Professor David L.

Van Vranken
Chemistry 201: Organic Reaction Mechanisms I

Topic 16: Enols, Enamines, and Enolates

.. .. .. +
O
.. H O
- H

Read: Molecular Orbitals and Organic Chemical Reactions

I. 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.
 Enols / Enol Ethers

■ What do you get when you mix two non-bonding lone pair MO with one pi MO?
0.618 -0.575

HOMO O
H
.. .. ..
O
.. H O+ EMO O
- H HOMO-1 H
STO-3G

HOMO-2 O
H

■ HOMO is π -like, not lone pair-like.

■ End carbon has larger HOMO coefficient, but the oxygen has more negative charge.

■ THP Protection
cat.
TsOH H
OH O+ O
O O
O O+ H

■ Ferrier rearrangement
MeOH +
O SnCl 4 O O OR w/ MeOH
- 76:14
AcO SnCl 4 CH 2Cl 2 AcO AcO α/β
25 °C, 30 min
O O+

Bhate, P.; Horton, D.; Priebe, W. Carbohydr Res. 1985, 144, 331.
Tautomer Stability

■ Keto/enol tautomerism

keto enol
K eq<10 -8 H
O O

EtO
.. EtO

O OH
10 -8

O OH
10 -5
H H
H
O O

C
Ph 10 -3.6
H2 H O π acceptor
O
O O H-bond
10 -2
RO RO
H
O O O O π acceptor
0.2 + H-bond

■ Enol ether tautomerization with transition

metal catalysts
Ir + cat.
Baudry, D.; Ephritikhine, M.; Felkin, H.
97% JCS, Chem. Commun. 1978, 694
MeO MeO
THF
22 °C, 33 h
Enamines

■ Imine/enamine equilibrium is unfavorable 0.620 -0.650

HOMO O
H
Keq = 2.6 H H
H H H ..
N N similar amounts N
.. N+ EMO
H - H STO-3G
(vs. keto/enol)
H
HOMO-1 O
H

Enamine formation driven by azeotropic removal of water. Common:

O
O H toluene N
N
distilled
+ H 2O N N
as azeotrope
120 °C

K. Lammertsma JACS 1994, 114, 642

■ Enolate equivalents
Br Br-

N
.. N H 2O O
+

■ Relative reactivity

.. .. ..
OH < N < O-Li
Regioselective Enolate Formation

■ Thermodynamic regiocontrol isn't very good for ketones

KO KO Olefins: more substituted = more stable

more
substituted Bu Bu

58 : 42
House, H.O.; Kramar, V. J. Org. Chem 1963, 28, 3362.

KO KO
Me Me

52 : 48
(±7) (±7)

■ Thermodynamic regiocontrol can be great with enamines

N N
Me Me
F. Johnson Chem. Rev. 1968, 375.

A 1,3 strain (Don't worry about it until Chem 202)

■ Kinetic regiocontrol is excellent with LDA

LDA
O inverse addn LiO LiO
Bu Bu Bu
THF, -78 °C
100 : 0

Stork, G.; Kraus, G. A.; Garcia, G. A. J. Org. Chem. 1974, 39, 3959.
Stereoselective Enolate Formation

■ With Et3N, NaH, KOtBu, you favor the Z enolate = more stable
-O O -O Z Excess ketone acts as
E
E/Z 16:84
Et Et Et a catalytic acid, H-A, and
catalyzes E/Z isomerization

JACS 1980, 102, 3959.

■ LDA deprotonates through 6-membered ring chair T.S. = “Ireland T.S.”

Don’t use the symbol B: for this mechanism.
more in Chem 204
- -
Li R Li R Li + R Li R R iPr
O: +O N
N .. R O N R O N H
R H H H O Li N iPr
Et Et chair Et Et
TS H
R Me
R. Ireland
JACS 1976, 2868

■ LDA: E enolate forms faster

Inverse addn = rapid, irreversible at -78 °C
Li Li Li Ireland, et. al. JOC 1991, 56, 650.
O O O
3-pentanone Ireland, et al. JACS 1978, 98, 2868
i-Pr2N–Li small big
Et EtO Ph Heathcock, et. al. JOC 1980, 45, 1066.
slight excess THF, -78 °C
E/Z ~ 70:30 Z/E 94 : 6 E/Z <2 : >98

(Caution! C.I.P. assignments are confusing!)

Enolate Formation with LDA

■ Recall: Li enolates = 99% dimer, but monomer alkylates faster

■ LDA is a dimer in THF… but reacts via the monomer rate ∝ [LDA]1/2

Dave Collum JACS 2000, 2452.

