Chap 11. Carbonyl Alpha-Substitution Reactions and Condensation Reactions Four fundamental reactions of carbonyl compounds 1) Nucleophilic addition (aldehydes and ketones) 2) Nucleophilic acyl substitution (carboxylic acid derivatives) 3) The alpha-substitution Reactions occur at the position next to the carbonyl group–the alpha position–and result in the substitution of an α hydrogen atom by some other electrophilic group, E+: O O E+ α H E + H+

4) The carbonyl condensation Reactions take place when two carbonyl compounds react with each other in such a way that the α carbon of one partner becomes bonded to the carbonyl carbon of the second partner. O H O OH 2 H

The key feature of the reactions (3, 4) is that they take place through the formation of either enol or enolate ion intermediates. H O O C C C C

11.1 Keto-Enol Tautomerism The interconversion between the keto and enol forms of carbonyl compounds is a special kind of isomerism called tautomerism. In Greek, tauto means “the same,” and meros means “part.” The interconversion of tautomers involves the movement of atoms (H), so they are different from resonance forms. H O Rapid O α H

Keto tautomer Enol tautomer

1 Most carbonyl compounds exist almost entirely in the keto form at equilibrium.

OOHO OH

99.9999% 0.0001% 99.999999% 0.000001%

Mechanism of keto-enol tautomerism Acid catalysis H A H H H O O O A O H H H + HA

Keto tautomer Enol tautomer

Base catalysis

HOH H OOOH OO H + OH

Keto tautomer Enol tautomer

11.2 Reactivity of Enols: The Mechanism of Alpha-Substitution Reactions Since their double bonds are electron-rich, enols behave as nucleophiles and react with electrophiles in the same way as alkenes do. H H Electron-rich O O

Enol tautomer

Base HHH O O Acid O O O E+ H E E E catalyst

The addition step is the same as that of alkene but the intermediate cation loses the –OH proton to regenerate a carbonyl compound. The net result of the reaction is α substitution.

2 11.3 Alpha Halogenation of Aldehydes and Ketones

Aldehydes and ketones are halogenated at their α positions by reaction with Cl2, Br2, or I2 in acidic solution.

H O CH3CO2H X O + X2 + HX

Deuterium-hydrogen exchange H O + O D + D O D3O D3O

Preparation of α,β-unsaturated ketones from α-bromo ketones O O O

Br2 pyridine Br + HBr CH3CO2H heat 62%

11.4 Acidity of Alpha Hydrogen Atoms: Enolate Ion Formation

O Base O O H

contribute more Anenolateion Why are carbonyl compounds weakly acidic? (The presence of the carbonyl group increases the acidity of the neighboring C–H by a factor of 1030) The enolate ion is stabilized by resonance, and the negative charge is shared by the electronegative oxygen and the α carbon.

Carbonyl compounds (pKa = 20) are more acidic than alkanes (50) for the same reason that carboxylic acids (5) are more acidic than alcohols (16).

Strong bases are needed to form enolate ions. OO Na NaH THF 100% 0.1% when NaOEt is used

3 compound pKa compound pKa compound pKa O H CH3CO2H 5 19 40 Ph CH3 O O CH3 NC 9 20 41 OEt CH3 CH3 HH O OO CH3 SCH3 ~23 H 9 O 43 HH O ~24 CH OEt CH3NO2 10 3 H 44

OO CH3CO2H ~24 11 OEt H 52 HH CH3 CCH 25 OO Substituent effects 13 EtO OEt CH3CN ~25 HH R (+)1~2

NH2 CH3OH 16 ~30 X (−)1~2

(−)5~7 EtOH 18 Ph3CH ~40 Ph- (−)5~7 O t-BuOH 19 CH3 SCH3 ~40 S (−)3~5

anion stabilizing effect

NO2 > COR > SO2R > CO2R > CN > SOR > Ph, SR >> H > R

The enolate ions derived from the β-dicarbonyl compounds are stabilized by sharing of the negative charge onto two neighboring carbonyl oxygens.

OO OO OO

11.5 Reactivity of Enolate Ions Enols vs. Enolate Ions 1. Pure enols can’t be isolated but are generated only as transient intermediates in low concentration. 2. Enols are neutral and are not reactive.

4 3. Stable solutions of pure enolate ions are easily prepared by treatment with a strong base. 4. Enolate ions have a negative charge that makes them much better nucleophiles.

