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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
Y
H
B:
baseO
Y
O
Y
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- pKa
conj = 35 RO- pKaconj = 16 (R = Me) - 18 R = t-Bu) R3N pKa
conj = 9-11 Conclusion:
MeO
O
OMe
O
pKa = 13
NaOMe
MeOH
(pKa = 16)
MeO
O
OMe
ONa
pKeq = 16-13 = 3
Keq = 103
O
NaOMe
MeOH
(pKa = 16)pKa = 17
ONa
pKeq = 16-17 = -1
Keq = 10-1
O
pKa = 17
OLi
pKeq = 35-17 = 18
Keq = 1018Li+ -N(i-Pr)2
+ HN(i-Pr)2
pKa = 35
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Structure of Enolates
A. C- vs O- Metallation
M
O OM
covalent C-M bond (true
for electronegative M,
e.g. Hg++, Cu++, Zn++)
ionic O-M bond
(electropositive M, e.g. Li+,
Na+, K+, Mg++)
although often drawn as resonance, this is usually tautomerism (a fast equilibrium)
note: !-diketones form cyclic chelate
R
O
R
OM
B. 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 Li
O
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
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C. Regiochemistry (which side of carbonyl deprotonates?) O
O
baseO O
more stable less stable
O Obase
O O O O
more stable less stable
base
O O
more stable less stable D. Stereochemistry
Obase
O O
Z-enolate E-enolate
OR
O
base
RO
OM
RO
OM
Z-enolate E-enolate
E-enolate Z-enolate(M = Li)
(M = Li)
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X
CH3
O
LDA
Stereochemistry of Deprotonation
X
CH3
OLi
X
OLi
CH3
+
"Z" "E"
X “E” “Z” OMe
95 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
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II. Generation of enolates A. Deprotonation of active hydrogens 1.) Thermodynamic conditions
O
NaOMe
MeOH
O Na
+ MeOH
Keq = 10-2 (favors s.m.)
MeO OMe
O ONaOMe
MeOHMeO OMe
O ONa
+ MeOH
essentially irreversible
O
0.95 eq LDA
O Li
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
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3.) Regiochemistry of deprotonation
O
1) LDA
2) TMS-Cl
1) Et3N
2) TMS-Cl
OTMS OTMS
OTMS
84% 7% 9%
13% 58% 29%
kinetic
thermo.
O
O Li
O K
LDA
t-BuOK
t-BuOH
or KH or LDA/HMPA (9:1) thermo.
> 95% kinetic
H
HO
H
HTMSO
H
HTMSO
+
1) Ph3C Li
2) TMS-Cl13% 87%
53% 47%1) .95 (eq) Ph3C Li
2) HMPA, TMS-Cl 4.) Stereochemistry of deprotonation
RCH3
OR
CH3
OM
Z
R
OM
CH3
E
House, JOC, 1963, 28, 3362
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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
O
O
OTMS
O
OTMS O
OTMS
O
OTMS
CO2TMS
O
OTMS
O
OTMS
CO2TMS
Z
E
[3,3]
[3,3]
syn
anti Ex:
O
CH3
O Li
base+
O Li
CH3
Z E
14 92
23
35
86
8
77
65
:
:
:
:
base
N
'', HMPA
LDA (-78˚)
LICA (-78˚)
Li (-78˚)
Why kinetic preference for E?
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Look at T.S. for deprotonation: JACS, 1976, 98, 2868
NH
O
Li
R'
R'
RH
not bad
NH
O
Li
R'
R'
HR
"1,3 diax."
N.B. e- 's abstracted proton to ! system "
E
Z
NH
O
Li
R'
'R
H
NH
O
Li
R'
'R
R
R
R
O
O
favorable
unfavorable
R
Ha
Hb
Hb
O
-Hb
-Ha
This view of the T.S accounts for both stereo- and regio- specificity
R = CH3 ⇒ 99:1 R = Ph ⇒ ≥ 99:1 R = OCH3 ⇒ 85:15 R = NMe2 ⇒ 98:2
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NH
O
Li
R'
R'
X
HMe
E
Z
LiNR'2
NH
O
Li
R'
R'
X
MeH
O
H Me
H
X
A(1,2)
For acyclic ketones, we have A(1,2) strain to consider
XMe
O
XMe
OLDA
X E:Z
OCH3Ot-BuEti-Prt-BuPhNEt2
95:595:577:2340:600:1000:1001:100
increasingbulk of X
All 3o amides give Z-enolates
caveat: need conditions in whichLi coordinates O (i.e., no HMPA, 18C-6, polar solvents)
Stereoselectivity of LDA/HMPA w/ ketones; esters - Ireland, JOC,1991, 56, 650-657
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Reactions Of Enolates enolates = functionalized carbon nucleophiles
(Others are CN, CCR, RMgX, RLi) ∴ react with electrophilic carbon
2 types: C XO
sp3
First type gives enolate alkylation
Enolate Alkylation
O MR X SN2
R
O
+ M X
(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
O R X
R
O
OR
a
b
a
b
What influences C- vs. O- ratio? House, JOC, 1973, 38, 515
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a. hard/soft electrophiles
O "hard" anion (localized)
"soft" anion (delocalized)
C- alkylation with soft electrophiles (R-I, R-Br)
OM
Also, O-M bond affects C/O ratio
(As O-M → covalent, O is less reactive) (As O-M → ionic, O is more reactive)
So:
Li Na K NMe4C/O ratio
covalent ionic
rate cyclic β-diketones are especially “hard”
O
O
O
OH
O
O
O
O
+
Br
K2CO3DMF
vinylogous acid
37% 15%
O- C- Also phenolates:
O Na
PhCH2Br
DMF
OPh
97%
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b. Solvent polar, aprotic solvents (HMPA, DMSO, DMF) solvate M+ ion ⇒ make “naked” anion (very hard) ⇒ favors O- alkylation
O Na
PhCH2Br
CF3CH2OH
OH
CH2Ph solvents which promote aggregation (e.g., THF) favor C-alkylation by making enolate less accessible
c. Structure of electrophile
OEt
O OR-Br
neat OEt
O O
R
+OEt
OR O
R= n-Pr
i-Pr
Br
PhCH2Br
97
73
100
100
:
:
:
:
3
27
0
0
Why? Hindered carbon is “harder”
Conclusion - Usually, use Li+ enolate in THF Ex:
O Li O
RR-X
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)