Post on 26-May-2020
Topic 17: Enols, Enamines, and Enolates
Read: Molecular Orbitals and Organic Chemical ReactionsI. Fleming; section 4.3.2
Advanced Organic Chemistry. Part A: Structure and Mechanisms, 5th Ed., Francis A. Carey and Richard J. Sundberg; sections 6.4, 6.5
Check out: Herbert Mayr, et al. “π-Nucleophilicity in Carbon−Carbon Bond-Forming Reactions”Acc. Chem. Res. 2003, 36, 66–77.
Professor David L. Van VrankenChemistry 201: Organic Reaction Mechanisms I
OH
OH
..-
+....
..
Enols / Enol Ethers
■ What do you get when you mix two non-bonding lone pair MO with one pi MO?
■ HOMO is π-like, not lone pair-like.
■ THP Protection
■ Ferrier rearrangement
Bhate, P.; Horton, D.; Priebe, W. Carbohydr Res. 1985, 144, 331.
■ End carbon has larger HOMO coefficient, but the oxygen has more negative charge.
OH
OH
..-
+
HOMO
HOMO-1
HOMO-2
EMOSTO-3G
OH
OH
OH
....
..
0.618 -0.575
OHO
cat.TsOH
O
H
+O OH+ O O
O
OAcO
OSnCl4
+
-
MeOHSnCl4
CH2Cl225 °C, 30 min
O
AcO
+O
AcO
OR w/ MeOH76:14α/β
Tautomer Stability
■ Keto/enol tautomerism
■ Enol ether tautomerization with transition metal catalysts
Baudry, D.; Ephritikhine, M.; Felkin, H.JCS, Chem. Commun. 1978, 694MeO MeO 97%
THF22 °C, 33 h
Ir+ cat.
O
EtO
O
EtO
O OH
O
H
OH
H
..
O
CH2
Ph
10-2
0.2
10-3.6π acceptor
ketoKeq<10-8
10-8
10-5
O H
OO
RO
OO
RO
H
OO OO H
enol
H-bond
π acceptor+ H-bond
H
Enamines
■ Imine/enamine equilibrium is unfavorable
Enamine formation driven by azeotropic removal of water.
K. Lammertsma JACS 1994, 114, 642
Common:
■ Enolate equivalents
■ Relative reactivity
OHHOMO-1
NH
NH
HOMO OH
..-
+..
0.620 -0.650
H HEMO
STO-3G
O HN N
+ H2Odistilled
as azeotrope
toluene
120 °CN N
O
OH N O-Li... ..
< <.
N N+
OH2O
Br
..
Br-
N NHKeq = 2.6 H
H
Hsimilar amounts(vs. keto/enol)
Regioselective Enolate Formation
■ Thermodynamic regiocontrol isn't very good for ketones
more substituted
A1,3 strain (Don't worry about it until Chem 202)
F. Johnson Chem. Rev. 1968, 375.
House, H.O.; Kramar, V. J. Org. Chem 1963, 28, 3362.
■ Kinetic regiocontrol is excellent with LDA
Stork, G.; Kraus, G. A.; Garcia, G. A. J. Org. Chem. 1974, 39, 3959.
■ Thermodynamic regiocontrol can be great with enamines
MeKO
MeKO
52 : 48(±7) (±7)
BuKO
BuKO
58 : 42
Olefins: more substituted = more stable
MeN
MeN
THF, -78 °C
LDAinverse addn
BuLiO
BuLiO
100 : 0Bu
O
Stereoselective Enolate Formation
■ Et3N, NaH, KOtBu: Z enolate is more stable
Excess ketone catalyzes
E/Z isomerization
■ LDA: E enolate forms faster
Inverse addn = rapid, irreversible at -78 °C
JACS 1980, 102, 3959.
Ireland, et. al. JOC 1991, 56, 650.Ireland, et al. JACS 1978, 98, 2868Heathcock, et. al. JOC 1980, 45, 1066.
(Caution! C.I.P. assignments are confusing!)
■ LDA deprotonates through 6-membered ring chair T.S.
R. Ireland JACS 1976, 2868
more in Chem 204Don’t use the symbol B: for this mechanism.
Et
-O
Et
O
Et
-OE/Z 16:84ZE
O
Et
: LiNR
RO
Et
LiNRR+
-
..H chair
TS
O
Et
LiNRR
-
H
+O
Et
Li RNR
H OHNLi
R
H
Me
iPr
iPr
i-Pr2N–LiTHF, -78 °C
Et
OLi
3-pentanone
slight excessE/Z ~ 70:30
EtO
OLi
Ph
OLi
Z/E 94 : 6 E/Z <2 : >98
small big
Enolate Formation with LDA
■ Recall: Li enolates = 99% dimer, but monomer alkylates faster
Dave Collum JACS 2000, 2452.Collum, D. B. Acc. Chem. Res. 1993, 26, 227.
