Enolate Formation & Selectivity
30
Enolate Formation and Reactivity Grace C. Wang MacMillan Group Meeting March 12, 2008
Transcript of Enolate Formation & Selectivity
Enolate Formation and Reactivity
Grace C. WangMacMillan 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. 1Ian Fleming, Frontier Orbitals and Organic Chemical ReactionsDavid A. Evans, Asymmetric Synthesis, Volume 3, Stereodifferentiating Additions Reactions, Part BPrimary literature cited within
E vs. Z selectivity
(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:
R
OLi
Me
R
O
Me
R
O
Me
O
Me
R
Li
R
OLi
Me
Rathke, M. W. JACS, 1980, 102, 3959.
R
O
Me
R
OLi
Me
R
OLi
Me
Li-NR2
Sterics Affect Enolization by Lithium Amides
(E)-enolatepreferred
(Z)-enolate
O
H
NLi
RMe
R
R
H
O
H
NLi
R
Me
H
R
R
Evans's 206 Notes, Lecture 24Adaptation from Ireland, et al. JACS, 1976, 98, 2868.
• Avoidance of a syn-pentane interaction in the transition state favors the (E)-enolate
i-Pr
O
i-Pr
OLi
Me
i-Pr
OLi
Me
Stereoelectronics Also Affect Enolization
(E)-enolate
(Z)-enolatepreferred
O
H
NLi
i-PrMe
H
PhCN
H
O
H
NLi
i-PrH
H
PhCN
Me
Xie, L. et al. JOC, 2003, 68, 641-3.
E:Z ratio was 2:980 °C, THF
Me
LiHN CN
i-Pr
O
i-Pr
OLi
Me
i-Pr
OLi
Me
Stereoelectronics Also Affect Enolization
(E)-enolate
(Z)-enolatepreferred
O
H
NLi
i-PrMe
Ph
Ph
H
O
H
NLi
i-PrH
Ph
Ph
Me
Xie, L. et al. JOC, 2003, 68, 641-3.
E:Z ratio was 0:1000 °C, THF
Me
LiN
Ph Ph
•Substantial stabilization of the electron density on the amide nitrogen leads to a significantly loose transition state, thus favoring the (Z)-enolate.
Me
OSnBu3
Et
Me
O
Me R3
Et Me5 mol% Bu3SnOMe
2 equiv R3CH2Xo-xylene, -27 °C, 48 h
73-86% yield76-81% 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
NCr
N
O OIMe2ThSiO
Me2ThSiO OSiThMe2
OSiThMe2
5 mol%
O
Me R3
nBu Me5 mol% Bu3SnOMe2 equiv R3CH2X
o-xylene, -27 °C, 48 h 77-97% yield84-78% ee
5 mol% {(salen)CrI}
Me
OSnBu3
Me
Et
+
1.8 : 1.0
Me
OSnBu3
nBu
MeMe
OSnBu3
Me
nBu
+
1.5 : 1.0
Me
O
Et Me
SnBu3
Me
O
nBu Me
SnBu3
Doyle, A. G.; Jacobsen, E. N. ACIEE, 2007, 46, 3701-5.
Enantioselective Alkylations of Tributyltin Enolates Catalyzed by a {Cr(salen)} Complex
RegioselectivityRegioselectivity in Enolate Formation
• Kinetic vs. thermodynamic control
O
R R'
• Product composition determined by relative rates of competing proton-abstraction reactions
• Deprotonation is rapid, quantitative, and irreversible.
• Favors less substituted enolate
+ B-
ka
kb
O
R'R
O
R'R
A
B
[A] ka
[B] kb=
Kinetic Control
Regioselectivity in Enolate Formation
• Kinetic vs. thermodynamic control
O
R R'+ B-
ka
kb
O
R'R
O
R'R
A
B
= K[A]
[B]K
Thermodynamic Control
• Product composition determined by relative thermodynamic stability of the enolates.
• Favors more substituted enolate (Zaitzev's Rule)
Regioselectivity
O
Me
base
conditions
OM
Me
OM
Me
base temp 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
Kinetic vs. Thermodynamic Control
A B
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.
0.98 equiv L-selectride-78 °C to 0 °C
N
OTf
CBzN
Cl
NTf2
N
OTf
CBz
9 : 173% yield
kineticthermodynamic
HN
NMe
MeO
Et TsOH-40 °C
50% NH
N
MeH Et
H
HN
N
O
CBz
Ar Ar
N
TfO
CBz
NH
Tasber, E. S.; Garbaccio, R. M. TL, 2003, 44, 9185-8.
A-1, 3 Strain Controls Enolate Regioselectivity
+
N
N
TfO H
H
Ar
H OTf
Ar
O
O
Ph
O
O
Ph
Ar N
O
CBz
0.98 equiv L-selectride-78 °C to 0 °C
N
Cl
NTf2
indole must adopt axial conformationto avoid syn-pentane interaction
thermodynamic kinetic
"H-"
N
OTf
CBz
N
OTf
CBz
Ar Ar
Tasber, E. S.; Garbaccio, R. M. TL, 2003, 44, 9185-8.
