Claiscn condensation

A Claiscn condensation is the acylation of an ester enolate by the corresponding ester. By deprotonating an ester with MOR, only a small concentration of the ester enolate is generated and this enolate is in an equilibrium with the ester (cf. Table 10.1). The mechanism of the Claisen condensation is illustrated in detail in Figure 10.51 for the example of the condensation of butyric add ethyl ester. Both the deprotonation of the ester to give enolate A and the subsequent acylation of the latter are reversible. This acylation occurs via a tetrahedral intermediate (B in Figure 10.51) just like the acylations of other nucleophiles (Chapter 6). The equilibrium between two molecules of butyric acid ester and one molecule each of the condensation product C and ethanol does not lie completely on the side of the products. In fact, Claisen condensations go to completion only... 

Fluorinated esters have synthetic utility in Claiscn condensations, c.g. formation of 26,28,29 and Dieckmann cyclizations.30... 

Note that the nccettsary 3-ketoesler comes from a cra.ssed Claiscn condensation. As a result, RCO2CH2CH3 must be an ester that does not do Claiscn conden.siitioiis with itself (i.e., R mu.st not have an a-CH2 group). Otherwise the cro.s.scd conden.salion will be a disaster. 

Claiscn-like condensation of malonyl ACP with acetyl synthase occurs, followed by decarboxylation to yield acetoacetyl ACP, a -keto thioester. 

The /3-chloropropionic acid is best isolated by direct distillation under reduced pressure (Note 1) using a 250-cc. modified Claiscn flask (Org. Syn. 1, 40). The nitric acid is collected up to ioo°/2omm. using a water condenser. The condenser is then removed and the residual /3-chloropropionic acid is fractionated, collecting as pure product the portion boiling at 105-107720mm. The yield is 3i 3i.5g. (S4—55 Per cent of the theoretical amount) (Note 2). The product solidifies on cooling and melts at 41 41.5°. 

To 68 g. (0.5 mole) of phenylacetic acid (Org. Syn. 2, 63) (Note 1) in a i-l. flask fitted with a reflux condenser and a system for absorbing hydrogen chloride (Org. Syn. 8, 27) (Note 2), is added 35 g. (0.25 mole) of phosphorus trichloride. The mixture is heated on a steam bath for one hour. While the contents of the flask are still warm, 400 cc. of dry benzene is added. The benzene solution of phenylacetyl chloride is decanted from the residue of phosphorous acid on 75 g. (0.56 mole) of anhydrous aluminum chloride in a dry, i-l. flask which can be fitted to the same condenser. The reaction is vigorous at first and cooling is necessary. The mixture is refluxed for one hour on a steam bath, then cooled and poured into a mixture of 500 g. of cracked ice and 200 g. of concentrated hydrochloric acid. The benzene layer is separated, and the aqueous layer is extracted once with a mixture of 100 cc. of benzene and 100 cc. of ether (Note 2). The ether-benzene solution is washed once with 100 cc. of water (Note 3), and then dried over 40-50 g. of calcium chloride. The solution is filtered (Note 4) with suction into a i-l. Claiscn flask and the solvent is removed by distillation under reduced pressure (Note 5) the residue consists of a brown oil which solidifies on cooling. 

When the addition of the bromine is complete, the flask is attached to a condenser set for distillation, and the carbon tetrachloride and excess cyclohexcne are distilled from a water bath (Notes 4 and 5). The dark-colored residue is transferred to a 500-cc. modified Claiscn flask (Org. Syn. 1, 40) and distilled under reduced pressure. There is a small low-boiling fraction, and then pure dibromoeyclohexane distils at 108 112725 mm. The yield is 238 281 g. (73 86 per cent of the theoretical amount) (Notes 6 and 7). 

In a 5-I. round-bottom flask equipped with a mechanical stirrer are mixed 385 g. (335 cc.) (3.8 moles) of 95 per cent furfural (Org. Syn. 1, 49) (Note 1) and 3 1. of water. Then 500 g. (630 cc.) (8.6 moles) of acetone is added. The mixture is stirred and cooled to io° and to it is added 75 cc. of 33 per cent sodium hydroxide solution (Note i), whereupon some heat is generated. Without cooling, the stirring is continued for four hours. At the end of this time 10 per cent sulfuric acid is added until the mixture is acid to litmus (about 350 cc.) (Note 2). The two layers which have formed are separated and the upper aqueous layer is distilled (Note 3) under ordinary pressure until the distillate no longer forms two layers. The bottom layer of this distillate is added to the original lower layer and distilled under reduced pressure from a i-l. modified Claiscn flask (Org. Syn. 1, 40) provided with an air condenser and heated in an oil bath. The... 

FIGURE 5.8 Examples of formation and cleavage of carbon—carbon bonds (a) aldol condensation, (b) Claiscn ester condensation, (c) decarboxylation of a P—keto acid. (Adapted from Voet Voet, 2004.)... 

The five-membered ring pyrazoles are even simpler as the starting material is a 1,3-dicarbonyl compound available from the aldol or Claiscn ester condensations. 

Claiscn comlcnsaiions. (a), (b), (c) involve two identical molecules (d), (e) are intramolecular examples (f). (g), (h), (i) are mixed condensations. Make your new carbon-carbon bond (boldface) between the carbonyl carbon of one ester and the a-carbon of another. 

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