Chapter 17: Enols and Enolate Anions as Nucleophileschem215/215-216 HH W12 notes-Ch 17.pdf · 2012-04-13 · Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 3 of 15. Date:

Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 1 of 15. Date: April 4, 2012

Chapter 17: Enols and Enolate Anions as Nucleophiles

!Enols: ! under acidic conditions! 1. H-X, H3O+ acids, (H3C)3Si-X: with enolates react at O !Enolates: !under basic conditions! (Si is oxophilic)

O OH

enol: weakly nucleophlic enolate: highly nucleophilic

I. Nucleophiles Electrophiles

Rx on ORx on C RR'

Oaldehydes/ketones

4. Z = Cl, OR'

5. R X alkyl, allyl, & benzyl halides

with enolates react atcarbanion C

Rx on C

RZ

O

2. Halogens (Cl2; Br2; I2)3.

(1) Generation of enolates

CH

O

HH

B

C

O

H

H(base)

C

O

H

H

H B carbanion enolate

nucleophilic sitenucleophilic site

ambident nucleophilealpha- (α-) carbon

alpha- (α-)hydrogens

• Halogens and most of the carbon electrophiles react at the carbanion center.

• The solution structures of carbanions closely resemble the structures of enolates. In addition, the only reason for the acidity of the α-hydrogen is the presence of a C=O group. Therefore, the following mechanism for the deprotonation of the α-hydrogen by a base is recommended:

CH

O

HH

B

α

O

H

H H B+

Enolate formation vs carbanion addition

CH

O

HH

C

α CH

O

HH

C

vs

CH

O

HH

H3CBrMg

CH

O

HH

H3C

BrMgnot much deprotonation

Kinetically, addition to the C=O carbon favored.

EO

+H3CMgBr

higher ΔEa for deprotonnationlower ΔEafor addition

OMgBrH3C

OMgBr+ CH4

(i) H3C-MgBr

•

Note: A carbanion addition reaction to a C=O is irreversible.


(ii) When (H3C)3C-Li or H3CCH2CHLi(CH3) is used, enolate formation is greatly favored due to the increased steric energy for the addition.

(iii) Commonly used non-nucleophilic bases:

II. Reactions of Enolates

O

H

H

M O

HHM

O

H

H

ElO

H

HEl

O

H

HEl

O

H

H

El O

H

H

El

Reactions with "slower"-reacting electrophiles.

Reactions with "fast"-reacting electrophiles.

"transition state" resembles the structure of the starting enolate

"transition state" resembles the structure of the more stable, C=O group containing product

The transition states for the reactions of enolates with highly reactive electrophiles, e.g., H-X, H3O*, and (H3C)3Si-Cl, closely resemble the structures of the starting enolates. In contrast, the reactions with slower-reacting carbon electrophiles, e.g., R-X and R-C(=O)-Z, go through the transitions states that have an energetically favorable, strong C=O bond character. This leads to the preferential reactions at the α-carbon.

Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 3 of 15. Date: April 4, 2012 Reactions of enolates with alkyl, allyl, and benzyl halides – Exclusive C-alkylation • Enolates readily undergo reactions on the α-carbons with alkyl, allyl, and benzyl halides.

OH

O

(1 mol equiv)NaH

Hα

NH2

diethyl ether(solvent)

OH

Enolate preformed, then treated with allyl bromide.

+ NH3

Br

O

H

+ NaBr60%

OH

OH

Br

Br

mechanistic drawing:

or

Note: Enols are not nucleophilic enough to have reactions with these halides. III. The Regioselectivity of the Enolate Reactions

(1) Kinetic enolates - Use of an extremely strong base; non-nucleophilic base in an aprotic solvent, typically in tetrahydrofuran (THF) - Use of a slight excess of the base at a low temperature (typically at - 78°C) ------ to ensure no equilibrium between the two enolates.

Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 4 of 15. Date: April 4, 2012 LDA: an extremely strong base and a bulky base; does not add to the C=O carbon. The bulky LDA approaches from the less-hindered side of the C=O.

OH

HH3C

H

Li N

HH3CH

O

major enolate

More hindered side!

OH

HH3C

H

Less hindered side!

