CH 22 REACTIONS AT THE ALPHA CARBON

- it is now evident that the carbon-oxygen double bond functionality (C=O) is common to several different classes of compounds:
O R C H & R O C R R O C OH R O C Lv

the carbonyl group (aldehydes & ketones)

the carboxyl group (carboxylic acids)

the acyl group (carboxylic acid derivatives)

- the chemistry of this ubiquitous functional group will now be reexamined, but at the carbon adjacent to the C=O, namely, the alpha carbon (-C) - the aforementioned compounds undergo substitution reactions at their alpha carbons with various electrophiles under acidic or basic conditions
O

O + E electrophile

C C H acidic -H

C C E + "H "

substn' @ -C

E = X, C=O, R, ...........

KETO-ENOL TAUTOMERISM
- compounds which possess alpha carbons can exist as two equilibrating structural isomers:
Keto-Enol Tautomers: O C

OH C C

C H

keto > 99%

enol < 0.1%

- note that the alpha hydrogen (-H) and the pi () bond migrate in the two tautomers - thus, the keto & enol forms are isomers, not resonance contributors - the keto form is usually predominant ; the carbon is more basic than the oxygen - to exhibit keto-enol tautomerism, the compound must have an alpha carbon (-C) with an alpha hydrogen (-H)

EX s no -H s; no keto-enol tautomerism
O H C H formaldehyde Ar O C H Ar O C Ar O H C OR formate esters Ar O C OR

aryl aldehydes (benzaldehydes)

diaryl ketones (benzophenones)

benzoate esters

Mechanism - the keto-enol tautomer equilibration can occur under acidic or basic catalytic conditions 1) Basic Catalysis A

2) Acidic Catalysis A

Enolization
- the configuration at an asymmetric alpha carbon can be partially inverted (racemized) under acidic or basic conditions as a result of keto-enol equilibrium
O C C H starting configuration A B H or B O C C B inverted configuration A H

- the enolization proceeds through the intermediate achiral enol which is formed under acidic or basic conditions as shown in the previous mechanisms
O C C H starting configuration OH C C A B achiral enol H or B O C C B inverted configuration A H

A B

H or B

EX.

O CH3 H OH

O H CH3

Acidity of Alpha Hydrogens

- keto-enol tautomerism, enolization as well as all the reactions yet to be examined in this chapter are a consequence of an alpha carbons acidic hydrogens - an alpha hydrogen (-H) can even compare in acidity to an alcohols hydroxyl (O-H) hydrogen in certain instances
FG Acidity Ranking: O C O H alcohol pKA = ~18

>

C H

>

C H

>

C H

>

C H

-carbon
~20

alkyne ~25

alkene ~40

alkane ~60

- resonance stabilization of the enolate anion is the rationale for the acidity of alpha hydrogens - the C=O group exerts its electron withdrawing effect through resonance (-R effect), causing delocalization of the electrons & charge in the carbanion resonance contributor, stabilizing the anionic resonance hybrid:
O C O C H

O C C

O C C RH

C C carbanion RC's

enolate

- note that a less substituted -C is more acidic because the carbanion resonance contributor is destabilized by the electron-donating inductive (-I ) effects of R groups

ALPHA HALOGENATION OF KETONES

- -Hs of ketones are substituted for by halogens under acidic or basic conditions

A. Base-Promoted Alpha Halogenation

O R C C H +

O X2 + B R C C

X + X

ketone X = Cl, Br, I

-haloketone
B: = OH , OR , ..........

Mechanism - proceeds through the resonance-stabilized enolate anion which acts as a nucleophile on the electrophilic halogen

- under basic conditions, alpha halogenation repeats on the less substituted (more acidic) -C until all its -Hs are replaced - the succeeding -H is more acidic than the previous one because of the electron-withdrawing inductive (-I ) effect of the substituting halogen
O 2 Br2 OH O Br Br

EX.

