Condensation Claisen

The Claisen Condensation. A classical reaction is the condensation of an ester enolate with an ester, illustrated by the self-condensation of ethyl butanoate in the presence of sodium ethoxide to give 3-keto-ester 167. Initial reaction with the base, under thermodynamic control in this case, generates the enolate anion (165). This anion attacks the carbonyl of a second molecule of ethyl butanoate to give 166. Displacement of ethoxide generates ketone 167. As shown here, this reaction is known as the Claisen condensation. A synthetic example is taken from Lubell s synthesis of indolizidine alkaloids, in which diester 168 was treated with LiN(SiMe3)2 in THF at -78°C to give the self-condensation product 169, in 52% yield. 

The reaction described for ethyl butanoate is a self-condensation, but as with the aldol condensation, Claisen condensation of two different esters can result in a mixture of products under thermodynamic control conditions. The reaction of two different esters is called the crossed-Claisen (or a mixed Claisen) condensation. A generalized reaction involving RC02Et and RlC02Et can lead to at least four different condensation 

There are two important variations of this condensation. In the first, an ester enolate is condensed with a ketone or aldehyde. This has been called the Claisen reaction. An example is taken from the Omura co- 

Reaction of an ester enolate with an acid chloride will also generate a (3-keto-ester and is a useful alternative to the Claisen condensation. Ketone enolates can also be condensed with acid chlorides. An ester enolate can be trapped with trimethylsilyl chloride, as with aldehydes and ketones. An interesting variation of this 

A variation of this condensation involves reaction with aldehydes, and it is called the Perkin reaction. Condensation of an aldehyde (having no enolizable protons) with the enolate of an acid anhydride leads to an acetoxy ester such as 182.10 Internal acyl substitution by the alkoxide forms the 0-acetyl ester and liberates the carboxylate anion (183). Subsequent reaction with more acetic anhydride generates a new mixed 

The term condensation refers to the joining of two molecules with the splitting out of a smaller molecule. The Claisen condensation is used extensively in the synthesis of dicarbonyl compounds. In biochemistry it is used to build fatty acids in the body. The Dieckmann condensation, the crossed Claisen condensation, and others (with other carbanions) cire variations of the Claisen condensation. In this section we briefly look at these variations. 

The Claisen condensation is one method of synthesizing (3-dicarbonyl compounds, specifically a (3-keto ester. This reaction begins with an ester and occurs in two steps. In the first step, a strong base, such as sodium ethoxide, removes a hydrogen ion from the carbon atom adjacent to the carbonyl group in the ester. (Resonance stabilizes the anion formed from the ester.) The anion can then attack a second molecule of the ester, which begins a series of mechanistic steps until the anion of the (3-dicarbonyl compound forms, which, in the second reaction step (acidification), gives the product. 

The Claisen condensation bears some resemblance to the Aldol condensation seen in Chapter 11. The initial step in the mechanisms are very similar in that in both cases a resonance-stabilized ion is formed. 

Collapse of the CTI forms the neutral P-keto ester product that will eventually be isolated, but the reaction mechanism does not stop here. Since the 1,3-dicarbonyl product has a highly acidic alpha proton (a to two EWGs), it becomes deprotonated in the basic reaction conditions to give a stabilized enolate. This deprotonation step is a necessary one, as it drives the equilibrium in the forward direction the Claisen condensation will not occur if there are not at least two alpha protons present in the ester starting material, and the acid-catalyzed Claisen condensation does not exist. Upon treatment with a mild aqueous workup, the enolate is protonated and the neutral P-keto ester product can be isolated. 

The product of this reaction is a P-keto ester that contains a newly formed carbon-carbon bond between the alpha carbon and one of the carbonyl carbons. This is the key bond to be identified in a P-keto ester TM a disconnection at this bond will lead to a Claisen retrosynthesis. 

A typical retrosynthesis of a P-keto ester involves making a disconnection from one of the carbonyls to the alpha carbon between the two carbonyls. The alpha carbon will be introduced as a nucleophilic enolate. The P-keto carbon used to be a carbonyl (E+), but how can it still be a carbonyl after being attacked by a nucleophile The P-keto carbonyl must have had a leaving group attached to it in order for the addition-elimination acyl substitution mechanism to take place. The alkoxy group is the preferred leaving group to select, since esters are stable, easy to work with, and commercially available. 

Since the disconnection in the example above leads to two identical pieces, this results in a simple synthesis and an ideal retrosynthesis (the more nearly equal the resulting pieces, the better the disconnection). The regioselectivity of a mixed Claisen reaction can be controlled in a stepwise synthesis that employs LDA, as done in a mixed aldol reaction. 

Synthesize the following target molecule using readily available starting materials and reagents. The synthesis must involve the formation of a new C-C bond. 

In the previous section, we saw that an enolate can attack a ketone  

In this section, we will explore what happens when an ester enolate attacks an ester  

An ester enolate is similar to a regular enolate an ester enolate is nucleophilic, and it will also attack a carbonyl group. When an ester enolate attacks an ester (shown above), the reaction that takes place is called a Claisen condensation. Here is the overall transformation  

The ester gets priority over the other carbonyl, so we label the carbon atoms (a, p, y, etc.) moving away from the ester 

At first glance, this product seems very different from the a,p-unsaturated ketones obtained from aldol condensations. But when we explore the mechanism, we will see the parallel between the aldol and Claisen condensations. 

