Ch. 7 - Enolates

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Ch. 7 - Enolates
651.06
Enolates
Enolates are the conjugate anions of carbonyl compounds. Although they have been
known and used since the turn of the 20th Century, it was the development of “specific
enolates” (see below) by H. O. House of MIT in the 1960-1970s that made carbanion
chemistry one of the most important tools for stereo- and regio-controlled carbon-carbon
bond formation in organic synthesis. That importance continues to this day.
Generation of enolates by α−deprotonation of carbonyls:
O
O
base
Y
O
Y
Y
H
B:
Y=H, alkyl, OR, NR2 , SR
•
Relevant acidity data:
Compound
pKa
aldehyde
~20
ketone
~20
cyclic ketone
~17
β-dicarbonyl
11-13
ester
~25
nitrile
~25
Compare these pKa’s to the basicity values (as conjugate acid pKa’s) of common bases:
R2N- pKaconj = 35
RO- pKaconj = 16 (R = Me) - 18 R = t-Bu)
R3N pKaconj = 9-11
Conclusion:
O
O
MeO
O
NaOMe
OMe
pKa = 13
MeOH
(pKa = 16)
O
Na
MeO
O
OMe
ONa
pKeq = 16-17 = -1
Keq = 10-1
NaOMe
pKa = 17
MeOH
(pKa = 16)
O
OLi
Li
pKa = 17
pKeq = 16-13 = 3
Keq = 103
+ -
N(i-Pr)2
+ HN(i-Pr)2
pKa = 35
209
pKeq = 35-17 = 18
Keq = 1018
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Structure of Enolates
A.
C- vs O- Metallation
OM
O
although often drawn as resonance, this is
usually tautomerism (a fast equilibrium)
M
note: !-diketones form cyclic chelate
covalent C-M bond (true
for electronegative M,
e.g. Hg++, Cu++, Zn ++)
B.
ionic O-M bond
(electropositive M, e.g. Li+,
Na+, K+, Mg++ )
O
R
M
O
R
Aggregation State
1.
Although typically drawn as monomeric species, enolates in solution are
usually found as higher aggregates (dimers, tetramers).
2.
The exact aggregation state depends on solvent and counterion.
Li
O
O
Li
O
Li
Li
O
generalized structure of solvated tetramer
3.
Smaller counterions (e.g. Li+) favor tetramer while larger ones (e.g. K+,
Cs+) favor dimer.
4.
Et2O favors dimer, but THF and DME favor tetramer.
5.
Generally speaking, tetrameric enolates react as carbon nucleophiles.
6.
References:
House, J. Org. Chem. 1971, 36, 2361 (original suggestion)
Jackman, Tetrahedron, 1977, 33, 273 (NMR studies)
Dunitz, Helv. Chim. Acta. 1981, 64, 2617 - 2622 (x-ray
st udies)
see also J. Am. Chem. Soc. 1985, 107, 5403; Tetrahedron
Lett. 1989, 447
210
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C.
Regiochemistry (which side of carbonyl deprotonates?)
O
O
base
O
more stable
O
O
O
base
O
O
more stable
O
O
less stable
O
less stable
O
base
more stable
D.
less stable
Stereochemistry
O
O
base
Z-enolate
E-enolate
OM
OM
O
base
OR
O
RO
RO
(M = Li)
E-enolate
Z-enolate
(M = Li)
Z-enolate
E-enolate
211
651.06
Stereochemistry of Deprotonation
OLi
O
CH3
X
LDA
OLi
CH3
X
+
X
CH3
"Z"
"E"
X
OMe
“E”
95
“Z”
5
Ot-Bu
95
5
Et
77
23
i-Pr
40
60
t-Bu
0
100
Ph
0
100
NEt2
0
100
Large X yields Z
212
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II. Generation of enolates
A. Deprotonation of active hydrogens
1.) Thermodynamic conditions
O
O Na
NaOMe
+ MeOH
MeOH
Keq = 10-2 (favors s.m.)
O
O
MeO
O
NaOMe
MeOH
OMe
Na
MeO
O
+
MeOH
OMe
essentially irreversible
O
O Li
0.95 eq LDA
equilibrium established with s.m.
O
O Na
NaH
Why an Equilibrium?
2.) “Kinetic” conditions
O
O
NH2
irreversible
KNH2, LiNH2, and NaNH2 are insoluble in organic solvents so LiNR2 was developed
R = Et, i-Pr, (i-Pr, cyclohexane), or t-Bu
development of “specific” enolates: House, JOC, 28, 1963, 3362
30, 1965, 1341, 2502
34, 1969, 2324
213
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3.) Regiochemistry of deprotonation
OTMS
OTMS
1) LDA
O
2) TMS-Cl
1) Et 3N
84%
7%
9%
OTMS
kinetic
13%
58%
29%
thermo.
2) TMS-Cl
O Li
O
LDA
> 95% kinetic
t-BuOK
O K
t-BuOH
or KH or LDA/HMPA
(9:1) thermo.