Haloform Reaction - methyl ketones are exhaustively halogenated at the more acidic -methyl group & the resulting trihalomethyl ketone is cleaved to a carboxylate anion & a haloform
O H R C H methyl ketone X = Cl, Br, I carboxylate haloform C H + 3 X2 + 3 OH

O R C O + CHX3 + 3 X + 3 H OH

Mechanism - base-promoted -halogenation repeats three times at the methyl group, followed by cleavage & irreversible proton transfer

EX.
H 3C CH3

O CH C CH3

I2 (xs) OH (xs)

O H 3C CH C O CH3 + CHI3 iodoform (yellow ppt)

B. Acid-Catalyzed Alpha Halogenation

O R C C H +

X2

O R C C

X +

ketone X = Cl, Br, I

-haloketone H = H2SO4, HCl, HOAc, ........ (catalyst)

Mechanism - proceeds through resonance-stabilized enol which acts as a nucleophile on the electrophilic halogen

- under acidic conditions, alpha halogenation occurs at the more substituted -C & does not repeat - the electron-withdrawing inductive (-I ) effect of the substituting halogen destabilizes the carbocationic intermediates & makes the oxygen less basic, slowing the reaction

EX s

O Cl2 H

O Cl

O H 3C CH C CH3 CH3

I2 H

I H 3C C

O C CH3

CH3

Summary - Alpha Halogenation: Basic conditions ; repeats @ less substituted -C Acidic conditions ; reacts once @ more substituted -C

- aldehydes are oxidized to carboxylic acids by halogens & hence, are not alpha-halogenated
O R C H O R C OH

X2

ALPHA BROMINATION OF CARBOXYLIC ACIDS

- also known as the Hell-Volhard-Zelinsky reaction, carboxylic acids are converted to their respective acid halides then alpha-halogenated & subsequently hydrolyzed back to the acid
O HO C acid Br2/PBr3 = Cl2/PCl3 , also PBr3 H2O O HO C

C H

+ Br2

C Br + HBr

-bromoacid

Mechanism - conversion to the acid bromide is required to remove the -H, since the carboxylic acid hydrogen is too acidic & would not allow the reaction to proceed

EX.

O OH Br2 PBr3 H2O Br

O OH

- the alpha bromination reaction can be repeated, if desired

ALDOL CONDENSATION
- in the first part of the overall condensation process, two carbonyl compounds react one acts as a nucleophile (-C) & the other acts as an electrophile (C=O) - the product of this initial reaction is a -hydroxycarbonyl compound also known as an aldol
O C

O + C

C H

O C C

OH C

aldehydes or ketones

-hydroxy carbonyl (an aldol)

B: = OH , OR , ..........

Mechanism - the carbanionic -C of one carbonyl compound executes a nucleophilic addition reaction on the carbonyl group of the other reactant

EX. two aldehydes react:

O H C CH3 + O H C CH3 OH O H C OH CH2 CH CH3

EX s two ketones react:

O H3 C C CH3 + H3 C O C CH3 OH O H3 C C OH CH2 C CH3 CH3

O 2 OH

HO

Dehydration of Aldol Products

- to complete the condensation process, the -hydroxycarbonyl product of the aldol reaction is dehydrated to an ,-unsaturated carbonyl compound - the dehydration of the aldol product is carried out either by heating the basic reaction mixture or by adding acid & heating
O C C OH C

B: or H

O C C

+ H2 O

H -hydroxycarbonyl (aldol product)

,unsaturated carbonyl

B: = OH , OR , .......... (from aldol rxn mix) H = H2SO4 , HCl , I2 , BF3 , .......

- the orientation of the elimination is dictated by the stabilizing conjugation of the carbon-carbon (alkene) double bond with the carbon-oxygen (carbonyl) double bond

Mechanism - in order for dehydration to be possible, the original -C must have at least two -H s 1) Acid-Catalyzed A
H H O C C O H

H + O C C

O H

O C C

OH C

C C

+ H catalyst

2) Base-Catalyzed A
(H2O) + H B O C B: (OH ) C

OH C

O C

OH C

O C RC'S O C

C C

OH

OH catalyst

- the overall addition-dehydration sequence is known as the aldol condensation - condensation is defined as a reaction which combines two molecules with the loss of another small molecule (hence, the sum is smaller than its parts) - the aldol condensation can thus be written as follows:
O C C H H aldehydes or ketones

O + C

B:

B: or H

O C C

H2 O

,unsaturated carbonyl ("enal" or "enone")

EX s
O H C

O H C CH2CH3

CH2CH3 +

OH

O H C

CH CH2CH3 + H2O

CH3

O + OH

O + H 2O

- with aromatic carbonyl compounds, dehydration is spontaneous - no heating is required & the aldol product is never isolated, because of the stabilizing conjugation of the newly created double bond with the arene delocalized system EX.
O C CH3 + H3C