H O

CH3

H

H

LiN

H3C CH3

H3C

H3C

axial α-H on the less-substituted side

O

HLi

N

H3C CH3

H3C

H3C

H3Csevere steric repulsion

More favored for deprotonation

Chair-like TS

Chair-like TS

Lessfavored for deprotonation

(2) Thermodynamic Enolates

OH

HH3C

H

HH3CH H

HH3C

O O+

Si

CH3CH3

CH3Si

CH3CH3

CH3Si

CH3CH3

CH3Cl

N(CH2CH3)3Δ

HCl•N(CH2CH3)3+22% 78% Mechanism:

OH

HH3C

H NR3

pKa 19-20

OHH3C

HH NR3 O

HH3CH

H

OH

HH3C

H

tautomerizationless-stable

enolate(kinetic enolate)reaction with

Cl-Si(CH3)3

HH3CH

OSi

CH3CH3

CH3

R3N

HH

H3CO

Si

CH3CH3

CH3 HH

H3CO

more-stable enolate(thermodynamic enolate)

reaction withCl-Si(CH3)3

Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 5 of 15. Date: April 4, 2012 These conditions allow equilibrium to occur and preferentially produce the more stable “thermodynamic enolate,” i.e., under the “thermodynamic control.”

Highly reactive electrophiles such as H-X, (H3C)3Si-X, H3O+ react at the enolate O site.

Thermodynamic enolates can be obtained:

• Nomally using a weak base • High temperatures • Excess ketone or proton source such as an alcohol.

Note: Even if LDA is used as a base, if less than 1.0 mol equiv of LDA is used at a higher temperature, such as 0 °C or room temperature, the equilibrium between the kinetically generated enolate and the starting ketone could be achieved, thus effectively creating the thermodynamic enolate.

(3) Reactions of Enolates: Examples kinetic enolate thermodynamic enolate

OH

H

HO

HH

Li O

H

LiHLDA

(1.1 mol equiv)

H3COOCH3

(1,2-dimethoxy-ethane; solvent)

0 °C

+

H3C

OCH3

H

H OH

CH3

HO

H

H

H3C

+ enantiiomercis trans76%

& +

I

(i)

(ii)

CH3Br

OH

H Br

OH

H

OH

H

HH

Li

CH3

Br

O

H

K

H

O CH3

91%

+ KBr

+ LiBrLDA (1.1 mol equiv)

H3CCH2OCH2CH3- 60 °C

kinetic enolate

thermodynamic enolate

80%(H3C)3C-O K(H3C)3C-OHΔ


Chapter 17: IV. Base-catalyzed Aldol Reactions and Condensation Reactions

H3C H

O2

NaOHH2O

5 °C, 1 h

H3O+ workup H3C H

HO H O

H Hβ α H3C H

H OH O

H Hβ α+

~50%

(β-hydroxy-aldehyde)Aldol products [aldehyde + ol]

Note these specfic reaction conditions.

Often difficult to stop at the stage of a β-hydroxy-aldehyde or ketone.

Aldol condensation reaction

O

HO

H3C

O

NaOH95% EtOHrt O

O+ H2O+

H

OH3C

OO

HIn this combination,

OC

O

HHH

this is the only "acidic" H (pKa ~18).

Note: H

O O

not acidicbase x

The resulting carbanion is notstabilized by the C=O π-electrons.

orthogonal: no orbital overlap

OC

OC

O

HHH

HO

OO

HH O

OH

H

(resonance stabilized)α-hydrogenspKa of H-OH is 15.7

1.

2. Whenever a nucleophilic base (e.g., HO-, H3CO-) is used, the base adds to the C=O carbon.

H

O OH3C

O

HO HOOH

OH

OH3C

O

OH

However, these adducted compounds are less stable than the original C=O compounds and do not undergo any other reactions but to go back to the original aldehyde/ketone.

The original aldol reaction:

Comments:

H


The reaction mechanism:

OC

O

HHH

HOO

OH

H

H

O

O OO

H--OR (R = H or C2H5)

HO OO

H HHO

HO OO

H

H OO

H

α,β-unsaturated ketone

or -OC2H5

a highly resonance-stabilizedclass of compound

A

B

C

Comments: (1) The conjugated ketone produced is primarily the more stable trans (or E) isomer. (2) The reaction of the ketone enolate with benzaldehyde takes place exclusively at the α-carbon.

O

OH

H

H

O

O

OH

H

H

OC-alkylation not O-alkylation

O

O

O-

because of the high C=Obond energy in the T.S.

α-carbon

(3) The last dehydration step should go through the ketone enolate intermediate as shown above. The alternative E2 process should require a higher energy of activation than the pathway that involves the enolate formation by deprotonation (i.e., the faster acid-base reaction).

OH OO

H H

HO or -OC2H5

An E2 process less likely. (4) The last dehydration step is thermodynamically driven, i.e., the formation of the highly stable α,β-unsaturated ketone. Problems: Provide in the following boxes the structures of appropriate compounds.