A-1, 3 Strain Controls Enolate Regioselectivity
Enolates: Ambident Nucleophiles
• Alkylation of an enolate can occur at either carbon or oxygen
R
O
+ R'XR
O
R'
R
O
+ R'XR
OR'
C-alkylation
O-alkylation
• What factors influence the C/O-alkylation ratio?
C vs. 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
• Prevalent in polar, aprotic solvents
• Metal chelators are effective additives
C-alkylation
• Favors smaller, harder cations due to tighter
coordination
• Prevalent in protic & apolar solvents
• Ideal in THF & DME
---Dissociation vs. clustering
Lithium, Sodium, and Potassium Enolates of PinacoloneExamples of Ion Clustering
Na
O
O
Na
Na O
NaO
OK
O KO
K
OK
KO
K
O
Li
O
O
Li
Li O
LiO
O
O
O
• Lithium enolate
• Sodium enolate
• Potassium enolate
OLi
ONa
OK
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
Me
OK
OEt
O
S
O
O
OEtEtO
Me
O
OEt
O
Et
+
solvent A B C
HMPA 15% 2% 83%
t-BuOH 94% 6% 0%
THF 94% 6% 0%
Me
O
OEt
O
Et
A B C
Et
• 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.
Me
OEt
OEt
O
O
!2
!1
!3
HOMO
LUMO
Using MO Theory to Understand Charge vs. Orbital Control
---Charge density/MO
O
!2
!1
!3
HOMO
LUMO
Using MO Theory to Understand Charge vs. Orbital Control
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.
O
!2
!1
!3
HOMO
LUMO
Using MO Theory to Understand Charge vs. Orbital Control
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.
---Hard-soft interactions
Nature of the Leaving Group
• Of the two nucleophilic sites on the enolate, oxygen is harder than carbon
Me
OK
OEt
O
Me
O
OEt
O
Et
+
X A B C
OTs 11% 1% 88%
Cl 32% 8% 60%
Br 38% 23% 39%
I 71% 16% 13%
Me
O
OEt
O
Et
A B C
Et
EtX
Me
OEt
OEt
O
• Hard---OTs > Cl > Br > I---Soft
• Greater O-alkylation is observed with harder electrophiles
• Greater C-alkylation is observed with softer nucleophiles
HMPA
Kurts, A. L. et al. Tet., 1971, 27, 4777.
Orbital Overlap(Baldwin's Suggestions)
• For enolate cyclizations, orbital overlap is imperative
• Oxygen and carbon sites on the enolate have different hybridizations
• Hybridization can have drastic effect on atom reactivity
O
R
sp2
sp3
O-M+
MeMe
Br
O-M+
MeMe
Br
MeMe
Br
O-M+O
O
Me
Me
not observed
Me
Me
productive overlap
single product
Baldwin, J. E.; Kruse, L. I. J. Chem. Com. 1977, 233-35.
M= K or Li
---Orbital overlap
Elements that dictate enolate !-facial selectivity
• Intraannular Chirality TransferAsymmetric center is connected to the enolate framework through cyclic array of covalent bonds.
•Extraannular Chirality TransferChiral moiety is not conformationally locked at "2 more contact points via covalent bonds to enolate
• Chelate-Enforced Intraannular Chirality TransferChelate 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.
Pi facial selectivity
O
OMe
LDA
MeI
-60 °CTHF
O
OMe
Me
> 99 : 1
O
OMe
Me
+
cis trans
Intraannular Chirality Transfer(Endocyclic Enolates)
Still, W. C.; Galynker, I. Tetrahedron, 1981, 37, 3981-96.
---Intraanular (endocyclicenolates)
O
HOMe
H
O
HOH
Me
O
MeOMe
H
H
O
MeOH
Me
H
O
OMe
LDA MeI
O
OMe
Me
back face of enolateshielded by ring
• Syn-pentane interactions discourage transition state necessary for forming trans product
O
OMe
LDA MeI
O
OMe
Me
syn-pentaneinteraction
• Lactone affords only (E)-enolate
• Ring shields one face of the formed enolate
Still, W. C.; Galynker, I. Tetrahedron, 1981, 37, 3981-96.
Intraannular Chirality Transfer
major product
minor product
Extraannular Chirality Transfer (Exocyclic Enolates)
• A-1, 3 strain dictates conformation of the imidazolate
• Bulky phenyl group directs alkylation toward Re face
N
N
Me
OLiH
Ph
Me PhCH2Br
-60 °CN
N
Me
OH
Ph
Me
N
N
CH2Ph
OH
Ph
MeCH2Ph Me+
>> 95 : 5
Schollkopf, U. et al. Liebigs. Ann. Chem. 1981, 439.
---Extraannular (exocyclicenolates)
---CHELATION!!!!!!!!!!!!
Me
OH
Me
O
OEt
1) 2 equiv. LDA2) ICH2CHR
Me
OH
Me
O
OEt
CHR
86% ee
Me
O
Me
O
OEt
Li
OLi O
H
Me
EtO
approach from side ofhydrogen less hindered
Chelation Affects Pi Facial Selectivity
Frater, G. TL, 1981, 22, 425.
• 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)
Summary
