Enolate Formation and Reactivity
Grace C. Wang
MacMillan Group Meeting
March 12, 2008
Aspects of Enolates that will be Discussed
• (E) versus (Z) selectivity
• Enolate formation regioselectivity
• O vs. C alkylation
• Factors that influence !-facial selectivity
Aspects of Enolates that will NOT be Discussed
• Aldol reactions
• Chiral auxiliaries
• Chiral catalysts
Important references:
Carey & Sundberg, Advanced Organic Chemistry, Part B, Ch. 1
Ian Fleming, Frontier Orbitals and Organic Chemical Reactions
David A. Evans, Asymmetric Synthesis, Volume 3, Stereodifferentiating Additions Reactions, Part B
Primary literature cited within
(E) vs. (Z) Selectivity
• In the absence of a catalyst or auxiliary, enolate selectivity can be difficult to maintain.
•Rathke proposes an aldol addition-reversion process for ketone enolate equilibrium:
O
OLi
R
O
Li
Me
R
R
Me
O
OLi
R
Me
R
Me
Me
Rathke, M. W. JACS, 1980, 102, 3959.
Sterics Affect Enolization by Lithium Amides
OLi
R
O
R
H
Li N R
H
R
Me
Me
(E)-enolate
preferred
O
Li-NR2
R
Me
OLi
R
O
R
H
Me
Li N R
H
R
Me
(Z)-enolate
• Avoidance of a syn-pentane interaction in the transition state favors the (E)-enolate
Evans's 206 Notes, Lecture 24
Adaptation from Ireland, et al. JACS, 1976, 98, 2868.
Stereoelectronics Also Affect Enolization
O
i-Pr
H
H
N
Li
H
Me
OLi
PhCN
i-Pr
Me
(E)-enolate
LiHN
O
i-Pr
CN
Me
0 °C, THF
E:Z ratio was 2:98
O
i-Pr
H
OLi
H
Me
Li
N
H
PhCN
i-Pr
Me
(Z)-enolate
preferred
Xie, L. et al. JOC, 2003, 68, 641-3.
Stereoelectronics Also Affect Enolization
O
i-Pr
Ph
H
N
Li
H
Me
OLi
Ph
i-Pr
Me
(E)-enolate
O
i-Pr
Ph
Li
N
Ph
Me
0 °C, THF
E:Z ratio was 0:100
O
i-Pr
H
OLi
Ph
Me
Li
N
H
Ph
i-Pr
Me
(Z)-enolate
preferred
•Substantial stabilization of the electron density on the amide nitrogen leads to a significantly loose
transition state, thus favoring the (Z)-enolate.
Xie, L. et al. JOC, 2003, 68, 641-3.
Enantioselective Alkylations of Tributyltin Enolates Catalyzed by a {Cr(salen)} Complex
N
N
Cr
O I O
Me2ThSiO
OSnBu3
O
SnBu3
Me
Et
OSnBu3
Me
Me
+
Et
Me
OSnBu3
SnBu3
Me
nBu
:
Me
Me
Me
1.0
O
5 mol%
Me
+
nBu
Me
Me
:
1.0
R3
Et
Me
73-86% yield
76-81% ee
O
OSnBu3
nBu
1.5
OSiThMe2
5 mol% Bu3SnOMe
2 equiv R3CH2X
o-xylene, -27 °C, 48 h
Me
1.8
O
Et
Me
Me2ThSiO
OSiThMe2
5 mol% {(salen)CrI}
5 mol% Bu3SnOMe
2 equiv R3CH2X
o-xylene, -27 °C, 48 h
Me
R3
nBu
Me
77-97% yield
84-78% ee
• A variety of sp3 alkyl bromides and alkyl iodides used as electrophiles
• Enantioselectivity of disubstituted ketone product not limited by E/Z ratio of enolate isomers
Doyle, A. G.; Jacobsen, E. N. ACIEE, 2007, 46, 3701-5.
Regioselectivity in Enolate Formation
• Kinetic vs. thermodynamic control
Kinetic Control
O
R'
R
A
ka
O
R
R'
+
[A]
[B]
B-
=
kb
O
R
R'
B
• Product composition determined by relative rates of competing proton-abstraction reactions
• Deprotonation is rapid, quantitative, and irreversible.
• Favors less substituted enolate
ka
kb
Regioselectivity in Enolate Formation
• Kinetic vs. thermodynamic control
Thermodynamic Control
O
R'
R
A
ka
O
R
R'
+
B-
[A]
[B]
K
kb
O
R
R'
B
• Product composition determined by relative thermodynamic stability of the enolates.
