REACTIONS OF a -HYDROGENS : ALKYLATION AND HALOGENATION REACTIONS

REACTIONS OF a-HYDROGENS : ALKYLATION AND HALOGENATION REACTIONS

REACTIONS OF CARBONYL CONTAINING COMPOUNDS Until now we have looked at reactions of the C=O group - nucleophilic additions and substitutions Chaps 16, 17, 18, 19 Good nucleophiles react at C=O Chap 21 Strong bases remove the a-hydrogens Now we will look at reactions that result from the acidity of the alpha hydrogen

ACIDITY OF a-HYDROGENS ENOLATE IONS

a-Hydrogens and Enolate Ions Major resonance contributor: charge is best on oxygen = “enolate ion” base :B a-hydrogen However, the ion is more nucleophilic at carbon. acidic : pKa ~ 25 Strong bases will remove a hydrogen on the carbon next to a carbonyl group (a-hydrogen) to make a resonance stabilized conjugate base. NaOH, KOH, NaOR, NaH, LDA, etc.

ACETONE ENOLATE ION The nucleophilic electron pair is in the HOMO HOMO density- HOMO REACTIVE SITE .. Charge is on oxygen but carbon is nucleophilic note the bonding NEGATIVE CHARGE - .. .. : : : - density- electrostatic potential .. major

Enolate Ions as Nucleophiles MORE NUCLEOPHILIC AT CARBON, BUT BEST REPRESENTED AS THE ENOLATE Mechanisms are often drawn from the enolate resonance form like this: enolate Rather than from the ketolate form like this: ketolate

. one shot ALKYLATION OF KETONES NON-CATALYTIC BASES = NaH, LDA REACT ONCE CATALYTIC BASES = NaOH, KOH, NaOR REACT REPEATEDLY It just keeps on going and going …..

. one shot CH3-I Alkylation of a Ketone NON-CATALYTIC BASES REACT ONCE one mole one mole + H2 a-hydrogens CH3-I one mole monoalkylation Sodium Hydride NaH “LDA” Lithium Diisopropyl Amide a strong base

ALKYLATION OF CYCLOHEXANONE CATALYTIC BASES REACT REPEATEDLY .. .. : : - NaOH : enolate ion difficult to stop at monoalkylation with NaOH or KOH .. - : : (catalyst, not used up) It just keeps on going and going …..

Sequence of Alkylation - Cyclohexanone and Base It is difficult to stop at monoalkylation even if one mole of CH3I is used. Alkylation follows the sequence shown below. Large or bulky groups may follow a different sequence than this one. - - This enolate has lower energy - the double bond is more substituted. Steric hindrance is not a problem. SAME SIDE FIRST This enolate has higher energy. CH3-I

ALKYLATION OF KETONES NON-CATALYTIC BASES = NaH, LDA

. one shot Monoalkylation is Obtained by Using “Non-Catalytic Bases” A “non-catalytic base” is used up, and not regenerated. .. .. .. - - Na+ : : : : - : + H2 gone one mole .. stoichiometric base : + NaI

. one shot Lithium Diisopropyl Amide “LDA” Lithium Diisopropyl Amide a strong base LDA is also a non-catalytic base. It is too strong a base to be regenerated after it is used to remove a proton from an aldehyde or ketone. .. - .. .. - X : : + a-H difficult (need to add Lio)

ALKYLATION OF KETONES ENAMINES

. one shot ALKYLATION OF CYCLOHEXANONE ENAMINES ALSO GIVE MONOALKYLATION - I .. + Alkylates once and stops ! To perform a second alkylation you must make the enamine all over again!

Sequence of Alkylation: Enamine ( pyrrolidine + CH3I ) Alkylations go one-at-a-time. You must make a new enamine each time. first time Notice the different order of methylation from that with base. Difficult to go beyond dialkylation because of steric hindrance. second time Steric hindrance This enamine is not favored. This enamine is favored. yellow area is planar

a-BROMINATION OF KETONES

Bromination It just keeps on going and going ….. - .. .. .. .. : : : : : .. .. : - Difficult to stop at monobromination

IODOFORM REACTION

Iodoform Reaction NaOH yellow + I2 precipitate NaOH NaOH H2O - : .. good leaving group I2 It just keeps on going and going ….. 2x more ..- : ..

REACTIONS OF a -HYDROGENS : ALKYLATION AND HALOGENATION REACTIONS