CHEM 4113 ORGANIC CHEMISTRY II CHAPTER 22

1. Introduction

LECTURE NOTES

The carbonyl group greatly increases the reactivity of the hydrogens on the carbons to the carbonyl. Thus, carbonyl compounds, especially aldehydes, esters and ketones, are able to undergo alpha substitution reactions. These substitution reactions occur via the formation of two key intermediates: enols and enolate ions. Carbonyl compounds form enols under acidic conditions, and enolates when treated with a base. 2. Alpha Substitution of Enols

Carbonyl compounds that have hydrogen atoms on their carbons are rapidly inter convertible with they enol forms when treated with acid. Enols are tautomers (structural isomers related by the shift of a hydrogen and one bond). Most carbonyl compounds exist almost exclusively as the keto form, however the enol form is always present, albeit in low concentrations. The rate at which the keto-enol inter convert is relatively slow unless catalyzed by H+, which greatly accelerates the process. However the addition of H+ does nothing to shift the equilibrium, it is only a catalyst. One class of carbonyl with a high percentage of enol present at equilibrium is the 1,3dicarbonyl compounds (or -dicarbonyl compounds). The enol form of a 1,3-dicarbonyl compound has stabilizing resonance conjugation between one carbonyl and the enol form of the other. O
Keq = 10

OH
-5

O C

Keq = 10

-7

CH3

OH C R CH2 OH C H CH2

O C

Keq = 10

-4

CH3

Enols are tautomers of carbonyl compounds Simple aldehydes and ketones have low concentrations of the enol form at equilibrium. Cyclic ketones have higher enol concentrations than acyclic ketones, aldehydes higher concentrations still.

Mechanism of acid catalyzed enol formation

O
H+

O H

O H H
-H

O H

Enols of Aldehydes and Ketones a. Alpha Halogenation of Aldehydes and Ketones (Halogenation in Acidic Solution)

Aldehydes and ketones are rapidly halogenated at the alpha position by reaction with chlorine, bromine or iodine in the presence of an acid (often glacial acetic acid is used as the solvent). The rate is independent of the halogen concentration; this means that the slow step (rate determining step) is the enolization process. The enol, once formed (in low concentrations) reacts rapidly with the halogenating agent to afford product. The halogenation is essentially irreversible, the equilibrium greatly favoring product. This removal of the enol cause the keto to tautomerize in order to maintain equilibrium; this to reacts with the halogen to form product. Halogenation in acidic solution

proceeds cleanly to the mono-halogenation carbonyl product . The inductive effect of the halogen retards further enolization of the -haloketone or aldehyde.

O
H+

O H

O H H
-H

O H Enol in low concentrations

Very Fast Further enolization and bromination of this product is prevented by the electronegative Br atom at the position. O Br -H+ Fast O H Br

Br2

O H Br

Mechanism of Alpha Halogenation of Aldehydes or Ketones Alpha halo ketones and aldehydes are useful in organic synthesis because they can be dehydrohalogenated by base to give ,unsaturated carbonyl compounds. The reaction occurs by an E2 mechanism will give high yields even with a weak base such as pyridine.

O HBr, Br2

O Br pyridine

Elimination of HX from halocarbonyl compounds results in the formation of ,unsaturated carbonyls

Mechanism of elimination O Br N H E2 pryridine acts as a weak base

O + N H Br pyridinium bromide

Synthesis of ,Unsaturated Carbonyls b. Alpha Bromination of Carboxylic Acids (Hell-Volhard-Zelenski Reaction)

Direct halogenation of carbonyl compounds is limited to aldehydes and ketones since the equilibrium enol content of esters, amides and carboxylic acids is very low (too low for halogenation to take place). Carboxylic acid can be brominate by a mixture of PBr3 and Br2 in a process called the Hell-Volhard-Zelinski reaction. The first step in the HVZ reaction is conversion of the acid into the acid bromide derivative by the action of PBr3 . The HBr released in this step catalyzes the enolization

of the acid bromide and the enol reacts rapidly with Br2. Hydrolysis of the bromo acid bromide with water forms the bromo acid.

Hell-Volhard-Zelinskii Reaction

HO

O C

1) PBr3, Br2 2) H2O

HO

O C Br
FAST addition of Br to enol

mechanism

HO

O C
conversion of acid to acid bromide

Br

O C

H O C Br
enolization enol present in low concentrations

Br

Br
- HBr

HO Synthesis of Alpha-Bromo Acids 3.