H O

H

O

NaOH/C2H5OH+

OKOt-Bu (base)


V. Acid-catalyzed Aldol Reactions/Condensation Reactions Acids can catalyze aldol reactions as well.

OCH3

OO

p-TsOH(catalytic)

Δ

mechanism:

OC

OH

H HH

OO H

H Hp-TsO HO

O H

H HH

O HOH H

O HO HH

H

p-TsO H

O HO HH

H

OH

O

OTs OTs

OTs

Alternatively, may use H - B and B for acid and conjugate base, respectively.

+ H2O

VI. Directed Aldol Reactions [In this case, the word “directed” refers to the regiochemistry of the enolate formation]. When a weak base such as NaOH and NaOCH2CH3 is used, only a small amount of an enolate is generated. Therefore, the initial aldol (addition) reaction product (i.e., β-hydroxy ketone) is exposed to such a base, thus often resulting in the formation of the aldol condensation product. The only practical way of ensuring the clean formation of the β-hydroxy ketone product is to use 1.0-1.1 mol equiv of a strong base such as LDA. Since the base will be used up completely for the enolate generation, there is no excess base left when the β-alkoxy ketone is formed, thus preventing the further reaction to form the aldol condensation product.

O O Li

H

O

O O Li

LDA(1.1 mol equiv)THF, -78 °C

H3O+-workup

O OH

α β

β-hydroxy ketone

p-TsOH, benzenereflux

O H

α

β

α,β-unsaturated ketone (mostly trans)

H


O OH

α β

H

mechanism for the dehydration step:

HH

O OH

α β

H

H

p-TsO H

O O

α β

H

H

H

H O

α β

H

H

H

O H

α

βα,β-unsaturated ketone

H

OTs

OTs

VII. Retro-Aldol Reactions under Basic or Acidic Conditions The Aldol reactions-condensations are reversible both under basic and acidic conditions.

mechanism under basic conditions:

OH

CH3

O

H3C

CH3

pulegone

O

CH3

H3C CH3

O+

NaOH, H2O, Δ

H3O+, H2O, Δ

mechanism under acidic conditions:

CH3

O

H3C

CH3

CH3

O

H3C

CH3

OH

HO

H

CH3

O

H3C

CH3

O

H

H OH

CH3

O

H3C

CH3

O

H

CH3

O

H3CCH3

OHO

H

CH3

O

H3C

CH3

H

HOH

pulegone

H

CH3

O

H3C

CH3

H

HO

H HOH

CH3

O

H3C

CH3

H

HO

HOH

HCH3

OH3C

CH3

H

HO

H

+O

CH3

O

CH3

H

CH3H3C

OH HO

H

H

O

CH3

H OH2

O

CH3

+

OH2

CH3H3C

O


Chapter 17: VIII. Reactions of Stabilized Enolate Anions with Alkyl Halides

Enolates of Active Methylene Systems. (1) Enolates from 1,3-diketone and β-Keto Esters: Hydrogens alpha to both of the carbonyl groups in 1,3-diketones and β-keto esters are highly acidic. Therefore, those Hs could readily be deprotonated by the use of a relatively weak base and the resulting enolates undergo facile alkylations with alkyl halides. These mono-anions are stabilized by resonance with both of the C=O groups.

H3C O CH2CH3

O O

H H

αβ

"active methylene"

K2CO3100 °C

N H

O

DMF (N,N-dimethyl-

formamide; solvent)

H3C O

O OCH2CH3

H

K H3C O CH2CH3

O O

H

αβ

I

I 99%+ KI

pKa ~ 11-12 (2) Dienolates from 1,3-diketone and β-Keto Esters: Mono-enolates (mono-anions) formed from 1,3-diketone and β-keto esters can further be deprotonated by the use of a stronger base (typically n-butyllithium or LDA) to generate di-enolate (dianions).

ZR'

O O

H H H H

active methylene Hs (highly acidic)

Z = R or OR"

Z

O O

H

R'

H Hmono-anion

(mono-enolate)

Considerably less acidic than typical α-Hs, thus requiring the use of n-butyllithium or LDA to deprotonate

weak base(1 mol equiv)

stronger base(1 mol equiv)

Z

O O

H H

R'

di-anion(di-enolate)

If these dianionic species is treated with one mol equiv of a carbon electrophile, the C-C bond forming reaction takes place selectively at the second deprotonation site.

H3C

O O

H H

HH3C

O O

H H

H

More basic; more nucleophilic!

(3) An example of the mono-alkylation of a dienolate.

