Esters condensation

So far, we have seen that an enolate anion is able to act as a nucleophile in an SN2 reaction (Sections 20.3 and 20.4) and also in an addition reaction to the carbonyl group of an aldehyde in the aldol condensation (Section 20.5). It also can act as a nucleophile in a substitution reaction with the carbonyl group of an ester as the electrophile. When an ester is treated with a base such as sodium ethoxide, the enolate ion that is produced can react with another molecule of the same ester. The product has the a-carbon of one ester molecule bonded to the carbonyl carbon of a second ester molecule, replacing the alkoxy group. Examples of this reaction, called the Claisen ester condensation, are provided by the following equations  

The reverse aldol reaction is catalyzed by an enzyme called aldolase. One of the roles of the enzyme is to stabilize the enolate anion intermediate because such ions are too basic to be produced under physiological conditions. In animals, aldolase accomplishes this task by forming an inline bond between the carbonyl group of fructose-1,6-bisphosphate and the amino group of a lysine amino acid of the enzyme. As a result, the product of the reverse aldol step is an enamine derived from DHAP rather than its enolate anion. (Section 20.8 shows that enamines are the synthetic equivalents of enolate anions.) The formation of the strongly basic enolate anion is avoided. This process is outlined here  

This enamine is hydrolyzed to DHAP, freeing the enzyme to catalyze another reverse aldol cleavage. 

O The base, ethoxide ion, removes an acidic hydrogen from the a-carbon of the ester. 

0 Workup with acid protonates the anion, producing the /3-ketoester. 

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The mechanism of the Claisen Ester condensation has been suggested along the following lines ... 

The compound (III) can however lose ethanol by an internal Claisen ester condensation (p. 264) to give the cyclohexane derivative (IV), which, being the ester of a (3-keto acid, in turn readily undergoes hydrolysis and decarboxylation to give 5,5Hiimethyl cyclohexan-i,3Hiione (V) or Dimedone, a valuable reagent for the detection and estimation of formaldehyde. 

The formation of ethyl acetoacetate is an example of a general reaction knowu as the acetoacetlc ester condensation in which an ester having hydrogen on the a-carbon atom condenses with a second molecule of the same ester or with another ester (which may or may not have hydrogen on the a-carbon atom) in the presence of a basic catalyst (sodium, sodium ethoxide, sodamide, sodium triphenylmethide) to form a p-keto-ester. The mechanism of the reaction may be illustrated by the condensation of ethyl acetate with another molecule of ethyl acetate by means of sodium ethoxide. ... 

The acetoacetic ester condensation (involving the acylation of an ester by an ester) is a special case of a more general reaction term the Claisen condensation. The latter is the condensation between a carboxylic ester and an ester (or ketone or nitrile) containing an a-hydrogen atom in the presence of a base (sodium, sodium alkoxide, sodamide, sodium triphenylmethide, etc.). If R—H is the compound containing the a- or active hydrogen atom, the Claisen condensation may be written ... 

The mechanism, of the base-catalysed acylation of ketones by esters probably involves several steps (compare acetoacetlc ester condensation see discussion prloi to Section 111,151) —... 

Simple esters (e.g., ethyl acetate) undergo the acetoacetic ester condense tion (compare Section 111,151). The effective condensing agent is sodium ethoxide, produced by the action of sodium upon traces of alcohol present in the ester ... 

The formation of acyloins (a-hydroxyketones of the general formula RCH(OH)COR, where R is an aliphatic residue) proceeds best by reaction between finely-divided sodium (2 atoms) and esters of aliphatic acids (1 mol) in anhydrous ether or in anhydrous benzene with exclusion of oxygen salts of enediols are produced, which are converted by hydrolysis into acyloins. The yield of acetoin from ethyl acetate is low (ca. 23 per cent, in ether) owing to the accompanying acetoacetic ester condensation the latter reaction is favoured when the ester is used as the solvent. Ethyl propionate and ethyl ji-butyrate give yields of 52 per cent, of propionoin and 72 per cent, of butyroin respectively in ether. 

Chapter III. 1 Heptene (111,10) alkyl iodides (KI H3PO4 method) (111,38) alkyl fluorides (KF-ethylene glycol method) (111,41) keten (nichrome wire method) (111,90) ion exchange resin catalyst method for esters (111,102) acetamide (urea method) (111,107) ethyl a bromopropionate (111,126) acetoacetatic ester condensation using sodium triphenylmethide (111,151). 

Acetoacetic ester condensation Amdt-Eistert reaction Bart reaction. ... 

Benzilic acid rearrangement Benzoin reaction (condensation) Blanc chloromethylation reaction Bouveault-Blanc reduction Bucherer hydantoin synthesis Bucherer reaction Cannizzaro reaction Claisen aldoi condensation Claisen condensation Claisen-Schmidt reaction. Clemmensen reduction Darzens glycidic ester condensation Diazoamino-aminoazo rearrangement Dieckmann reaction Diels-Alder reaction Doebner reaction Erlenmeyer azlactone synthesis Fischer indole synthesis Fischer-Speior esterification Friedel-Crafts reaction... 

Synthesis This cyclisation version of the Claisen ester condensation is sometimes called the Dieckmann Reaction. 

