Enol and enolate ions. Organic chemistry

Chemistry of enol and enolate ions in short

1. Summary Sheet 2: Enols and Enolates
version 1.0, 4/13/10
copyright James Ashenhurst, 2010.
suggestions/questions/comments?
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O
δ
δ
+
–
Structural Features of the Carbonyl Group:
•Carbon, oxygen: sp
2
hybridized
•O–C–C 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)
The carbonyl is an electron withdrawing π system with
low-lying π* orbitals. It stabilizes adjacent negative charge.
H
3CCH
3
CH
3
O
OMe
Ethane
pKa = ~50
Methyl propionate
pKa = ~25
~10
25
more acidic just by
replacing H with a carbonyl!
Why the huge difference in acidity? The lone pair is
stabilized by donation into the carbonyl π system.
H
2CCH
3
M
Conjugate base
CH
3
O
OMe
M
Conjugate base (enolate)
CH
3
O
OMe
M
CH
3
O
OMe
M
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.
Enolate
(Carbanion resonance form)
Enolate
(oxy-anion resonance form)
Question: How do you explain the relative acidity of the
following series?
H
3C
O
CF
3H
3C
O
CH
3H
3C
O
OR H
3C
O
NR
2
> > >
most acidic least acidic
The aromatic electrophilic substitution chart is a good proxy
for the ability of a functional group to donate to a carbonyl:
Substitution of the α-carbon by a second carbonyl
derivative makes the α-proton even more acidic:
O
Me
O
Me
O
OMe
O
Me
O
OMe
O
MeO
pKa = 9 pKa = 11 pKa = 13
NR
2 , O>OH > OR, NHAc > CH
3, R > Cl, Br, F, I > C(O)OR
CF
3, etc.
CH
2
H H
H H
LiNEt
2
NEt
2
M
highly unstable
CH
3
NEt
2
does not form
H
H H
LiNEt
2
O
O
H
Et
2N
O
O
t-Bu
Li
Et
2N
O
O
t-Bu
H
H
X
X
forms readily!
t-Bu
Likewise, the presence of a carbonyl group activates alkenes toward
nucleophilic attack:
enolate: stabilized!
O
CF
3
O
Me
O
OR
O
NR
2
The reactivity of the alkene toward nucleophilic attack is directly related
to the stability of the enolate that forms -
> > >
increasing reactivity toward nucleophilic attack
increasing stability of enolate
Can predict the course of the reaction by pKa!
Enolate = deprotonated enol
Carbonyl compound
H
3C
O
OEt
O
OEt
H
H
ester enolate
O-bound form
O
OEt
H
H
N
i-Pri-Pr
Li (LDA)
Li
Li
C-bound form
(or other
strong base)
Important: the Enolate is a NUCLEOPHILE
Two key examples:
O
OEt
O
R H
M O
OEt
OH
R
O
OEt
O
R OR
M O
OEt
OH
R
note: though an ester enolate
is shown here, the reaction of
any enolate with an aldehyde
is generally called an "Aldol".
Aldol reaction
Claisen Condensation
Key Reaction: Enolate Formation
O
OR
O
RO
>
Amphiphilic =nucleophilic at both O and C;
here we focus on the reactions at C.
Name Structure
aldehyde
R
O
H
ketone
R
O
R'
ester
R
O
OR
amide
R
O
NR
2
carboxylic
acid R
O
OH
acid
chlorideR
O
Cl
anhydride
R
O
O
nitrile R–CN
lactone
(cyclic
ester)
O
O
( )
n
lactam
(cyclic
amide)
O
NH(R)
( )
n
*
*
NH
2 = 1° amide
NHR = 2 ° amide
NR
1R
2 = 3 ° amide
O
R
1)evans.harvard.edu/pdf/evans_pKa_table.pdf
2) www.chem.wisc.edu/areas/reich/pkatable/
Key Concept: Tautomerism
O
C
H
2
R
OH
R
H
H
keto form enol form
Tautomerism: a form of isomerism where
a keto converts to an enol through the movement of
a proton and shifting of bonding electrons
H
For acetone (R=CH
3) the keto:enol ratio is ~6600:1 at 23
°C. Main reason is the difference in bond strengths between
the two species.
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. >10
6
: 1 keto: enol for ethyl acetate)
Acetone in D
2O will slowly incorporate deuterium at the α−
carbon. The enol form is responsible for this behavior.
The rate of keto/enol tautomerism is greatly increased by
acid (see below right)
Example pKA* of
H
H
3C
O
H
17
H
3C
O
Me
20
H
3C
O
OMe
H
2CO
O
H
2CN
O
Me
O
NMe
2H
2C
H
3C
O
OH
H
3C
O
Cl
H
3C
O
O
O
Me
Me-CN
For a comprehensive list of pKa values see:
25
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.
The goal here is clarity and consistency. I
would greatly appreciate feedback on any
errors, omissions, or suggestions for
improvements. Thanks!
30
Note 2
Note 2
Note 1
Note 1: The carboxylic acid is deprotonated
first. Subsequent deprotonation of the α-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.
Note 2: It is difficult to measure the pKa of
these species due to their reactivity.
Effects on acidity of alkyl groups Effect on reactivity of alkenes:
The rate of keto/enol interconversion isgreatly enhanced by acid:
Five factors that influence the relative
proportion of keto/enol:
O
R
R
HH
H X
O
R
R
H
H
X:
Acid makes carbonyl more electrophilic, increasing acidity of α-
protons, facilitating formation of enol: this increases K
1
O
R
R
HH
Keto Enol
Enol is nucleophilic at α-carbon, acid is
excellent electrophile: this increases K
2
K
1
K
2
H
H X
Net result: Addition of acid speeds proton
exchange between the keto and enol forms.
*source: P. Y. Bruice, "Organic Chemistry"
25
1. Aromaticity
O OH
ExclusiveNot observed
2. Hydrogen bonding stabilizes the enol form.
O O
MeMe
O O
MeMe
H
H-bond
24 : 76(at 23 °C)
3. Strongly hydrogen bonding solvents can disrupt
this, however. The above equilibrium is 81:19
using water as solvent.
O
Me
4. . Conjugation is stabilizing.
OH
Me
Preferred enol form
5. As with alkenes, increasing substitution increases
thermodynamic stability (assuming equal steric factors)