• Favors more substituted enolate (Zaitzev's Rule)
= K
Kinetic vs. Thermodynamic Control
base
O
Me
OM
OM
Me
conditions
A
base
temp
Me
B
ratio (A/B) control
LiN(i-C3H7)2
0 °C
99:1
kinetic
KN(SiMe3)2
-78 °C
95:5
kinetic
Ph3CLi
-78 °C
90:10
kinetic
Ph3CK
25 °C
67:33
kinetic
Ph3CK
25 °C
38:62
thermodynamic
NaH
25 °C
26:74
thermodynamic
Ph3CLi
25 °C
10:90
thermodynamic
House, H. O. et al. JOC, 1969, 34, 2324.
Brown, C. A. JOC, 1974, 39, 3913.
Stork, G., Hudrlik, P. F. JACS, 1968, 90, 4464.
A-1, 3 Strain Controls Enolate Regioselectivity
TfO
O
N
N
Me
N
H
Et
Me
N
TsOH
-40 °C
Et
CBz
H
Me
H
N
H
50%
HN
OTf
O
OTf
0.98 equiv L-selectride
-78 °C to 0 °C
N
HN
+
Cl
Ar
N
Ar
CBz
CBz
N
N
CBz
NTf2
thermodynamic
kinetic
9
1
:
73% yield
Tasber, E. S.; Garbaccio, R. M. TL, 2003, 44, 9185-8.
A-1, 3 Strain Controls Enolate Regioselectivity
O
Ar
"H-"
N
CBz
Cl
0.98 equiv L-selectride
-78 °C to 0 °C
N
NTf2
Ar
O
O
H
N
TfO
H
Ar
H N
Ph
O
Ph
O
thermodynamic
kinetic
OTf
Ar
N
CBz
OTf
indole must adopt
axial conformation
to avoid synpentane interaction
OTf
Ar
N
CBz
Tasber, E. S.; Garbaccio, R. M. TL, 2003, 44, 9185-8.
Enolates: Ambident Nucleophiles
• Alkylation of an enolate can occur at either carbon or oxygen
O
O
+
R
R'X
R
C-alkylation
R'
O
R
OR'
+
R'X
• What factors influence the C/O-alkylation ratio?
R
O-alkylation
Elements that Dictate O-Alkylation vs. C-Alkylation Ratios
• Dissociation vs. clustering of ions
Metal
Solvent
• Charge vs. Orbital Control
• Hard-soft compatibility
Leaving group
• Stereoelectronics
Orbital Overlap
Dissociated versus Aggregated Enolates
• O-alkylation is prevalent when the enolate is dissociated
• C-alkylation is prevalent where ion clustering occurs
O-Alkylation
C-alkylation
• Prevalent in polar, aprotic solvents
• Favors smaller, harder cations due to tighter
coordination
• Metal chelators are effective additives
• Prevalent in protic & apolar solvents
• Ideal in THF & DME
Lithium, Sodium, and Potassium Enolates of Pinacolone
Examples of Ion Clustering
• Lithium enolate
O
Li
O
Li
OLi
O
Li
• Sodium enolate
ONa
O
Li
O
O
Na
O
O
Na
O
Na
• Potassium enolate
K
OK
O
O
K
O
K
O
Na
O
K
O
K
O
K
O
Williard, P.G. and Carpenter, G.B. JACS, 1986, 108, 462-8.
Seebach, D.; Dunitz, J.D. et al. Helv. Chim. Acta. 1981, 64, 2617.
Dissociation vs. clustering of ions
• O-alkylation is prevalent when the enolate is dissociated
• C-alkylation is prevalent where ion clustering occurs
OK
Me
O
O
OEt
+
EtO
S
O
O
OEt
Me
O
OEt
Et
A
solvent
A
O
O
Et
Et
Me
OEt
OEt
B
O
Me
OEt
C
B
C
HMPA
15%
2%
83%
t-BuOH
94%
6%
0%
THF
94%
6%
0%
• HMPA promotes ion dissociation, favoring O-alkylation
• THF promotes ion clustering, favoring C-alkylation
• t-BuOH hydrogen-bonds with enolate anion, favoring C-alkylation
Kurts, A.L. et al. Dokl. Akad. Nauk. SSR (Engl. Transl.) 1969, 187, 595.
Using MO Theory to Understand Charge vs. Orbital Control
!3
LUMO
!2
HOMO
!1
O
Using MO Theory to Understand Charge vs. Orbital Control
!3
LUMO
!2
HOMO
!1
O
Charge control
• Reaction occurs at the atom carrying the highest total electron density
• Predominant with charged electrophiles (e.g., H+)
Klopman, G.; Hudson, R. F. Theoret. Chim. Acta (Berl.) 1967, 8, 165-74.
Using MO Theory to Understand Charge vs. Orbital Control
!3
LUMO
!2
HOMO
!1
O
Charge control
• Reaction occurs at the atom carrying the highest total electron density
• Predominant with charged electrophiles (e.g., H+)
Orbital control
• Reaction occurs at the atom whose frontier electron density is the highest
• Predominant with neutral electrophiles with relatively low-lying LUMOs
Klopman, G.; Hudson, R. F. Theoret. Chim. Acta (Berl.) 1967, 8, 165-74.
