CHAPTER 18 Enols, Enolates, and the Aldol Condensation: a,b-Unsaturated Aldehydes and Ketones

18-1 Acidity of Aldehydes and Ketones: Enolate Ions

The carbon alpha to the carbonyl carbon of ketones and aldehydes can be deprotonated with moderately strong bases, including hydroxide ion. The pKa of these acids falls in the range of 16-20, with aldehydes being slightly more acidic than ketones. The anion derived by deprotonation is called an enolate anion and is resonance stabilized which accounts for the enhanced acidity imparted by the carbonyl group.

18-2 Keto-Enol Equilibria

Resonance stabilization of enolates places negative charge on both oxygen and carbon. Protonation can occur at either oxygen or carbon. Protonation at oxygen generates and enol whereas protonation at carbon forms the ketone or aldehyde. Ketones and their corresponding enols are in rapid equilibrium in the presence of acid or base. The equilibrium favors the ketone (or aldehyde) except in special cases.

18-3 Halogenation of Aldehydes and Ketones

Conversion of a ketone to an enol catalyzed by acid in the presence of a halogen such as molecular bromine results in the formation of an alpha bromoketone. Further reaction to form a dibromoketone is slower than the first bromination because the presence of the bromine slows protonation of the ketone, the first step in formation of the enol. Under basic conditions, ketones form enolates which also react with halogens such as molecular bromine. However, the first formed alpha-bromoketone is converted more rapidly to its enolate than is the starting ketone and bromination continues until all alpha protons have been replaced with bromine. In the case of methy ketones, bromination continues to a tribromoketone that then reacts with hydroxide to form the carboxylate anion of a carboxylic acid. This reaction is know has the haloform reaction.

18-4 Alkylation of Aldehydes and Ketones

Enolate anions derived from ketones and aldehydes react with alkyl halides forming a new C—C bond. The reaction works best with primary and methyl halides. It is important that the ketone be converted essentially quatitatively to its enolate with a base used in 1:1 stoiciometry. Under these conditions, there is no remaining base present as the product is formed and thus the product is not deprotonated to its enolate anion which can also undergo alkylation. The standard base used is lithium diispropylamide.

18-5 Attack by Enolates on the Carbonyl Function: Aldol Condensation

Enolate anions can also act as nucleophiles with carbonyl groups. In the most simple example, a single carbony compound is partially converted to its enolate with a moderately strong base such as hydroxide. Under these conditions, the enolate is formed in the presence of starting material and the enolate anion reacts to form a new C—C bond, producing, after protonation, an aldol. Upon heating in the presence of base, the aldol undegoes loss of water to form an alpha,beta unsaturated carbonyl compound. Formation of the aldol is known as the aldol reaction and formation of the unsaturated product is called the aldol condensation reaction. All of these reactions are reversible. Formation of the aldol from ketones is thermodynamically unfavorable but the reaction can be driven to the condensation product by removal of water.

18-6 Crossed Aldol Condensation

Because the aldol reaction uses a carbonyl group as both a nucleophile and an electrophile, the reaction works best when only a single carbonyl compound is used---otherwise, in most cases, four different products can result. There are special, but very limited cases where two different carbonyl compounds can be used in what is known as a crossed aldol reaction.

18-7 Intramolecular Aldol Condensation

The presence of two carbonyl groups on a carbon chain sets the stage for an intramolecular aldol reaction. Because the aldol is a reversible reaction, it is not possible to formed the strained three- and four-membered ring products. Further, closure to form a seven-membered ring is slower than intermolecular reaction. Thus, the intramolecular aldol is restricted to formation of five- and six-membered rings. With both ring sizes, but especially with five-membered ring products, loss of water to form the condensation often proceeds at the same or faster rate the the aldol.

18-8 Properties of a,b-Unsaturated Aldehydes and Ketones

a,b-Unsaturated aldehydes and ketones undergo reactions typical of each functional group. The alkene can be selectively reduced with H2 and Pt whereas the ketone can be reduced with NaBH4. Reaction with alkyl lithiums proceeds with addition to the carbonyl carbon, leading to a product alcohol in a 1,2-addition.

18-9 Conjugate Additions to a,b-Unsaturated Aldehydes and Ketones

a,b-unsaturated aldehydes and ketones undergo reaction with nucleophiles in two modes: addition of the nucleophile to the carbonyl carbon resulting in an allylic alcohol; and addition of the nucleophile to the b-carbon, resulting in a ketone. As the latter reaction preserves the strong C=O p bond and the former does not, the latter results in the more stable product. Addition to the b-carbon is know as 1,4 addition, but better as conjugate addition. Addition to the carbonyl carbonyl is called 1,2-addition because the nucleophile adds to one atom and a proton adds to the adjacent oxygen. When addition of the nucleophile is reverisble, addition occurs in the conjugate sense. Irreversible reactions vary with the nucleophile. Alkyl lithium reagents add 1,2 whereas lithium dialkyl cuprate reagents add 1,4. The rationale for the former regiochemistry is that the lithium has strong affinity for the oxygen. The cuprate reaction proceeds by transfer of one electron from copper to the unsaturated ketone, resulting in a radical anion. The extra electron is added to the LUMO (first antibonding orbital) and, as a result of repulsion from the 4 electrons in the 2 bonding orbitals, as more electron density at the end distant from the oxygen to which the bonding electrons are attracted.

18-10 1,2- and 1,4-Additions of Organometallic Reagents

Reaction with alkyl lithiums proceeds with addition to the carbonyl carbon, leading to a product alcohol in a 1,2-addition. On the other hand, reaction with dialkyl cuprate reagents (R2CuLi) adds the alkyl group of the cuprate to the beta carbon, generating a product ketone (or aldehyde). The preference for 1,2-addition with alkyl lithiums is attributed to the affinity of lithium for the oxygen of the carbonyl group. With cuprate reagents, the reaction is believed to proceed by the transfer of one electron from the cuprate to the unsaturated ketone, forming a radical anion with the addition of the electron to the LUMO (lowest unoccupied molecular orbital). Whereas the electron density of the four bonding electrons is pulled toward the oxygen, the density of the electron in the LUMO is predominately at the other end. The R2Cu. the transfers an R radical, forming a C—C bond at the end with the greatest density of the electron in the LUMO.

18-11 Conjugate Additions of Enolate Ions: Michael Addition and Robinson Annulation

When an enolate anion adds in a conjugate addition fashion to an a,b-unsaturated aldehyde or ketone, a dicarbonyl compound results where the two carbonyl groups are 1,5 to each other. These dicarbonyl compounds undergo intramolecular condensation under the reaction conditions by which they were formed, generating a six-membered ring. The process of adding a ring to an existing structure is know as the Robinson ring annulation, after Sir Robert Robinson, a Knighted British chemist.