H
H
+
H
TMSO
1) Ph3C Li
13%
2) TMS-Cl
O
H
TMSO
H
1) .95 (eq) Ph3C Li
53%
2) HMPA, TMS-Cl
H
87%
47%
4.) Stereochemistry of deprotonation
OM
O
R
C H3
R
Z
C H3
OM
E
R
C H3
House, JOC, 1963, 28, 3362
214
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How to Determine? Make Si(CH3)3 ether: 1H-NMR, 13C–NMR
(Heathcock, JACS, 1979, 44, 429)
nOe (Oppolzer, TL, 1983, 24, 495)
Ireland does Claisen:
O
[3,3]
OTMS
OTMS
O
O
OTMS
CO2TMS
O
syn
Z
O
O
OTMS
OTMS
O
O
[3,3]
OTMS
anti
E
Ex:
C H3
base
C H3
O
+
O Li
O Li
base
Li
N
CO2TMS
Z
E
(-78˚)
14
:
86
'', HMPA
92
:
8
LDA (-78˚)
23
:
77
LICA (-78˚)
35
:
65
Why kinetic preference for E?
215
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Look at T.S. for deprotonation:
H
O
JACS, 1976, 98, 2868
R
E
Li
R'
N
H
R'
N.B. e- 's abstracted proton " to ! system
not bad
R
O
H
Z
Li
R'
N
H
R'
"1,3 diax."
This view of the T.S accounts for both stereo- and regio- specificity
O
R
-Hb
H
'R
O
Hb
O
Li
N H
favorable
R'
R
Ha
Hb
O
R
-Ha
R
'R
O
Li
N
H
R'
R = CH3 ⇒ 99:1
R = Ph ⇒ ≥ 99:1
R = OCH3 ⇒ 85:15
R = NMe2 ⇒ 98:2
216
unfavorable
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For acyclic ketones, we have A(1,2) strain to consider
A(1,2)
H
Me
X
O
X
H
H
O
Me
Li
R'
N H
R'
O
X
E
Me
LiNR'2
X
Me
O
H
Z
Li
R'
N H
R'
O
X
increasing
bulk of
X
Me
LDA
X
E:Z
OCH3
Ot-Bu
Et
i-Pr
t-Bu
Ph
NEt2
95:5
95:5
77:23
40:60
0:100
0:100
1:100
caveat: need conditions in which
Li coordinates O
(i.e., no HMPA, 18C-6, polar solvents)
All 3o amides give Z-enolates
Stereoselectivity of LDA/HMPA w/ ketones; esters - Ireland, JOC,1991, 56, 650-657
217
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Reactions Of Enolates
enolates = functionalized carbon nucleophiles
(Others are CN, CCR, RMgX, RLi)
∴ react with electrophilic carbon
2 types:
C X
O
sp3
First type gives enolate alkylation
Enolate Alkylation
M
O
R
X
SN2
O
R
+
MX
(note: X must be Br, I, OTs, OMs or OTf to get decent reactivity)
Considerations:
C- vs. O- alkylation
enolates are ambident nucleophiles; can react at C or O
a
O
R
X
a
O
R
b
b
O
R
What influences C- vs. O- ratio?
House, JOC, 1973, 38, 515
218
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a. hard/soft electrophiles
O
"hard" anion (localized)
"soft" anion (delocalized)
C- alkylation with soft electrophiles (R-I, R-Br)
M
O
O-M bond affects C/O ratio
Also,
(As O-M → covalent, O is less reactive)
(As O-M → ionic, O is more reactive)
So:
Li
Na
K
NMe4
covalent
C/O ratio
ionic
rate
cyclic β-diketones are especially “hard”
O
O
O
O
Br
+
K2CO3
OH DMF
O
vinylogous
acid
O
O
37%
15%
O-
C-
Also phenolates:
O Na
O
PhCH2 Br
DMF
97%
219
Ph
651.06
b. Solvent
polar, aprotic solvents (HMPA, DMSO, DMF) solvate M+ ion
⇒ make “naked” anion (very hard) ⇒ favors O- alkylation
O Na
OH
PhCH2 Br
CF3CH2OH
C H2Ph
solvents which promote aggregation (e.g., THF) favor C-alkylation by making enolate
less accessible
c. Structure of electrophile
O
O
R-Br
OEt
O
O
OR
neat
OEt
O
+
OEt
R
R=
n-Pr
i-Pr
Br
:
:
:
:
97
73
100
100
PhCH2 Br
3
27
0
0
Why? Hindered carbon is “harder”
Conclusion - Usually, use Li+ enolate in THF
Ex:
O Li
O
R-X
R
THF
also, R will usually be methyl, 1˚, allylic, benzylic, (2˚ gives elimination)
X = -Br, -I
-When reactivity is a problem, we can increase rate using K+ as counterion (but run the
risk of competing reactions arising from basicity of enolate)
220

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