O C

OH

O C CH C CH3 + H2O

Crossed Aldol Condensation

- two different carbonyl compounds condense two different aldehydes; two different ketones; an aldehyde with a ketone; or a ketone with an aldehyde are all possibilities - a crossed aldol condensation is practical (synthetically useful), only if one of the reactants has no

alpha hydrogens
- if both carbonyl reactants have alpha hydrogens, four different aldol products can result - not a useful reaction outcome

EX.
O H C CH3 + CH3

O C

CH3

OH

O H C O H C CH2 CH2

OH CH CH3 OH C CH3 + CH3 CH3 + CH3 O C

O C CH2

OH C OH CH3 CH3

CH2

CH CH3

- if however, only one carbonyl reactant has alpha hydrogens, the crossed aldol condensation is an extremely useful synthetic methodology

EX s
O H C CH2CH3

O + H C H no -H's

OH

O H C

CH C H CH3 H

OH

O H C

CH2 + H2O

-H's

CH3

O C -H's

CH3

O + H C no -H's

OH

O C

CH CH

+ H2 O

- dicarbonyl compounds can undergo intramolecular crossed aldol condensations to produce cyclized ,-unsaturated carbonyls

EX.
2 3

O
1

OH H O
5 6

1 6

OH

1 5

OH O

2 5 3 4

Use in Synthesis
- the aldol condensation can be used to acquire the following synthetic targets:
O C OH C

O or C

hydroxycarbonyl

,unsaturated carbonyl

EX. Synthesize:
O FROM CH2OH & OH

O OH

O + H

O PCC

CH2OH

CrO3

H OH

CLAISEN CONDENSATION
- like aldehydes & ketones, the alpha hydrogens (-Hs) of esters are also acidic - removing the -H under basic conditions creates a carbanionic alpha carbon which perpetrates nucleophilic attack on another acyl or carbonyl (C=O) carbon in an aldol-like condensation - the product of the Claisen condensation is a -ketoester

O RO C

C H + esters

O C OR

B:

O RO C C

O C

+ R O H

-ketoester no OH (hydrolyzes ester)

= OR

mostly (R = Me, Et, i-Pr, t-Bu, ...)

H+ added in 2nd step to isolate product

Mechanism - the carbanionic -C of one ester executes a nucleophilic acyl substitution reaction at the acyl carbon of the other ester - the initial -ketoester product has an even more acidic -H which is removed by the base, generating a resonance stabilized anion which can be isolated as a salt - acidification is required to recover the neutral condensation product

EX s
CH3O

O C

CH3

O + CH3O C CH3

CH3O

O CH3O C

CH2

O C CH3 + CH3OH

CH3CH2O C CH2

O + CH3CH2O C CH2

CH3CH2O

O CH3CH2O C

CH C

O CH2

+ CH3CH2OH

- diesters undergo intramolecular Claisen condensations to produce cyclized -ketoesters in a variation known as the Dieckmann condensation
O
3 4 5 6 2 1

EX.

O OCH3 CH3O H
3 4 5 6 2 7 1

O
7

OCH3

OCH3

Crossed Claisen Condensation

- in a reaction analogous to the crossed aldol condensation, two different esters condense - as before, a crossed Claisen condensation is practical (synthetically useful), only if one of the ester reactants has no alpha hydrogens - if both ester reactants have alpha hydrogens, four different -ketoester products can result not a useful reaction outcome - however, if only one ester reactant has alpha hydrogens, the crossed Claisen condensation is an extremely powerful synthetic methodology

EX s formate & benzoate esters are useful 6 no -Hs

O CH3CH2O C -H's

O + CH3CH2O C H no -H's

CH2

CH3CH2O

O CH3CH2O C

CH C H + CH3CH2OH

O CH3O C

CH2CH3 +

O CH3O C no -H's

CH3O

O CH3O C

CH C CH3

O + CH3OH

-H's

EX s carbonate & oxalate esters make -diesters

O CH3CH2O C -H's O OCH2CH3 O CH3CH2O C O C OCH2CH3 + CH3CH2OH

CH3 + CH3CH2O C

CH3CH2O

CH2

diethyl carbonate no -H's

-diester

- ketones can react with esters in a variation of the crossed Claisen condensation - the ketones alpha hydrogens are more acidic than the esters, rendering the ketone as the carbanionic nucleophile in the reaction - an esters -Hs are less acidic than a ketones because of the electron-donating resonance (+R) effect of the alkoxy (OR) group which destabilizes the resonance hybrid for the ester - thus, a satisfactory yield of one product can be obtained even if both reactants have -Hs

