ch. 7 - enolates - purdue university · 651.06 209 enolates enolates are the conjugate anions of...

651.06

209

Enolates

Enolates are the conjugate anions of carbonyl compounds. Although they have been known and used since the turn of the 20th Century, it was the development of “specific enolates” (see below) by H. O. House of MIT in the 1960-1970s that made carbanion chemistry one of the most important tools for stereo- and regio-controlled carbon-carbon bond formation in organic synthesis. That importance continues to this day. Generation of enolates by α−deprotonation of carbonyls:

O

Y

H

B:

baseO

Y

O

Y

Y=H, alkyl, OR, NR2, SR • Relevant acidity data:

Compound pKa aldehyde ~20 ketone ~20

cyclic ketone ~17 β-dicarbonyl 11-13

ester ~25 nitrile ~25

Compare these pKa’s to the basicity values (as conjugate acid pKa’s) of common bases: R2N- pKa

conj = 35 RO- pKaconj = 16 (R = Me) - 18 R = t-Bu) R3N pKa

conj = 9-11 Conclusion:

MeO

O

OMe

O

pKa = 13

NaOMe

MeOH

(pKa = 16)

MeO

O

OMe

ONa

pKeq = 16-13 = 3

Keq = 103

O

NaOMe

MeOH

(pKa = 16)pKa = 17

ONa

pKeq = 16-17 = -1

Keq = 10-1

O

pKa = 17

OLi

pKeq = 35-17 = 18

Keq = 1018Li+ -N(i-Pr)2

+ HN(i-Pr)2

pKa = 35

651.06

210

Structure of Enolates

A. C- vs O- Metallation

M

O OM

covalent C-M bond (true

for electronegative M,

e.g. Hg++, Cu++, Zn++)

ionic O-M bond

(electropositive M, e.g. Li+,

Na+, K+, Mg++)

although often drawn as resonance, this is usually tautomerism (a fast equilibrium)

note: !-diketones form cyclic chelate

R

O

R

OM

B. Aggregation State 1. Although typically drawn as monomeric species, enolates in solution are usually found as higher aggregates (dimers, tetramers). 2. The exact aggregation state depends on solvent and counterion.

Li

O Li

O

O Li

Li O

generalized structure of solvated tetramer 3. Smaller counterions (e.g. Li+) favor tetramer while larger ones (e.g. K+, Cs+) favor dimer. 4. Et2O favors dimer, but THF and DME favor tetramer. 5. Generally speaking, tetrameric enolates react as carbon nucleophiles. 6. References: House, J. Org. Chem. 1971, 36, 2361 (original suggestion) Jackman, Tetrahedron, 1977, 33, 273 (NMR studies) Dunitz, Helv. Chim. Acta. 1981, 64, 2617 - 2622 (x-ray st udies) see also J. Am. Chem. Soc. 1985, 107, 5403; Tetrahedron Lett. 1989, 447

651.06

211

C. Regiochemistry (which side of carbonyl deprotonates?) O

O

baseO O

more stable less stable

O Obase

O O O O

more stable less stable

base

O O

more stable less stable D. Stereochemistry

Obase

O O

Z-enolate E-enolate

OR

O

base

RO

OM

RO

OM

Z-enolate E-enolate

E-enolate Z-enolate(M = Li)

(M = Li)

651.06

212

X

CH3

O

LDA

Stereochemistry of Deprotonation

X

CH3

OLi

X

OLi

CH3

+

"Z" "E"

X “E” “Z” OMe

95 5

Ot-Bu

95 5

Et

77 23

i-Pr

40 60

t-Bu

0 100

Ph

0 100

NEt2 0 100 Large X yields Z

651.06

213

II. Generation of enolates A. Deprotonation of active hydrogens 1.) Thermodynamic conditions

O

NaOMe

MeOH

O Na

+ MeOH

Keq = 10-2 (favors s.m.)

MeO OMe

O ONaOMe

MeOHMeO OMe

O ONa

+ MeOH

essentially irreversible

O

0.95 eq LDA

O Li

equilibrium established with s.m.

O O Na

NaH Why an Equilibrium?

2.) “Kinetic” conditions

O O

NH2

irreversible

KNH2, LiNH2, and NaNH2 are insoluble in organic solvents so LiNR2 was developed R = Et, i-Pr, (i-Pr, cyclohexane), or t-Bu development of “specific” enolates: House, JOC, 28, 1963, 3362 30, 1965, 1341, 2502 34, 1969, 2324

651.06

214

3.) Regiochemistry of deprotonation

O

1) LDA

2) TMS-Cl

1) Et3N

2) TMS-Cl

OTMS OTMS

OTMS

84% 7% 9%

13% 58% 29%

kinetic

thermo.