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Claisen condensation Condensation of an ester with another ester, a ketone or a nitrile in the presence of sodium ethoxide, sodium or sodamidc, with the elimination of an alcohol. The result is the formation of a / -ketonic ester, ketone, or nitrile respectively, e.g. 

Clearly, the nex.t step will be to investigate the physicochemical effects, such as charge distribution and inductive and resonance effects, at the reaction center to obtain a deeper insight into the mechanisms of these biochemical reactions and the finer details of similar reactions. Here, it should be emphasized that biochemical reactions arc ruled and driven basically by the same effects as organic reactions. Figure 10.3-22 compares the Claisen condensation of acetic esters to acctoacctic esters with the analogous biochemical reaction in the human body. 

The Claisen condensation is initiated by deprotonation of an ester molecule by sodium ethanolate to give a carbanion that is stabilized, mostly by resonance, as an enolate. This carbanion makes a nucleophilic attack at the partially positively charged carbon atom of the e.ster group, leading to the formation of a C-C bond and the elimination ofan ethanolate ion, This Claisen condensation only proceeds in strongly basic conditions with a pH of about 14. 

Figure 10.3-22. Coinparison of a Claisen condensation with its biochemical counterpart.

This preparation was discovered independently by Geuther (1863) and by Frankland and Duppa (1865). The reaction was subsequently investigated in detail and so w idely extended by Claisen that it has become solely a specific example of the more general process known as the Claisen Condensation. Claisen showed that an ester under the influence of sodium ethoxide would not only condense with itself (as in the preparation of ethyl acetoacetate), but also with (i) another ester, (ii) a ketone, if of formula RCHgCOR, (iii) a nitrile, if of formula RCH CN, in each case with the elimination of alcohol. Examples of these modifications are ... 

Many other examples of the Claisen Condensation will be found in textbooks of theoretical organic chemistry. 

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 ... 

This reaction must be distinguished from the Claisen condensation, which is an acylation process (see discussion before Section 111,151). 

The preparation of benzoylacctone Is another example of the acylation of a ketone (acetophenone) by ethyl acetate to a p diketone (Claisen condensation compare preceding Section) ... 

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... 

The Claisen condensation of an aliphatic ester and a thiazolic ester gives after acidic hydrolysis a thiazolylketone (56). For example, the Claisen condensation of ethyl 4-methyl-5-thiazolecarboxylate with ethyl acetate followed by acid hydrolysis gives methyl 4-methyl-5-thiazolyl ketone in 16% yield. 

Before describing how p keto esters are used as reagents for organic synthesis we need to see how these compounds themselves are prepared The mam method for the prepa ration of p keto esters is the Claisen condensation... 

Claisen condensations involve two distinct experimental operations The first stage concludes m step 4 of Figure 21 1 where the base removes a proton from C 2 of the p keto ester Because this hydrogen is relatively acidic the position of equilibrium for step 4 lies far to the right... 

Ludwig Claisen was a Ger man chemist who worked during the last two decades of the nineteenth century and the first two decades of the twentieth His name is associated with three reac tions The Claisen-Schmidt reaction was presented in Section 18 10 the Claisen condensation is discussed in this section and the C/a/sen rearrangement will be intro duced in Section 24 13... 

FIGURE 21 1 The mechanism of the Claisen condensation of ethyl acetate... 

Organic chemists sometimes write equations for the Claisen condensation m a form that shows both stages explicitly... 

Like aldol condensations Claisen condensations always involve bond formation between the a carbon atom of one molecule and the carbonyl carbon of another... 

One of the following esters cannot undergo the Claisen con densation Which one Write structural formulas for the Claisen condensation products of the other two... 

Unless the p keto ester can form a stable anion by deprotonation as m step 4 of Figure 21 1 the Claisen condensation product is present m only trace amounts at equi librium Ethyl 2 methylpropanoate for example does not give any of its condensation product under the customary conditions of the Claisen condensation... 

At least two protons must be present at the a carbon for the equilibrium to favor prod uct formation Claisen condensation is possible for esters of the type RCH2CO2R but not for R2CHCO2R ... 

The following equation shows an example of a mixed Claisen condensation m which a benzoate ester is used as the nonenohzable component... 

Give the structure of the product obtained when ethyl phenyl acetat C6H CH2C02CH2CH3) is treated with each of the following esters under conditions of the mixed Claisen condensation... 

In a reaction related to the mixed Claisen condensation nonenolizable esters are used as acylatmg agents for ketone enolates Ketones (via their enolates) are converted to p keto esters by reaction with diethyl carbonate... 

The sequence begins with a Claisen condensation of ethyl pentanoate to give a p keto ester The ester is hydrolyzed and the resulting p keto acid decarboxylates to yield the desired ketone... 

We already know what happens when simple esters are treated with alkoxide bases— they undergo the Claisen condensation (Section 211) Simple esters have s of approximately 22 and give only a small amount of enolate when treated with alkoxide bases The small amount of enolate that is formed reacts by nucleophilic addition to the carbonyl group of the ester... 

Dieckmann cyclization (Section 21 2) An intra molecular analog of the Claisen condensation Cy die p keto esters in which the ring is five to seven membered may be formed by using this reaction... 

The following questions pertain to the esters shown and their behavior under conditions of the Claisen condensation... 

Ethyl benzoate cannot undergo the Claisen condensation... 

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