EX s
O C -H's O

CH3

O + CH3CH2O C H no -H's

CH3CH2O

O C

CH2 C H

O + CH3CH2OH

-ketoaldehyde O O

O + CH3O C CH3

CH3O

CH3OH

more acidic -H's

less acidic -H's

-diketone

Use in Synthesis
- the Claisen condensation can be used to acquire the following synthetic targets:

O RO C

O C

O or RO C

C OR

O or C

O C

ketoester or formylester

diester

dicarbonyl

MALONIC ESTER SYNTHESIS

- esters of propanedioic or malonic acid are known as dialkyl propanedioates or malonic esters - a malonic ester has two acidic alpha hydrogens (-Hs) which can be sequentially removed by base & substituted for by alkyl groups - the resulting monoalkylated or dialkylated malonic ester is then hydrolyzed & decarboxylated, yielding a monosubstituted or disubstituted acetic acid
O H O RO C C H

C OR

R' X R'' X

H H2O,

O HO C

CH R' R''

+ 2 ROH + CO2 + 2 X

mono or disubstituted acetic acid (R''= H) R = CH3, CH2CH3, ......... B = CH3O , CH3CH2O , ......... no OH (hydrolyzes ester) R'X & R''X = 1o R-CH2-X (best); 2o R2CH-X (OK); R' & R" can be same or different X = Cl, Br, I, ... No 3o R3C-X; No Ar-X

- alkylation at the alpha carbon of other carboxyl or acyl compounds is a difficult process to control ; oversubstitution often occurs - the ability to mono or disubstitute with the same or different alkyl groups makes malonic ester synthesis an exceptionally versatile methodology

Mechanism 1) Monoalkylation A
O RO + B C H C

O C H OR RO

O C H C

O C OR + RO

O C C

O C OR RO

O C C H

O C OR

H R' X RC's O RO C H C

SN2 BSA

O C R' OR + X

monoalkylated malonate

2) Dialkylation A
O RO + B C R' C

O C H OR RO

O C R' C

O C OR + RO

O C C R' R'' X

O C OR RO

O C C R'

O C OR

RC's O RO C R' C

SN2 BSA

O C R'' OR + X

dialkylated malonate

3) Hydrolysis & Decarboxylation (R= H, also) A

H O RO C R' C

O C R'' OR H H 2O HO

O C R' C

O C R'' OH HO

O C R' C

O C R'' O

H + C R'' R' enol

O C O

HO

mono or dialkylated malonate

-diacid

O HO C

H keto

C R'' R'

mono or disubstituted acetic acid

Use in Synthesis
- to gain synthetic access via malonic ester synthesis, view any carboxylic acid as a substituted

acetic acid
EX. Synthesize:
O CH3 O FROM CH3CH2O C O CH2 C OCH2CH3 & R X 's

CH3CH2 CH C OH

O HO C CH CH2CH3 CH3

O C OH CH2CH3 C H H2 O CH3CH2O

O C C

O OCH2CH3 CH2CH3 C CH3 Br EtO O O C OCH2CH3 CH2CH3 C

HO

H 3C

H 3C

O CH3CH2O C

O CH2 C OCH2CH3

EtO

CH3CH2 I

CH3CH2O

C H

ACETOACETIC ESTER SYNTHESIS

- the sequence is identical to malonic ester synthesis except one alkoxy group (OR) is replaced by a methyl group (CH3) - alkyl 3-oxobutanoates are known as acetoacetic esters - acetoacetic ester has two acidic alpha hydrogens (-Hs) which can be sequentially removed by base & substituted for by alkyl groups - the resulting monoalkylated or dialkylated acetoacetic ester is then hydrolyzed & decarboxylated, yielding a monosubstituted or disubstituted acetone
O H O CH3 C C

C OR

R' X R'' X

H H2O,

O CH3 C

CH R' R''

+ ROH + CO2 + 2 X

H alkyl 3-oxobutanoate acetoacetic ester R = CH3, CH2CH3, .........