O C Br

H2O hydrolysis to acid

Br

O C Br

Acidity of Hydrogen atoms - Enolate Formation CH2 C H C H H2

H CH3
pKa = 55

H C H2

O C
25

OR H C H2

O C R
19

H C H2

O C H
17

INCREASING ACIDITY CASE 1 Ketone of aldehyde enolates:

O C+ H C R H2 O C+ H C OR H2

-H+

O C H2C R H2C

O C R

CASE 2 Ester enolates:

O -H+ C H C OR H2

O C H2C OR H2C

O C OR

The partial charge on the carbonyl weakens the C-H bond on the carbon. Esters have an important resonanceform that neutralizes the amount of positive charge at the carbonyl carbon; this is why esters are less acidic than either ketones or aldehydes.

Resonance and Electronic Effects in Enolates

Alpha hydrogen atoms of carbonyl compounds are acidic and can be abstracted by strong bases to yield enolate anions. Two factors are important in determining the acidity of protons of carbonyl compounds. The first factor relates to the inductive effect of the carbonyl group which withdraws electron density from the adjacent C-H bonds. Any substitution of the carbonyl group which increases the partial positive charge on the carbon of the carbonyl will increase the acidity of the protons(decreases the pKa). Also, any substitution of the carbonyl which slightly decreases the positive charge will decrease the acidity of the C-H bond. This is why aldehydes are slightly more acidic than ketones (the alkyl group of the ketone is electron donating by hyperconjugation). A more dramatic example of this effect is seen in esters where resonance donation of the lone pair electrons of the alkoxy group partly neutralizes the positive charge of the carbonyl carbon, making the C-H bond less acidic than in a ketone. The factor which most determines the acidity of carbonyl compounds is the resonance stabilization afforded to the product enolate anion . Enolate anions are highly reactive as nucleophiles because of their negative charge . a. Halogenation of Aldehydes and Ketones in Basic Solution

While halogenation of carbonyl compounds under acidic conditions is easily controlled to stop at the mono-halo stage, this is not the case when the reaction is done in basic solution. The reason for this difference is that the initially produced mono-halo ketone or aldehyde is more acidic (because of the inductive effect of the halogen) than the original compound. Thus, the enolate anion of this new product is more likely to form (are present in higher concentrations) than the parent carbonyl compound. The more abundant enolates then undergo preferential reaction with the halogenating agent. The reaction proceeds rapidly to the trihalo product . When all the acidic protons have been replaced by halogens(especially iodine atoms), the trihalomethyl group has acquired enough electron-withdrawing groups to facilitate breaking a carbon-carbon bond . In the case of a triiodomethyl group, the addition of water or dilute aqueous acid is able to hydrolyze the compound, leading to the formation of an acid and iodoform.

O C

NaOH

CH3

O Na C R CH2
I2 FAST

pKa = 19

O C

NaOH

CH2I

O C

Na

Reaction occurs by three consecutive halogenations of the enolate anion.

CHI
I2 FAST

pKa = 17

O C

R O
+ CHI3

O C

CHI2

O C

Na

CI2

pKa = 15

O C

NaOH

OH

+ CI3

I2 FAST CI - anion is relatively 3 stable: CI3 is a good O leaving group during C R CI3 acyl substitution

Acidity of reaction product increases as further halogenation occurs

The Iodoform Reaction: Halogenation of Methyl Ketones in Base. b. Direct Alkylation of Enolates Derived from Aldehydes, Ketones and Esters

Simple aldehydes (pKa=17), Ketones (pKa=19) and esters (pKa=25) don not form high concentrations of enolates when treated with relatively weak bases like hydroxide and alkoxides (pKa of water, alcohols ~16-18). To effect carbon alkylation of these enolates, and to avoid Aldol and Claisen condensation reactions (chapter 23), it is necessary to use very strong bases such as sodium hydride (NaH) and Sodium amide (NaNH 2 ). A useful addition to these reagents is Lithium Diisopropyl Amide (LDA ) which rapidly and quantitatively deprotonates aldehydes, ketones and esters at temperatures as low as -78C. The relative bulk of LDA allows us to selectively remove the least hindered acidic proton. After the highly nucleophilic enolate has been formed it can be treated with electrophiles and various substituted carbonyl compounds can be formed.

pKa = 35 + n-BuLi +

pKa = 50 n-Butane

N H
Diisopropylamine

Li Lithium diisopropyl amide LDA Keq = 10-3 to -5

O C

CH3

+ OH

O C

CH2

+ H2O

Y = H, R or OR

O C

Keq = 1011 to13 +

CH3

O C

CH2

N H

LDA rapidly and quantitatively deprotonates aldehydes, ketones and esters to form enolates.