The resonance hybrid enolate ions α-keto carbanions or vinyl alkoxides– enolate ions can react with electrophiles either on oxygen or on carbon. E O O O O E+ E+ E

α-Keto carbanion Vinylic alkoxide

11.6 Alkylation of Enolate Ions

The nucleophilic enolate ion reacts with the electrophilic alkyl halide in an SN2 reaction, displacing the halide ion.

O O C X SN2 + C + X

Alkylations are successful only when a primary alkyl halide or methyl halide is used. The leaving group X can be chloride, bromide, or iodide.

Malonic ester synthesis – for preparing a substituted acetic acid from an alkyl halide. O

R X R CH2 C OH Alkylation

OO OO OO NaOEt R X EtO OEt EtOH EtO OEt EtO OEt Na R pKa = 13 pKa = 16 malonic ester

OO OO 1. NaOEt EtO OEt EtO OEt 2. R' X R R' R

5 Hydrolysis and decarboxylation H H OO OO O O 1. NaOH −CO 2 R EtO OEt OOH OH + Heat OH 2. H3O R R R

Example

OO OO O 1. OH− + n-BuBr Bu EtO OEt EtO OEt + OH 2. H3O Na Bu 84% 3. heat 75%

11.7 Enolate Alkylation and the Dawn of Modern Medicine The Synthesis of Barbiturates (a potent sedative) in early 1900s. O O 1. NaOEt O H O N EtO 2. CH3CH2Br EtO H2NNH2 O EtO 3. NaOEt EtO NaOEt N O 4. (CH3)2CHCH2CH2Br O H O

11.8 Carbonyl Condensation Reactions Carbonyl compounds can behave as either electrophiles or nucleophiles.

δ− O O δ+ + Nu E

Electrophilic carbonyl group Nucleophilic enolate ion is attacked by nucleophiles attacks electrophiles.

Carbonyl condensation reactions take place between two carbonyl partners and involve a combination of nucleophilic addition and α-substitution steps. One partner is converted into an enolate ion and undergoes an α-substitution reaction, while the other partner undergoes a nucleophilic addition reaction.

11.9 Condensations of Aldehydes and Ketones: The Aldol Reaction A rapid and reversible condensation of aldehyde under a base catalyst in an alcohol solvent to produce β-hydroxy aldehyde (aldol).

6 O NaOEt OH O 2 CH3 H EtOH CH3 H Aldol (β-hydroxy aldehyde)

Mechanism

O HO H O O O O O OH H OH + OH R R R R H2O

Aldol reaction is a general reaction of all aldehydes and ketones with α hydrogen atoms. If the aldehyde or ketone does not have an α hydrogen atom, aldol condensation can’t occur.

The position of the aldol equilibrium depends both on reaction conditions and on substrate structure.

O NaOH OH O 2 H EtOH H HH 90%

O O NaOH 2 EtOH OH

11.10 Dehydration of Aldol Products: Synthesis of Enones The β-hydroxy ketones and aldehydes are easily dehydrated to yield conjugated (α,β-unsaturated) enones. O OH O H+ or + H2O OH− H

β-hydroxy ketone conjugated enone

7 Mechanism Base-catalyzed OOH OOH O OH− +OH H enolate ion

Acid-catalyzed

H OOH OOH O + 2 H + +H3O H enol

11.11 Condensation of Esters: The Claisen Condensation Reaction A reversible condensation reaction of an ester with an α hydrogen under 1 equivalent of a base to yield a β-keto ester product. O 1. NaOEt, EtOH OO + EtOH 2 + OEt 2. H3O OEt

β-keto ester 75%

Mechanism Combination of α-substitution reaction and nucleophilic acyl substitution reaction of esters. O O O OO OO OEt H H H EtO H + OEt EtO EtO EtO EtO OEt

O O OO + OO H3O H + OEt H + EtOH EtO EtO EtO H H H pKa = 11 pKa = 16

There should be at least two α hydrogens in esters for the Claisen condensation reaction.

8 Homework Draw the major product of the following reaction. 1. O 1. NaOEt OEt EtO + 2. H3O O

2. O 1. NaOEt OEt + 2. H3O O

3. O CH MgBr H O+ O 3 3 (1 equiv) O

4.

OO + NaOEt H3O EtO OEt

5.

CO2Et + NaOEt H3O CO2Et

CO2Et

6. O 1. NaOEt EtO 2. H O+ 3

Propose the best synthesis of the following product using any reagents with C5 or less. O

9