Directed Aldol Reactions

The aldol reaction is potentially a powerful synthetic tool. As demonstrated by the following equation, a directed aldol reaction between different aldehydes would produce a single crossed aldol product (the new bond is colored maroon) and create two new stereogenic centers (colored blue). However, conducting this reaction with aqueous NaOH usually generates a mixture of four different adducts, and frequently β-elimination of water when possible.

R1CH2CHO	+	R2CH2CHO	base	R1CH2CH(OH)—CH(R2)CHO
Carbonyl Acceptor		Enolate Donor		One Crossed Aldol Product

In this section methods of controlling the enolate donor and carbonyl acceptor reactants to produce a single aldol product will be described and discussed. Several important principles must be taken into consideration for this purpose.

• The conventional aldol reaction is reversible. (aqueous base at room temperature)
• The initial aldol product may undergo beta-elimination of water, depending on reaction conditions.
• Regioselective enolate anion formation may be achieved by using differences in kinetic vs. equilibrium acidities of α-hydrogens.
• Enolate anions may be trapped as silyl ethers and used subsequently for controlled aldol reactions.
• Enolate-like species may be used for aldol-like reactions with carbonyl compounds, and hydrolyzed later to aldol products.
• Metal cations or other electrophilic moieties may act to orient the reactants in specific ways.

The reversibility of conventional aldol reactions is illustrated by the crossed aldol condensation of 2-butanone with benzaldehyde, illustrated below. The methyl hydrogens are kinetically more acidic than the methylene hydrogens, so the α'-enolate is generated more rapidly than the more substituted α-enolate. As a rule, ketone enolate bases react more rapidly with aldehydes than with ketones, so self condensation of the ketone is minimal. Both enolate anions add reversibly to benzaldehyde to form β-hydroxy ketones; however, the α-enolate product (on the left) reverts to reactants faster than it eliminates water. In contrast, the isomeric α'-enolate product (on the right) undergoes rapid β-elimination to the observed 5-phenyl-4-penten-3-one final product.

Acid catalysis of the 2-butanone-benzaldehyde reaction gives the isomer, 3-methyl-4-phenyl-3-buten-2-one, as the chief product, thanks to the predominance of the more substituted α-enol as an intermediate. In this case both β-hydroxy ketone intermediates undergo reversible dehydration.

مواضيع ذات صلة

Organic compounds are more soluble in water as ions

Heterocyclic aromatic compounds

Hückel’s rule tells us if compounds are aromatic

Molecular orbitals and aromaticity

The π molecular orbitals of other conjugated cyclic hydrocarbons

Benzene has six π molecular orbitals

Varying the number of electrons

Heats of hydrogenation of benzene and cyclooctatetraene

? What makes benzene special

Aromaticity

Conjugation and reactivity: looking forward to Chapter 10

The amide group