Quantitative Enolate Formation Treatment of an enolate with an alkyl halide will result in alkylation at the position with formation of a new C-C bond . This reaction proceeds smoothly when R is a primary or unhindered secondary alkyl halide.

O C

LDA

CH2CH3

THF -78C

O C

CHCH3

O C

R X CHCH3
FAST reaction rapidly converts the enolate to product

Y = H aldehydes R ketones OR esters

LDA quantitatively converts carbonyl compounds to the enolate

Y Alkylation of Enolates

O C

R CH CH3

CH3

O C

O C CH2 CH3 CH CH3

O C CH2

CH3 CH CH3 CH3 C CH3

CH3 CH2 CH3I

CH CH3 O + CH3 C C CH3 CH3 CH3

O C

CH3

O C CH3

CH3 CH CH3

LDA THF -78C

O C CH2

CH3 CH CH3

CH3I CH3 CH2

O C

CH3 CH CH3

LDA is a "bulky" base and will abstract the least hindered, most accessable proton

Regioselectivity of LDA Enolates react with benzeneseleneyl bromide to yield phenylselenenylated products, which in turn give ,unsaturated carbonyl compounds when treated with H 2 O2 . Br O C
LDA THF -78C generation of enolate anion

O C

Se Ph Y
selenation of enolate anion

O C SePh

H2O2

O C
+ PhSe-OH

Y=H R OR

oxidation and elimination

mechanism of elimination

O C Se

H H

H2O2 Oxidation to form selenoxide

O C Se

H H O

Y
Intramolecular Elimination to ,unsaturated carbonyl

O C
+

H Se OH

Ph

Ph

Ph

Enone Synthesis via Selenylation of Enolate ions c. Malonic Ester Synthesis and Acetoacetic Ester Synthesis

The malonic ester synthesis involves alkylation of diethyl malonate with one or two alkyl halides, provides a method for preparing mono or dialkylated acetic acid derivatives. The two ester groups of malonic ester activate the central methylene toward deprotonation since the enolate derived from deprotonation of malonic ester can be more extensively delocalized than in a simple ester. The methylene hydrogens of malonic ester are highly acidic (pKa = 13). Thus alkoxide anions derived

form alcohols (pKa= 16-18) will rapidly and quantitatively carry out the deprotonation to form the enolate. The enolate so produced may be sequentially alkylated with alkyl halides via the SN2 reaction. Acid catalyzed hydrolysis of the two ester moieties, followed by acid catalyzed decarboxylation at elevated temperature affords the substituted acetic acid derivative.
Malonate Ester Enolate

EtO

O C CH2

O C

Na

OEt

OEt

EtO

O C

CH

O C

OEt O C CH

EtO O C

O C

CH

O C

OEt

pKa = 13

EtO

OEt

Sodium ethoxide rapidly and quantitatively deprotonates malonic ester

EtO

O C

CH2

O C

NaOEt

OEt EtOH

EtO O C

O C

O Na C OEt CH O C

R1

X EtO

O C

CH R1

O C

OEt

H3O

EtO

C R2 R1

OEt

1) NaOEt, EtOH 2)R2 X

H3O+

R1

CH R2

O C

OH

R1

CH2

O C

OH

The Malonic Ester Synthesis

O EtO C

O C
H3O
+

O
heat -2 EtOH FIRST STEP: Acid catalyzed hydrolysis of diester

H+

O H O C

O H

C OEt R1 R2

HO

C C OH R1 R2

C C OH R1 R2
- H+ - CO2

SECOND STEP: acid catalyzed cecarboxylation

1,3-diacids and 1,3-ketoacids rapidly undergo decarboxylation under conditions of acid and heat.

O R1 CH R2 C OH

Tautomerization

O H R1 C R2 C OH

Mechanism of Acid Catalyzed Decarboxylation

9
Acetoacetic ester enolate

EtO

O C CH2

O C

Na

OEt

CH3
pKa = 19

EtO

O C

CH

O C

CH3 O C CH

EtO O C

O C

CH

O C

CH3

pKa = 11

EtO

CH3

Sodium ethoxide rapidly and quantitatively deprotonates acetoacetic ester

EtO

O C

CH2

O C

NaOEt

CH3 EtOH

EtO O C

O C

O Na C CH3 CH O C

R1

X EtO

O C

CH R1

O C

CH3

H3O

EtO

C R2 R1

CH3

1) NaOEt, EtOH 2)R2 X

H3O+

R1

CH R2

O C

CH3

R1

CH2

O C

CH3

The AcetoaceticEster Synthesis