+O +O +O
Collum, D. B. Acc. Chem. Res. 1993, 26, 227.
R Li -2 R R Li-2 R + Li
-2
+
N N N O N O
R + Li + R R .. R
-2 H H
O OR OR
+

■ HMPA disrupts coordination of lithium. THF + HMPA generates E ester enolates

-
- Li
O Li +O N O
N O+ .. Ireland, et. al. JOC 1991, 56, 650.
P P Also Fataftah, et al. JACS 1980, 102, 3959.
Me2N NMe2 Me2N NMe2 OEt
NMe2 OEt NMe2
H

HMPA disrupts Ireland T.S.

Note: LDA is still a dimer in HMPA!
 Enolate Formation by Metalation

■ n-BuLi has a half-life of 107 minutes in THF at 20 °C! R-Li T t1/2

Stanetty, P.; Mihovilovic, M. D. J. Org. Chem. 1997, 62, 1514. n-BuLi +20 °C 107 min
n-BuLi -20 °C stable
s-BuLi -20 °C 78 min
t-BuLi -20 °C 42 min

■ Lithiated THF fragments to give acetaldehyde enolate

-
n-BuLi LiR
O O

25 °C Li+

- LiR
O O+
Li Li

Honeycutt, S. C. J. Organomet. Chem. 1971, 29, 1.

■ Acetaldehyde enolate can't be made efficiently by deprotonation. Instead, you make it from THF.

O LDA OLi aldol

 Regiochemical Reactions of Enolates: C vs. O

■ C vs. O alkylation

C alkylation O alkylation
Et Kurts, A. L., et. al. Tetrahedron 1971, 27, 4777.
K+ O - O Et-X O O O O
vs
Gompper, R.; Vogt, H.-H. Chem. Ber. 1981, 114, 2866.
OEt HMPA OEt OEt
Et

C-alkylation : O-alkylation Li-O > Na-O > K-O > Cs-O > Et4N+ -O

O O
C-alkylation : O-alkylation R-I > R-Br > R-Cl > R P OMe > R S Tol
O O
OMe O

-
Li O-alkylation
:O O+
97% OTs
.. K O OEt
TsO CH3 O R big δ+
R small δ-
small δ+ K ..
OEt
I O O
97% H3C I big δ-
C-alkylation OEt

■ Importance of the reagent

neg. charge is big here
Hard Electrophiles: nO-Li
Me 3SiCl, Ac2O
Li .. • Big δ+ O
O • High LUMO (σO-Li)
Softer Electrophiles:
R-X, RCHO
πC=C • Small δ+
MO is big here • Low LUMO
Regiochemical Reactions of Enolates: C vs. O

■ C acylation

O
O O
O OMe :OLi O O O
MeO Cl NC OMe OMe MeO CN
Mander's reagent

Mander, L. N.; Sethi, S. P. TL 1983, 24,5425.

■ Lithium aldol via 6-membered transition state

- -
Li Li + O Li O H -
O O O+ Chem 204
O O Li
tBu O+
Ph Ph tBu Ph R Zimmerman-Traxler
transition state
Mayr Tables and Equation: Addition of Electrophiles to C=C pi bonds

log k20 °C = sN (N + E)
E = electrophilicity parameter
N = nucleophilicity parameter
sN = nucleophile-specific sensitivity parameter
(N and SN are solvent dependent)
Using the Mayr Tables
■ Relative reactivity again (Mayr tables, etc)
Me
- Si F Li
CH 3 OEt OSiMe3 OSiMe3 NR 2 O Me O
< ~ < < < Me <
OMe

x104 x104 x10

■ Mukaiyama aldol: Lewis acid catalysis (predictable from Mayr rule of thumb)

N =6 E < -14 Mayr Rule of thumb:

SiMe3 O OSiMe3 NO RXN
O O PhCHO If E+N > -5
w/o BF 3
R Ph Plausible rates at r.t.
Ph cat. BF 3
R

F 3B Me 3Si BF 3
- O+ +O O -
E = -1.5 Ph R Ph

Me 3Si M(OTf) n Me 3Si +

O O O OSiMe3 OSiMe3 O Me 3SiOTf
is the active
R Ph R Ph R Ph catalyst
T. Keith Hollis, B. Bosnich JACS 1995,117, 4570.

■ Nucleophilic catalysis (like Hosomi rxn) ■ Enol boronates = L.A. + nuc.

:F- R R
n -Bu
SiMe 3 PhCHO BR 2 -B
4N+ O O O- O :O O+
n-Bu4N +F- O
R R Ph R Ph R Ph
Me - F
Si Me
:O Me O

R Ph