H3C CH3

O O

H HH3C CH3

O O

H

Na+ H2

H3C

O O

H

Na

H

HLi

NaH (1 mole equiv)THF (solvent)

-15 °C

Li(n-butyllithium)

1 mol equiv.at around 0 °C

(1 mol equiv)

I H O-THPH O-THP

H3C

OO

Hdienolate

H O-THP

H3C

OO

H H

aq NH4Cl

CH3CH2CH2CH3 +

Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 11 of 15. Date: April 4, 2012 IX. Formation of β-Keto Esters and Their Reactions

R OR'

O O

H H

αβ

β-keto esters

"active methylene" pKa ~ 11-12

H3C OCH2CH3

O O

H H

αβ

pKa 10.7

O OCH2CH3

O O

H H

αβ

pKa 13.3

H3CCH2

C C

H H

pKa 11

NNH3C CH3

O O

H H

αβ

pKa 9pKa values of some 1,3-C=O or CN compounds

(1) Synthesis of β-keto esters from ketone enolates

O OLi O

OCH2CH3

O

+ LiClLDA

(1.0 mol equiv)THF, -78 °C

Cl OCH2CH3

O

OLi

Cl OCH2CH3

O

O

Cl

OCH2CH3

O O

O CH2CH3

O

ketone enolateβ-keto ester

mechanism:

(2) Synthesis of β-keto esters from esters

(i) The Claisen Condensation: between two ester compounds; intermolecular reaction

H3C OCH2CH3

O

OCH2CH32 x

(1 mol equiv)

+H3C O

CH2CH3

O

H

O

H O CH2CH3pKa 17

+

H3C OHO

H3C OCH2CH3

O

H

O

Hethyl acetoacetate

Na

Na

OCH2CH3

OHH H

OCH2CH3

OCH2CH3

OH

H

H O CH2CH3+

H3C

OCH2CH3

O

O CH2CH3

OCH2CH3

OH

H

H3CO

O CH2CH3

OH

H

H3C O

OCH2CH3

+

OH

H3C O

H O CH2CH3+

Reaction end-products before acidic workup.

H3C OHO

OH

H3C O HOH

H3C O

H tautomerizationOCH2CH3OCH2CH3OCH2CH3

Na

Na

Na

mechanism:

pKa ~11

Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 12 of 15. Date: April 4, 2012 IX. (2) (ii) The Dieckmann Condensation: an intramolecular version of the Claisen condensation.

O

O

OCH2CH3

OCH2CH3

OCH2CH3

OCH2CH3

O

O

KH (1 mol equiv)

THF (solvent) OCH2CH3

O

O

K workup with acetic acid

OCH2CH3

O

OH

+ HOCH2CH3

mechanism:

HH

H

O

O

OCH2CH3

OCH2CH3

H H

OOCH2CH3

OOCH2CH3

H

O

OCH2CH3

O

OCH2CH3

+ H2+

OCH2CH3

O

O

K

+ HOCH2CH3

K

K

K

OCH2CH3

O

OH

OCH2CH3

OH

O

H3C OH

Otautomerism

acidic!

86% yield Reversible reactions observed for the β-keto ester products lacking an active methylene H.

O

O

OCH2CH3

OCH2CH3

H3CH

1. Na OCH2CH3

2. workup with

H3C OH

O

(1 mol equiv)

H3C O

OOCH2CH3

H

H Not formed!

H3C O

OOCH2CH3

H

O

O

OCH2CH3

OCH2CH3

H3C

H3C O

OCH2CH3

O

H3C O

OCH2CH3

O

O

O

OCH2CH3OCH2CH3

H3CH

H

H3C O

OOCH2CH3

H

H

OCH2CH3

OCH2CH3

stable enolate product;reaction endproduct under the basic conditions prior to acidic workup

gets immediately deprotonated

gets destroyed back to the enolate at the left initiated by the attack by the alkoxide anion

No acidic H present!


Chapter 17: IX. Formation of β-Keto Esters and Their Reactions (cont’d)

(3) Decarboxylation of β-keto acid and malonic acid and substituted malonic acid Carboxylic acids with a C=O group β-to the carboxylic acid C=O are unstable and lose CO2 gas upon warming/heating. These carboxylic acids include b-keto acid and malonic and substituted malonic acids. These acids can be obtained by the acid catalyzed or base catalyzed hydrolysis followed by acidification of the corresponding esters. The decaboxylation is shown to go through a six-membered cyclic transition state. As such, the two carbonyl groups need to be located at the 1,3-positions or the β-position to the carboxylic acid C=O. The resulting enols undergo tautomerization to provide the more stable C=O structures.

R O-H

O O

R'R O

O O

R'

H

R

OH

R'R

O

R'

HHH

HH tautomerizationdecarboxylation!

