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.