Carbonyl Alpha-Substitution Reactions

McMurry Chapter 22

Alpha Hydrogen’s

 

•      The alpha hydrogen’s are more reactive than normal C-H bonds.

 

 

 

 

 

 

Reactions with Electrophiles

•      Could be at C or O.

l   H+ as an example

 

 

 

 

 

 

 

 

 

l   Other electrophiles (E+) could be used.

Keto-Enol Tautomerism

•      We have seen this before.

l   These are not resonance forms (Why?)

 

 

 

 

 

l   The keto form is the more stable (Why?)

Equilibrium Concentrations

 

•      Very little enol exist for most ketones

 

 

 

 

 

 

 

 

Acidity of a-Hydrogen’s

•      Write the carbonyl compound as an acid.

 

 

 

 

•      pKa about 20 - 21.

•      What is the pKa of an alkane?

Enolates & Acids

•      Oxygen stabilizes the negative charge better than carbon.

 

 

 

 

 

 

 

What are the pKa’s?

•      Relative acidity

 

 

 

 

 

 

Rate of Enolization

•      Both acid and base catalyzed

l   Acid catalysis

l   Acid does not effect the equilibrium constant

 

 

 

 

 

 

 

 

 

 

Rate of Enolization

•      Base catalysis

 

 

 

 

 

 

 

 

Halogenation of Ketones

•      The enol reacts rapidly with Cl2 or Br2.

 

 

 

 

•      Rate of halogenation = k[ketone][H+]

•      Independent of halogen concentration

Mechanism: Acid Catalyzed

 

 

 

 

 

 

 

 

 

 

 

 

 

Mechanism: Base catalyzed

 

 

 

 

 

 

 

Hell-Volhard-Zelinskii

•      Bromination of acids

l   The acid does not enolize easily.

 

 

 

 

 

Mechanism

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Examples

a-Bromo acids have application in amino acid synthesis

 

 

 

 

 

 

 

 

 

 

 

Problems with Enolate Formation

•      We will see that enols react with ketones

•      Must have complete formation of the enolate without any ketone present.

•      Lithium diisopropylamide (LDA) works

 

Lithium Diisopropylamide (LDA)

•      The acid base reaction is complete

 

 

 

 

 

 

 

 

 

b-Diketone Anions

•      H between two ketones even more acidic

 

 

 

 

 

 

 

 

Enolate Reactions

•      Haloform reaction - methyl ketones

 

 

 

 

 

•      What happened?

Haloform Mechanism

•      First enolate halogenation (3 times).

 

 

 

 

 

 

 

 

 

 

 

 

Use of the Haloform Reaction

•      Oxidation of methyl ketones to acids with one less carbon

 

 

 

 

 

 

 

Iodoform Test

•      Iodoform is a yellow solid, m.p. 119 oC
A compound of formula C5H10O. It shows a IR absorption at 1715 cm-1. The MS showed peaks at 86, 71, and 43. On reaction of the compound with I2 in basic solution a yellow solid of m.p. 119oC was formed. What is a possible structure for the compound?

Alkylation of Enolates

•       Enolates are nucleophilic and react with electrophiles.

 

 

 

 

 

•       X must be a good leaving group; halogen or tosylate

Example

•      Make C-C bonds

 

 

 

 

 

 

 

Alkylation of b-Diketones

•      Alkoxide is a strong enough base to remove the proton.

 

 

 

 

 

 

 

 

Malonic Ester Synthesis

•      Several reactions

 

 

 

 

 

 

 

 

 

 

 

 

 

Decarboxylation Mechanism

•      6 Centered mechanism

 

 

 

 

Planning a Malonate Ester Synthesis

•      Generates a substituted acetic acid.

 

 

 

 

 

 

 

 

 

Acetoacetic Ester Synthesis

•      A variation

 

 

 

 

 

 

 

Decarboxylation

•      Similar to malonic acid decarboxylation

 

 

 

 

 

 

 

 

 

 

Acetoacetic Ester Synthesis
(cont..)

•      Yields a substituted acetone.

 

 

 

 

 

 

 

 

Direct Alkylation of Ketones

•      LDA converts ketones to enolates which can be alkylated

 

 

 

 

 

Alkylation of Other Carbonyl Compounds

•      Esters

 

 

 

 

 

•      Nitriles