O

O Li

O K

LDA

t-BuOK

t-BuOH

or KH or LDA/HMPA (9:1) thermo.

> 95% kinetic

H

HO

H

HTMSO

H

HTMSO

+

1) Ph3C Li

2) TMS-Cl13% 87%

53% 47%1) .95 (eq) Ph3C Li

2) HMPA, TMS-Cl 4.) Stereochemistry of deprotonation

RCH3

OR

CH3

OM

Z

R

OM

CH3

E

House, JOC, 1963, 28, 3362

651.06

215

How to Determine? Make Si(CH3)3 ether: 1H-NMR, 13C–NMR (Heathcock, JACS, 1979, 44, 429)

nOe (Oppolzer, TL, 1983, 24, 495)

Ireland does Claisen:

O

O

O

OTMS

O

OTMS O

OTMS

O

OTMS

CO2TMS

O

OTMS

O

OTMS

CO2TMS

Z

E

[3,3]

[3,3]

syn

anti Ex:

O

CH3

O Li

base+

O Li

CH3

Z E

14 92

23

35

86

8

77

65

:

:

:

:

base

N

'', HMPA

LDA (-78˚)

LICA (-78˚)

Li (-78˚)

Why kinetic preference for E?

651.06

216

Look at T.S. for deprotonation: JACS, 1976, 98, 2868

NH

O

Li

R'

R'

RH

not bad

NH

O

Li

R'

R'

HR

"1,3 diax."

N.B. e- 's abstracted proton to ! system "

E

Z

NH

O

Li

R'

'R

H

NH

O

Li

R'

'R

R

R

R

O

O

favorable

unfavorable

R

Ha

Hb

Hb

O

-Hb

-Ha

This view of the T.S accounts for both stereo- and regio- specificity

R = CH3 ⇒ 99:1 R = Ph ⇒ ≥ 99:1 R = OCH3 ⇒ 85:15 R = NMe2 ⇒ 98:2

651.06

217

NH

O

Li

R'

R'

X

HMe

E

Z

LiNR'2

NH

O

Li

R'

R'

X

MeH

O

H Me

H

X

A(1,2)

For acyclic ketones, we have A(1,2) strain to consider

XMe

O

XMe

OLDA

X E:Z

OCH3Ot-BuEti-Prt-BuPhNEt2

95:595:577:2340:600:1000:1001:100

increasingbulk of X

All 3o amides give Z-enolates

caveat: need conditions in whichLi coordinates O (i.e., no HMPA, 18C-6, polar solvents)

Stereoselectivity of LDA/HMPA w/ ketones; esters - Ireland, JOC,1991, 56, 650-657

651.06

218

Reactions Of Enolates enolates = functionalized carbon nucleophiles

(Others are CN, CCR, RMgX, RLi) ∴ react with electrophilic carbon

2 types: C XO

sp3

First type gives enolate alkylation

Enolate Alkylation

O MR X SN2

R

O

+ M X

(note: X must be Br, I, OTs, OMs or OTf to get decent reactivity)

Considerations:

C- vs. O- alkylation enolates are ambident nucleophiles; can react at C or O

O R X

R

O

OR

a

b

a

b

What influences C- vs. O- ratio? House, JOC, 1973, 38, 515

651.06

219

a. hard/soft electrophiles

O "hard" anion (localized)

"soft" anion (delocalized)

C- alkylation with soft electrophiles (R-I, R-Br)

OM

Also, O-M bond affects C/O ratio

(As O-M → covalent, O is less reactive) (As O-M → ionic, O is more reactive)

So:

Li Na K NMe4C/O ratio

covalent ionic

rate cyclic β-diketones are especially “hard”

O

O

O

OH

O

O

O

O

+

Br

K2CO3DMF

vinylogous acid

37% 15%

O- C- Also phenolates:

O Na

PhCH2Br

DMF

OPh

97%

651.06

220

b. Solvent polar, aprotic solvents (HMPA, DMSO, DMF) solvate M+ ion ⇒ make “naked” anion (very hard) ⇒ favors O- alkylation

O Na

PhCH2Br

CF3CH2OH

OH

CH2Ph solvents which promote aggregation (e.g., THF) favor C-alkylation by making enolate less accessible

c. Structure of electrophile

OEt

O OR-Br

neat OEt

O O

R

+OEt

OR O

R= n-Pr

i-Pr

Br

PhCH2Br

97

73

100

100

:

:

:

:

3

27

0

0

Why? Hindered carbon is “harder”

Conclusion - Usually, use Li+ enolate in THF Ex:

O Li O

RR-X

THF

also, R will usually be methyl, 1˚, allylic, benzylic, (2˚ gives elimination) X = -Br, -I -When reactivity is a problem, we can increase rate using K+ as counterion (but run the risk of competing reactions arising from basicity of enolate)