Aldol additions and ester condensations have always been and still are the most popular reactions for the formation of carbon-carbon bonds (A.T. Nielsen, 1968). The earbonyl group acts as an a -synthon, the enoi or enolate as a d -synthon. Both reactions will be treated together here, and arguments, which are given for aldol additions, are also valid for ester condensations. Many famous name reactions belong to this category ). The products of aldol additions may be either /J-hydroxy carbonyl compounds or, after dehydration, or, -unsaturated carbonyl compounds. 

The usual base or acid catalyzed aldol addition or ester condensation reactions can only be applied as a useful synthetic reaction, if both carbonyl components are identical. Otherwise complicated mixtures of products are formed. If two different aldehydes or esters are to be combined, it is essential that one of the components is transformed quantitatively into an enol whereas the other component remains as a carbonyl compound in the reaction mixture. 

Cydopentane reagents used in synthesis are usually derived from cyclopentanone (R.A. Ellison, 1973). Classically they are made by base-catalyzed intramolecular aldol or ester condensations (see also p. 55). An important example is 2-methylcydopentane-l,3-dione. It is synthesized by intramolecular acylation of diethyl propionylsucdnate dianion followed by saponification and decarboxylation. This cyclization only worked with potassium t-butoxide in boiling xylene (R. Bucourt, 1965). Faster routes to this diketone start with succinic acid or its anhydride. A Friedel-Crafts acylation with 2-acetoxy-2-butene in nitrobenzene or with pro-pionyl chloride in nitromethane leads to acylated adducts, which are deacylated in aqueous acids (V.J. Grenda, 1967 L.E. Schick, 1969). A new promising route to substituted cyclopent-2-enones makes use of intermediate 5-nitro-l,3-diones (D. Seebach, 1977). 

Reaction with Alkyl Halide. The active methylene group of an Al-acylamino-malonic acid ester or Ai-acylamino cyanoacetic acid ester condenses readily with primary alkyl hahdes. 

Succinic esters condense with aldehydes and ketones in the presence of bases, eg, sodium alkoxide or piperidine, to form monoesters of alkybdenesuccinic acids, eg, condensation of diethyl succinate with acetone yields ethyl 2-isopropyhdenesuccinate (eq. 3). This reaction, known as Stobbe condensation, is specific for succinic esters and substituted succinic esters (98,99). 

Bis(chloroformic esters) condense with diamines to give polyurethanes (60) (see Urethane polymers). 

Claisen ester condensation, 6, 279 Thiazolecarboxylic acid chlorides reactions, 6, 279-280 Thiazolecarboxylic acid hydrazides synthesis, 6, 280 Thiazolecarboxylic acids acidity, 6, 279 decarboxylation, 6, 279 reactions, S, 92 6, 274 Thiazole-2-carboxylic acids decarboxylation, S, 92 Thiazole-4-carboxylic acids stability, S, 92 Thiazole-5-carboxylic acids decarboxylation, S, 92 Thiazole-4,5-dicarboxylic acid, 2-amino-diethyl ester reduction, 6, 279 Thiazole-4,5-dicarboxylic acids diethyl ester saponification, 6, 279 Thiazolediones diazo coupling, 5, 59 Thiazoles, 6, 235-331 ab initio calculations, 6, 236 acidity, S, 49 acylation, 6, 256 alkylation, S, 58, 73 6, 253, 256 analytical uses, 6, 328 antifogging agents... 

CLAISEN - GEUTER - OIECKMANN Ester condensation Synthesis ot open chain or cyclic p keloesters by aldol type condensation... 

A. Ester condensation. A suspension of 9.40 g. (0.41 gram atom) of powdered sodium in 100 ml. of absolute ether is placed in a 1-1. three-necked flask (Note 1) fitted with a reflux condenser, dropping funnel, and a calcium chloride tube. A solution of 23.8 ml. (0.41 mole) of absolute alcohol (Note 2) in 50 ml. of abso-... 

In the first century of "organic" chemistry much attention was given to the structures of carbogens and their transformations. Reactions were classified according to the types of substrates that underwent the chemical change (for example "aromatic substitution," "carbonyl addition," "halide displacement," "ester condensation"). Chemistry was taught and learned as transformations characteristic of a structural class (e.g. phenol, aldehyde) or structural subunit... 

Darzens glycidic ester condensation generally involves the condensation of an aldehyde or ketone 2 with the enolate of an a-halo ester 1 which leads to an a,P-epoxy ester (a glycidic ester) (3). Thus the reaction adds two carbons to the electrophile however, the reaction has been primarily developed as a one-carbon homologation method. That is, subsequent to the condensation, the ester is saponified and decarboxylation ensues to give the corresponding aldehyde or ketone 5.2... 

This modification has become the standard procedure for the acyloin ester condensation. By doing so, the formation of products from the otherwise competitive Dieckmann condensation (Claisen ester condensation) can be avoided. A product formed by ring closure through a Dieckmann condensation consists of a ring that is smaller by one carbon atom than the corresponding cyclic acyloin. 

A spectacular application of the acyloin ester condensation was the preparation of catenaries like 11. These were prepared by a statistical synthesis which means that an acyloin reaction of the diester 10 has been carried out in the presence of an excess of a large ring compound such as 9, with the hope that some diester molecules would be threaded through a ring, and would then undergo ring closure to give the catena compound ... 

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