■ LDA is a dimer in THF… but reacts via the monomer rate ∝ [LDA]1/2
■ THF + HMPA generates E ester enolates
Ireland, et. al. JOC 1991, 56, 650.Also Fataftah, et al. JACS 1980, 102, 3959.
HMPA disrupts Ireland T.S.Note: LDA is still a dimer in HMPA!
THF, 23% HMPA -78 °C
EtO
OLi
ester
E/Z >90 : <10
SiMe3N
LiMe3Si
Enolate Formation by Metalation
■ Acetaldehyde enolate can't be made efficiently by deprotonation. Instead, you make it from THF.
Stanetty, P.; Mihovilovic, M. D. J. Org. Chem. 1997, 62, 1514.
■ n-BuLi has a half-life of 107 minutes in THF at 20 °C!
O LDA OLi aldol
Honeycutt, S. C. J. Organomet. Chem. 1971, 29, 1.
■ Lithiated THF fragments to give acetaldehyde enolate
n-BuLi
25 °C
O
Li
O
Li
LiR
OLiO
+-
Regiochemical Reactions of Enolates: C vs. O
■ Importance of the reagent
■ C vs. O alkylation
Gompper, R.; Vogt, H.-H. Chem. Ber. 1981, 114, 2866.
Kurts, A. L., et. al. Tetrahedron 1971, 27, 4777.
O - O
OEt
K+
O O
OEt
Li-
+
: :..
R
I
:
small δ-small δ+ big δ+R
OTs
big δ-
C-alkylation
O-alkylation
Et-X O O
OEtEt
O O
OEt
EtC alkylation O alkylation
X = OTs: 11X = I:
HMPA
O - O
OEt
K+
I
Li+
Br
Na+
Cl
K+
OP
OOMe
OMe
Cs+
OTs
Et4N+> > > >
> > > >
C-alkylation : O-alkylation
C-alkylation : O-alkylation
: 8871 : 13
OLi ..Me3SiCl, Ac2O
R-X, RCHO
Hard Electrophiles:• Big δ+• High LUMO
Softer Electrophiles:• Small δ+• Low LUMO
πC=C
nO-Li
(σO-Li)O
MO is big here
neg. charge is big here
Regiochemical Reactions of Enolates: C vs. O
■ Lithium aldol via 6-membered transition state
■ C acylation
Mander, L. N.; Sethi, S. P. TL 1983, 24,5425.
Chem 204
OLi O
OMe
O O
CNMeOMander's reagent
O
NC OMe
O
ClMeOO OMe
O
:
OLiO
R
H
Zimmerman-Traxlertransition state
Ph
O O
Ph
OLi O
tBu Ph
OLi
O +
tBu
-Li+-
+
-
Mayr Tables and Equation: Addition of Electrophiles to C=C pi bonds
log k20 °C = sN (N + E)
E = electrophilicity parameterN = nucleophilicity parametersN = nucleophile-specific sensitivity parameter(N and SN are solvent dependent)
Using the Mayr Tables
■ Relative reactivity again (Mayr tables, etc)
■ Mukaiyama aldol: Lewis acid catalysis (predictable from Mayr rule of thumb)
■ Nucleophilic catalysis (like Hosomi rxn) ■ Enol boronates = L.A. + nuc.
T. Keith Hollis, B. Bosnich JACS 1995,117, 4570.
OEt OSiMe3 NR2 O LiO SiMe
MeMeF-
< < <OSiMe3
OMe<CH3 < ~
x104 x104 x10
PhCHO
R
OSiMe3
R
O
Ph
OSiMe3
R
O
Ph
OMe3Si BF3-+
NO RXNw/o BF3
cat. BF3
O
Ph
N = 6
O
Ph
F3B +-
E = -1.5
E < -14
R
OMe3Si O
Ph
M(OTf)n Me3SiOTfis the active
catalystR
O
Ph
OSiMe3 O
Ph
Me3Si +
R
OSiMe3
R
OSiMe3 PhCHO
n-Bu4N+F-R
O
Ph
O-
R
OSi
O
Ph
FMe
MeMe
-
F-n-Bu4N+
:
:
R
OBO+
Ph
R R-
R
OBR2 O
Ph
:
Mayr Rule of thumb: If E+N > -5 Plausible rates at r.t.