Ch 21

enols

ketone and enols are tautomers, position of equilibrium favors ketone

enolates

ambident nucleophiles because they possess two nucleophilic sites

more reactive than enols

acid-base equilibrium favors weaker acid (higher pKa)

keto-enol tautomerization

alpha carbon can act as a carbon nucleophile under acidic or basic conditions

choosing a base for enolate formation

alkoxide ion; equilibrium where alkoxide ion and enolate ion are both present

sodium hydride; completely converts ketone into enolate

LDA; irreversible enolate formation

alpha halogenation in acidic conditions

ketones and aldehydes undergo halogenation at alpha position, occurs at more substituted position

can undergo elimination with variety of bases like pyridine, Li2CO3, or KTbuOk

Hell-Volhard-Zelinksy reaction

alpha bromination of carboxylic acids with PBr3

haloform reaction

alpha halogenation in basic conditions of ketones

aldol addition

product exhibits both aldehydic and hydroxyl group

aldol condensation

when heated in acidic or basic conditions, product of an aldol addition reaction undergoes elimination to produce unsaturation between the alpha and beta positions

dehydration product is irreversible, called a thermodynamic sink

product is an a,B-unsaturated ketone/aldehyde

condensation

any reaction in which two molecules undergo addition accompanied by loss of a small molecule such as water, carbon dioxide, or nitrogen gas

E1cB Reaction

A unimolecular elimination reaction in which a proton is first removed to give a carbanion intermediate, which then expels the leaving group in a separate step

cb = conjugate base

1 = first order reaction

crossed aldol reactions

occurs between two different partners

only aldehydes with no alpha protons can act as electrophile

intramolecular aldol reactions

compounds that possess two carbonyl groups can undergo intramolecular aldol reactions; forms five- and six-membered rings

Claisen condensation

enolate ion of one ester acts as nucleophile attacking another ester

crossed claisen condensation

claisen condensation reaction that occurs between two different partners

Dieckmann Cyclization

intramolecular claisen condensation; forms five- and six- membered rings

alkylation via enolate ions

alkylate alpha position with formation of an enolate followed by treatment with alkyl halide; sn2

use LDA for less substituted product (kinetic enolate), NaH for more-substituted product (thermodynamic enolate)

Malonic ester synthesis

enables the transformation of a halide into a carboxylic acid with the introduction of two new carbon atoms

done with diethyl malonate

acetoacetic ester synthesis

converts an alkyl halide into a methyl ketone with the introduction of three new carbon atoms

Conjugate addition

Strongly basic nucleophiles react at the carbonyl carbon

Less basic nucleophiles react at the beta-carbon (1,4-addition)

thermodynamic control

most stable product obtained from reaction (1,4 product)

Kinetic control

products are reflective of the path that reacts fastest (1,2 product)

Michael reaction

1,4 nucleophilic addition of enolate anion or enamine to a,b-unsaturated carbonyl (done over EtO- and EtOH)

stork enamine synthesis

effective Michael donors

Robinson Annulation Reaction

forms a ring, Michael addition is followed by an intramolecular aldol condensation

Synthesis strategies

Stork enamine synthesis produces 1,5-difunctionalized compounds

aldol addition reactions and claisen condensation reactions produce 1,3-difunctionalized compounds

alkylation of alpha and beta positions

instead of quenching an enolate ion in a Michael addition, treat with an alkyl halide to get alkylation of the alpha position