of 6.
Date: October 14, 2011
(4) Aromatic Carboxylic Acids
• Inductive effect in aromatic carboxylic acids
O
C
O
O
C
H
O
O
C
H
O
O
C
H
F
H
F
4.2
pKa
O
F
4.1
3.9
3.3
stronger acid; F closer to the C(=O)OH
note: Inductive effect through the σ-bond framework
• Combination of inductive and resonance effects
O
C
O
O
H
O
C
pKa 3.4
N
O
O
weak inductive effect
& strong resonance effect
N
O
H
O
C
pKa 3.5
N
O
O
H
O
O
pKa 2.2
strong inductive effect &
extremely strong resonance effect
mostly inductive effect
Resonance structures of the conjugate base of 4-nitrobenzoic acid:
O
C
O
O
C
O
O
N
O
O
C
O
O
N
O
O
C
O
O
N
O
attractive chargecharge interaction
O
N
O
(5) Aromatic amines (or anilines)
Instead of using the basicity scale (pKb), the dissociation acidity (pKa) of the conjugate
acids is typically used. So, a stronger base has a higher pKa of its conjugate acid.
pKa
BH
+
B
H
H
H
N
H
H
H3C N H
H
H
H
N
H
N
H
pKa 4.6
pKa 10.6
Because of the delocalizable N lone pair in aniline (as a result
of resonance with the benzene π-system), the aniline N atom is
considerably less basic compared with that of R-NH2.
Substituted anilines
H
H
N
H
H
H
N
H
pKa 4.60
O
N
O
pKa 1.00
H
H
N
H
H3C
O
pKa 5.31
Chem 215 F11 Notes – Dr. Masato Koreeda - Page 3 of 6.
Date: October 14, 2011
Explanation based upon resonance structures of the conjugate acids:
H
H
N
H
H
H
N
H
O
O
N
O
H3C
N
O
H
H
N
H
H
H
N
H
H3C
O
charge-charge
repulsion
The BH+ form is destabilized by the presence of
the 4-nitro group.
more acidic than PhNH3+
O
charge-charge
stabilizing
interaction
The BH+ form is stabilized by the presence of
the 4-OCH3 group.
less acidic than PhNH3+
Alternatively, these pKa values can be explained by using the resonance structures of
substituted anilines (i.e., B instead of BH+).
II. Carbon Acids
(1) Carbanions
C
pKa >50
H
C
C
sp3 = 25% s character
C
sp = 50% s character
extremely strong
nucleophiles and bases
pKa ~40
H
C
pKa 26
H
C
2
sp = 33% s character
Inductive effect:
Cl
Cl C
+
H
Cl
Cl C
OH
+
Cl
Cl
H
OH
pKa 15.7
pKa ~25
Cl
Cl
much weaker base than
C
C
Cl
But, note: H3CO
H3CO
H3CO
C
H
not acidic at all!
(2) Electron-withdrawing groups (in terms of resonance) & pKa
H
H
H C C H
H
H
pKa >50
H
C
H
H
O
C
H
C
H
H
pKa 19
O
O
N
C
H
H
H
pKa 10.2
O
O
N
C
H
O
O
N
H
both inductive effect & resonance stabilization
of the carbanion
C
H
H
Chem 215 F11 Notes – Dr. Masato Koreeda - Page 4 of 6.
Date: October 14, 2011
III. Enols and Enolates (16-4, 5)
(1) Deprotonation of an α-Hydrogen by a Base
α−carbons
resonance-stabilized carbanion and enolate
(i.e., alpha or the first C's from C=O)
H
H
C
C
H
H
H
H
H
H
C
C
C
H
H
H
H
pKa 19
+
H OH
pKa 15.7
O OH
OH
enolate
carbanion
note: OH is also a nucleophile.
O
H
C
C
C H
H
H
H
H
C
C
C
H
H
H
H
OH
O
α−hydrogens
So,
O
O
O
C
takes place as well.
Ambident Nucleophilic Nature of Enolates: can react at either anionic center (i.e., C- and O-).
C-: more nucleophilic site
oxygen nucleophile
C: less electronegative and will
O
O
share electrons with electrophiles
more easily
H
C
C
C
H
H
H
H carbanion
enolate
H
C
C
C H
H
H
H
==============================================================
pKa’s of carbonyl compounds:
ketone
O
H
H
α C
C
H
O
O
CH3
H
H
C
C
H
CH3
C
C
CH3
H
pKa 19
ester
O
H
H
α C
C
H
a O b
OCH3
pKa 24
H
H
C
C
a
b
O
a
OCH3
H
C
C
OCH3
H
b
O
H
H
C
C
OCH3
The presence of unshared pairs of
electrons on the O of the alkoxy group
diminishes the effectiveness of the
carbonyl group of the ester in
delocalizing the charge.
Chem 215 F11 Notes – Dr. Masato Koreeda - Page 5 of 6.
Date: October 14, 2011
amide
O
H
H
a O b
α C
C
H
N(CH3)2
H
H
pKa 27
C
C
a
a
C
C
N(CH3)2
Explanation for the lower acidity of the amide α-H
is the same as the one used for an ester α-H and
even more so here.
b
O
H
b
O
H
N(CH3)2
C
H
H
C
N(CH3)2
(2) Protonation of an enolate anion
H OH
O
enolate anion
H
C
C
C H
H
H
H
O
H
pKa 10.9
H
C
C
C H
H
enol
H
H
form
(3) Keto-Enol Tautomerization
stabler form of the two by ~5 Kacal/mol
O
OH
H
H
C
C
C
H
H
H
H
H
C
H
C
C
H
H
H
H2O
25 °C
(extremely slow)
>99.999%
at equilibrium
Constitutional isomers (called tautomers or proton tautomers):
different connectivity, but interconvertible constitutional isomers
(4) Acid catalyzed-Enol Formation (Enolization)
O
H3O+
H
H
C
C
C
H
H
H
H
ketone
OH
H
C
H
C
C
H
H
H enol
Mechanism for the acid catalyzed-enol formation:
H
O
O
H
H
H
C
C
C
H
H
H
H
H
O
H
H
H
C
C
C
H
H
H
H
OH2
OH
H
C
H
C
C
H
H
H
Chem 215 F11 Notes – Dr. Masato Koreeda - Page 6 of 6.
Date: October 14, 2011
(5) Active methylene compounds
O
O
H3C
O
O
CH3
H H
OCH3
active methylene group
or active methylene Hs
pKa 9
H H
pKa 11
These Hs are highly acidic as
the corresponding carbanions
are doubly stabilized by resonance
with the two C=O groups.
(6) Racemization/epimerization of Stereocenters at the α-C Atoms
(a) Racemization
α-Hydrogen atoms can be deprotonated by a base or ketones can form enols under acidic conditions, thus
losing the original stereochemistry. In the example shown below, treatment of the R-enantiomer with
NaOCH3/HOCH3 results in the formation of a racemic mixture.
H
R
CH3
CH3
H
NaOCH3
HOCH3
S
O
CH3
CH3
CH3
CH3
O
O
via this achiral enolate anion
(b) Epimerization
H
H
CH3ONa/CH3OH
O
1,3-diaxial interactions
H
CH3
O
H
CH3
H
H
less stable
O
H
CH3
H
H
H
H
O
H
CH3
O
CH3
H
more stable
enolate intermediate
Epimers: Diastereomers differing in configuration at only one of two or more chiral
centers.
Epimerize: To interconvert diastereomers by change of configuration at only one of two or
more chiral centers.