Hard-Soft Acid Base Interactions
(Leaving-Group Effects)
O-alkylation (charge control)
• Predominant with hard leaving groups
• Favored by an early transition state, where charge distribution is the most important factor
•Favored by conditions that afford a dissociated, more reactive enolate
C-alkylation (orbital control)
• Predominant with soft leaving groups
• Favored by a later transition state, where partial bond formation is the dominant factor
• More stable than the O-alkylation product
E (C=O + C-C) > E (C=C + C-O)
(745 + 347) kJ/mol > (614 + 358) kJ/mol
1097 kJ/mol > 972 kJ/mol d
Bond energy values taken from Zumdahl, Chemical Principles, 5th ed.
Nature of the Leaving Group
• Of the two nucleophilic sites on the enolate, oxygen is harder than carbon
OK
Me
O
HMPA
OEt
+
O
O
O
EtX
Me
OEt
Me
Et
OEt
OEt
Et
A
X
O
O
Me
OEt
Et
B
C
A
B
C
OTs
11%
1%
88%
Cl
32%
8%
60%
Br
38%
23%
39%
I
71%
16%
13%
• Hard---OTs > Cl > Br > I---Soft
• Greater O-alkylation is observed with harder electrophiles
• Greater C-alkylation is observed with softer nucleophiles
Kurts, A. L. et al. Tet., 1971, 27, 4777.
Orbital Overlap
(Baldwin's Suggestions)
• For enolate cyclizations, orbital overlap is imperative
sp3
• Oxygen and carbon sites on the enolate have different hybridizations
O
• Hybridization can have drastic effect on atom reactivity
R
sp2
O-M+
Me
Me
O-M+
Br
M= K or Li
Me
Me
not observed
Br
Me
Me
O
Me
Me
O-M+
Me
Me
O
single product
Br
productive overlap
Baldwin, J. E.; Kruse, L. I. J. Chem. Com. 1977, 233-35.
Pi facial selectivity
Elements that dictate enolate !-facial selectivity
• Intraannular Chirality Transfer
Asymmetric center is connected to the enolate framework through cyclic array of covalent bonds.
•Extraannular Chirality Transfer
Chiral moiety is not conformationally locked at "2 more contact points via covalent bonds to enolate
• Chelate-Enforced Intraannular Chirality Transfer
Chelate provides organizational role in fixing orientation between resident asymmetric center and enolate
system.
Evans, D. A. "Stereoselective Alkylation Reactions of Chiral Metal Enolates". Asymmetric Synthesis. Vol. 3, 1-110.
enolates)
Intraannular Chirality Transfer
(Endocyclic Enolates)
LDA
MeI
O
Me
O
-60 °C
THF
O
Me
Me
+
O
> 99
cis
O
Me
:
Me
O
1
trans
Still, W. C.; Galynker, I. Tetrahedron, 1981, 37, 3981-96.
Intraannular Chirality Transfer
• Lactone affords only (E)-enolate
• Ring shields one face of the formed enolate
LDA
O
Me
Me
O
H
O
H
MeI
Me
O
H
Me
O
H
O
O
Me
back face of enolate
shielded by ring
Me
O
major product
• Syn-pentane interactions discourage transition state necessary for forming trans product
LDA
O
Me
H
O
Me
O
H
O
syn-pentane
interaction
MeI
H
H
Me
O
Me
O
Me
O
Me
O
minor product
Still, W. C.; Galynker, I. Tetrahedron, 1981, 37, 3981-96.
enolates)
Extraannular Chirality Transfer
(Exocyclic Enolates)
• A-1, 3 strain dictates conformation of the imidazolate
• Bulky phenyl group directs alkylation toward Re face
Me
Ph
OLi
H
Me
N
N
PhCH2Br
-60 °C
Me
Ph
O
H
CH2Ph
Me
N
+
Me
Ph
O
H
Me
CH2Ph
N
N
>> 95
N
:
5
Schollkopf, U. et al. Liebigs. Ann. Chem. 1981, 439.
Chelation Affects Pi Facial Selectivity
OH
O
OEt
Me
OH
1) 2 equiv. LDA
2) ICH2CHR
O
Me
Me
OEt
Me
CHR
86% ee
O
Li
Me
EtO
O
OEt
Me
O
Li O
H
approach from side of
hydrogen less hindered
Me
Frater, G. TL, 1981, 22, 425.
Summary
• Enolate formation
• (E) vs. (Z) selectivity (sterics, electronics)
• Regioselectivity (thermodynamics vs. kinetics, sterics)
• Enolate Reactivity
• O vs. C alkylation (dissociation vs. clustering of ions, charge vs. orbital control, hard-soft interactions,
orbital overlap)
• Pi facial selectivity (intraannular chirality transfer, extraannular chirality transfer, chelation)