CO2

six-memberedcyclic transition state

Δ

R O-Ro

O O

R' H

H3O+, Δor i) HO ; ii) H3O+

H-O O-H

O Omalonic acid

H-O O-H

O O substituted malonic acid

R' R"

Example:

OCH2CH3

O O

OCH2CH3

O O

1. KH (1 mol equiv)2. n-butyllithium (1 mol equiv)

KLi

More reactive here!

OCH2CH3

O O

PhCH2-Br(1 mol equiv)

+ KBr/LiBr

KLi or

H3O+

(pH ~2)

OCH2CH3

O O1. NaOH-H2O2. H3O+, Δ

CH3

O

O

O

OH

OH

H H

H

H

CO2

CH3

Otautomerization


Chapter 17 X: Conjugate Addition to α ,β-Unsaturated Carbonyl Compounds

(1) Conjugate Addition (or 1,4-Addition) – with “weaker” or “softer” nucleophiles

R

O

R

O

ααββ

12

3

4

"electrophilic C""electrophilic alkene"

"electrophilic C"

+

+

+

Examples of conjugate addition reactions1.

H CH3

H O

H

NH

H3C OH

O0 °C

N CH3

O

α

β

β α

68%

Mechanism:

H CH3

H O

H

βα

NH

N CH3

O

H

NH

N CH3

O

HO CH3

ON CH3

Oα

β

HH H H

2.H OCH3

H O

H

β α2 H2S

O CH3

O

Na(catalytic)

H3CO S OCH3

O O

Mechanism:

HS

HO CH3

O

H OCH3

H O

H

β αH S

H OCH3

H O

Hα

SH

O CH3

O

HO CH3

OH

H OCH3

H O

H

SH

O CH3

O

H

O CH3

O

H OCH3

H O

H

S

H

O CH3

OH

HH3CO

HO

H

βαH OCH3

H O

H

S

HHH3CO

HO

Hα

H

H3CO S OCH3

O O

O CH3

O+

re-generationof the catalyst

Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 15 of 15. Date: April 4, 2012 Chapter 17 X: Conjugate (or 1,4-) Addition to α ,β-Unsaturated Carbonyl Compounds (2) 1,2- vs 1,4-Addition reactions

ONu

ONu

O

Nu

O

Nukinetic product(1,2-product)

thermodynamic product(1,4-product)

23

4

• 1,4-addition products (thermodynamic products): formed with “weaker” or “softer” nucleophiles; those nucleophiles with pKa of the conjugate acids in the range of 8 – 25 generally produce 1,4-adducts (those nucleophiles include RS-, RR’R”N, and ketone/ester enolates); the conjugate addition reactions with enolates are referred to as the Michael reactions. • 1,2-addition products (kinetic products): formed with strong nucleophiles such as RMgBr and RLi (these addition products are formed irreversibly).

CH3

Oβ

12

3

4

H3C MgBr

H3C MgBr aq NH4Cl

highly nucleophilic(reactive)δ δ

CH3

OH

CH3

+

CH3

O

β

12

3

4

H3C

CH3

OH3CH

H

CH3

OH3CH

"hypothetical, mildly nucleophilic CH3 anion"

H3O+

The most commonly used such mildly nucleophilic reagents are "organocuprates."

RCu

R'Li

organocuprates

H3CCu

H3CLi (H3C)2CuLi

e.g.,

These cuprate reagents are prepared from:2 H3CLi + CuI (H3C)2CuLi + LiIdiethyl ether (solvent)

The organocuprates undergo: conjugate addition (to, e.g., α,β-unsaturated ketones/esters), SN2reactions (onto, e.g., RCH2X and epoxides).

1. Homocuprates (R = R'): only one of these two groups (R=R') works as a nucleophile; H3CCu produced by the reaction is not nucleophilic enough to undergo the reaction.2. Heterocuprates (R R')

e.g., (NC)RCuLi and H3CCH2CH2C CCuRLi: only R group works as a nucleophile.

O (H3CCH2CH2CH2)2CuLi (1 mol equiv)

O(tetrahydrofuran=THF;

solvent)-78 °C

O Li

H3CCH2CH2CH3Cu(not reactive)

(-30 °C)1.

2. aq NH4Cl

OCH3

H3C I

+ enantoimer[mostly trans-diastereomer]

Example:

Conjugate-adding organometallic reagents:

Documents

Chapter 17: Enols and Enolate Anions as Nucleophileschem215/215-216 HH W12 notes-Ch 17.pdf · 2012-04-13 · Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 3 of 15. Date: