Summary Sheet 2: Enols and Enolates
Name
Structure
pKA* of
H
Example
O
H
H3C
O
ketone
R'
H3C
O
OR
H3C
amide
O
NR2
H2C
NH2 = 1 amide
NHR = 2 amide
NR1R2 = 3 amide
O
lactam
(cyclic
amide)
)n
C
H2
O
OH
H3C
R
O
anhydride
nitrile
Note 1
OH
O
*
H3C
Cl
O
O
RCN
Note 2
Cl
O
*
R H3C
CH3
Tautomerism: a form of isomerism where
a keto converts to an enol through the movement of
a proton and shifting of bonding electrons
O
O
Note 2
Me
Me-CN
Note 2: It is difficult to measure the pKa of
these species due to their reactivity.
*source: P. Y. Bruice, "Organic Chemistry"
Note that some of of these values differ slightly from
textbook to textbook and instructor to instructor.
However, there is universal agreement that for
a given structure, pKas increase in the order
aldehyde < ketone < ester < amide
If you have a vastlyl different set of values I
would appreciate it if you brought it to my attention.
For a comprehensive list of pKa values see:
1)evans.harvard.edu/pdf/evans_pKa_table.pdf
2) www.chem.wisc.edu/areas/reich/pkatable/
H
H
> OH > OR, NHAc > CH3, R > Cl, Br, F, I > C(O)OR
CF3, etc.
Substitution of the -carbon by a second carbonyl
derivative makes the -proton even more acidic:
Me
Me
Me
24 : 76 (at 23 C)
Me
Me Me
pKa = 9
pKa = 11
H X
t-Bu
O
Et2N
forms readily!
O
NR2 >
O
OR >
O
Me >
O
>
CF3
RO
O
OR
increasing reactivity toward nucleophilic attack
increasing stability of enolate
Can predict the course of the reaction by pKa!
Key Reaction: Enolate Formation
Enolate = deprotonated enol
i-Pr
O
H3C
OEt
i-Pr
N
Li (LDA)
O Li
H
(or other
strong base)
Carbonyl compound
OEt
H
ester enolate
O-bound form
Important: the Enolate is a NUCLEOPHILE
Amphiphilic =nucleophilic at both O and C;
here we focus on the reactions at C.
OMe MeO
t-Bu
Et2N
OMe
Two key examples:
O
O M
pKa = 13
OEt
The rate of keto/enol interconversion isgreatly enhanced by acid:
Acid makes carbonyl more electrophilic, increasing acidity of protons, facilitating formation of enol: this increases K1
4. . Conjugation is stabilizing.
O
OH
Me
Li
OEt
H
C-bound form
note: though an ester enolate
is shown here, the reaction of
any enolate with an aldehyde
is generally called an "Aldol".
OH O
H
OEt
Aldol reaction
Me
3. Strongly hydrogen bonding solvents can disrupt
this, however. The above equilibrium is 81:19
using water as solvent.
does not form
NEt2
Enolate
(oxy-anion resonance form)
The aromatic electrophilic substitution chart is a good proxy
for the ability of a functional group to donate to a carbonyl:
2. Hydrogen bonding stabilizes the enol form.
H-bond
H
O
O
O
O
t-Bu LiNEt
2
least acidic
CH3
The reactivity of the alkene toward nucleophilic attack is directly related
to the stability of the enolate that forms -
OMe
CH3
most acidic
Exclusive
NEt2
Li
Answer: The more electron-poor the carbonyl, the greater will
be its ability to stabilize negative charge. Conversely, the
greater the donating ability of a substitutent on the carbonyl,
the less it will be able to stabilize negative charge.
NR2 , O
CH2
enolate: stabilized!
Question: How do you explain the relative acidity of the
following series?
O
O
O
O
>
>
>
H3C
NR2
H3C
CF3
H3C
CH3
H3C
OR
25
Note 1: The carboxylic acid is deprotonated
first. Subsequent deprotonation of the -carbon
would form a dianion, which has a high
activation barrier due to charge repulsion. It
can be done, but it requires a very strong base.
CH3
Enolate
(Carbanion resonance form)
Five factors that influence the relative
proportion of keto/enol:
1. Aromaticity
O
OH
Not observed
Acetone in D2O will slowly incorporate deuterium at the
carbon. The enol form is responsible for this behavior.
The rate of keto/enol tautomerism is greatly increased by
acid (see below right)
LiNEt2
highly unstable
M
Conjugate base (enolate)
25
~10 more acidic just by
replacing H with a carbonyl!
OMe
CH3
Why the huge difference in acidity? The lone pair is
stabilized by donation into the carbonyl system.
enol form
OMe
The enol tautomer is most significant for ketones and
aldehydes. (You may also encounter it with acid chlorides in
the mechanism of the Hell-Vollhard-Zolinsky reaction). Esters
and amides are less acidic and exist almost exclusively as the
keto form (e.g. >106 : 1 keto: enol for ethyl acetate)
N Me
O
acid
chloride
Likewise, the presence of a carbonyl group activates alkenes toward
nucleophilic attack:
H2C CH3
Methyl propionate
pKa = ~25
For acetone (R=CH3) the keto:enol ratio is ~6600:1 at 23
C. Main reason is the difference in bond strengths between
the two species.
O
carboxylic
R
acid
30
NMe2
NH(R)H C
2
Conjugate base
OMe
OH
keto form
O
Ethane
pKa = ~50
Key Concept: Tautomerism
O
H2C
)n
H3C CH3
OMe
Effect on reactivity of alkenes:
The carbonyl is an electron withdrawing system with
low-lying * orbitals. It stabilizes adjacent negative charge.
25
O
O
(
20
Me
O
lactone
(cyclic
ester)
O
ester
Effects on acidity of alkyl groups
Carbon, oxygen: sp2 hybridized
OCC bond angle ~120
C=O bond strongly polarized
toward oxygen.
Carbonyl carbon is partially positive
therefore electrophilic!
Lone pairs render oxygen weakly
nucleophilic (will react with strong acid)
17
aldehyde
R
Structural Features of the Carbonyl Group:
Me
Preferred enol form
5. As with alkenes, increasing substitution increases
thermodynamic stability (assuming equal steric factors)
H X
R
H H
Keto
K1
R
H H
X:
K2
H O
R
H X
H
Enol
Enol is nucleophilic at -carbon, acid is
excellent electrophile: this increases K2
Net result: Addition of acid speeds proton
exchange between the keto and enol forms.
O M
OEt
OH O
OR
Claisen Condensation
OEt
The goal here is clarity and consistency. I
would greatly appreciate feedback on any
errors, omissions, or suggestions for
improvements. Thanks!
version 1.0, 4/13/10
copyright James Ashenhurst, 2010.
suggestions/questions/comments?
[email protected]masterorganicchemistry.wordpress.com