mono or disubstituted acetone (R''= H)

B = CH3O , CH3CH2O , ......... no OH (hydrolyzes ester) R'X & R''X = 1o R-CH2-X (best); 2o R2CH-X (OK); R' & R" can be same or different X = Cl, Br, I, ... No 3o R3C-X; No Ar-X

- alkylation at the alpha carbon of other carbonyl compounds is a difficult process to control ; oversubstitution often occurs - the ability to mono or disubstitute with the same or different alkyl groups makes acetoacetic ester synthesis an exceptionally versatile methodology Mechanism 1) Monoalkylation A
O CH3 + B C H C O C H OR CH3 O C H + SN2 BSA R' X C O C OR CH3 O C C H RC's O CH3 C H C O C R' OR + X O C OR CH3 O C C H O C OR

monoalkylated acetoacetate

2) Dialkylation A
O CH3 + B C R' C O C H OR CH3 O C R' + SN2 BSA R'' X C O C OR CH3 O C C R' RC's O CH3 C R' C O C R'' OR + X O C OR CH3 O C C R' O C OR

dialkylated acetoacetate

3) Hydrolysis & Decarboxylation (R= H, also) A

O CH3 C R' C O C R'' OR H H 2O CH3 O C R' C O C R'' OH CH3 O C R' H O C R'' O CH3 C O O CH3 C R' H + C R'' enol H C R'' R' keto O C O

mono or dialkylated acetoacetate

-ketoacid

mono or disubstituted acetone

Use in Synthesis
- to gain synthetic access via acetoacetic ester synthesis, view any methyl ketone as a substituted

acetone
EX. Synthesize:
O CH CH3 CH2CH3 FROM O CH3 C O CH2 C OCH2CH3 & R X 's

CH3 C

O CH3 C CH CH2CH3 CH3

CH3

O C C

O OH CH2CH3 C

H H2 O CH3

O C C

O OCH2CH3 CH2CH3 C

CH3 Br EtO

H 3C

H3 C

O CH3 C

O CH2 C OCH2CH3

O EtO CH3CH2 I CH3 C H C

O OCH2CH3 CH2CH3 C

MICHAEL ADDITION
- a specific example of a more general class of reactions known as conjugate addition L nucleophilic addition to the double bond of an ,-unsaturated carbonyl or acyl compound
Conjugate Addition: H Nu nucleophilic reagent + C

C O

C O

,-unsatd' carbonyl or acyl compound

Nu H conjugate adduct

H-Nu = H2O, HX, NH3, -C, .......... C O from RCHO, R2CO, RCO2R', RCONR'2 ,........

Mechanism - the elements of H-Nu execute a 1,4-addition to the conjugated system - after tautomerizing, a regiospecific attachment of the hydrogen to the alpha carbon & the nucleophile to the beta carbon occurs at the carbon-carbon double bond

O RC's Nu

H Nu C O

Nu enolate

keto

C O

O H

Nu H keto Alternatively:

Nu enol (1,4-adduct)

Nu enolate

Nu carbanion

H Nu

C O

Nu H

- the Michael addition employs a beta-dicarbonyl or beta-diacyl compound as the nucleophile in a conjugate addition to an ,-unsaturated carbonyl or acyl compound (as shown above)
Michael Addition: O C C H Michael donor (-dicarbonyl or diacyl) Michael acceptor (,-unsatd' carbonyl or acyl) Michael adduct (-tricarbonyl or triacyl) O C + B O C O C

C O

C C

C O

O Michael donor (H Nu) = C C

O C ,

O C C H C N , ...

H (mostly) Michael acceptor (C C C O)

from RCHO, R2CO, RCO2R', RCONR2 ,........

B = CH3O , CH3CH2O , ......... with acyls no OH (hydrolyzes)

Mechanism - the Michael donor, after deprotonation of its -C by the base attacks the -C of the Michael acceptor, thereby establishing the regiospecificity of the conjugate addition - the carbanionic -C of the Michael acceptor is then protonated by the conjugate acid of the base, completing the reaction

EX s
O C OCH3 CH2 C OCH3 O + CH2

CH C

CH3O

C OCH3 CH CH2 CH C OCH3 O H

O C

O OCH2CH3 O O CH3CH2O

O OCH2CH3