Carboxylic acid derivatives organometallic reagents

The most common reactions of carboxylic acid derivatives are substitution by water (hydrolysis) to yield an acid, by an alcohol (alcoholysis) to yield an ester, by an amine (aminolysis) to yield an amide, by hydride ion to yield an alcohol (reduction), and by an organometallic reagent to yield an alcohol (Grignard reaction). 

Now we see an analogy with the LAH reduction sequence (see Section 7.11), in that this ketone intermediate also reacts with the organometallic reagent, rather more readily than the initial carboxylic acid derivative, so that this ketone cannot usually be isolated. The final product is thus a tertiary alcohol, which contains two alkyl or aryl groups from the organometallic reagent. 

The present procedure provides a facile and versatile synthesis, on large scale, of a variety of pyrrole-2-carboxylic acid derivatives without necessitating the use of moisture-sensitive organometallic reagents. The use of alcohols other than ethanol in the alcoholysis reaction provides virtually any desired ester. Ammonia or aliphatic amines readily give amides in high yields, and aqueous base can be used to give the free acid. 

The reactions of several carboxylic acid derivatives with organomagnesium and organolithium compounds were described in Section 14-12. The key step in these reactions is addition of the organometallic compound, as R60MS , to the carbonyl group. For a Grignard reagent,... 

The nucleophilic addition of a trifluoromethyl anion or its equivalent to an activated carboxylic acid derivative is another potential method for the synthesis of trifluoromethyl ketones (Scheme 8). Due to the well-known instability of the trifluoromethyl anion, the organometallic approach (Section 15.1.4.3.3) is often difficult to utilize. However, a trifluoromethyl anion equivalent, (trifluoromethyl)trimethylsilane (CF3TMS), was developed in 1984 by Ruppert and co-workers.[30] This reagent, known as Ruppert s reagent, is stable and does not undergo fluoride elimination like other equivalent trifluoromethyl anions. An obvious limitation to this method is that it is only useful for the synthesis of a-amino trifluoromethyl ketones unless other fluoroalkyl analogues of Ruppert s reagent are developed. 

Predict the products and propose mechanisms for the reactions of carboxylic acid derivatives with reducing agents, alcohols, amines, and organometallic reagents. Q Propose multistep syntheses using acid derivatives as starting materials and intermediates. 

Reaction of organometallic reagents with carboxylic acid derivatives... 

Reaction of Organometallic Reagents with Carboxylic Acid Derivatives... 

Organometallic reagents react with carboxylic acid derivatives (RCOZ) to form two different products, depending on the identity of both the leaving group Z and the reagent R-M. The most useful reactions are carried out with esters and acid chlorides, forming either ketones or 3° alcohols. 

To form a ketone fiom a carboxylic acid derivative, a less reactive organometallic reagent— namely an organocuprate—is needed. Acid chlorides, which have the hest leavii group (CO of the carboxylic acid derivatives, react with R 2CuLi, to give a ketone as product. 

The stability of the intermediate formed by the addition of an organometallic reagent to a carboxylic acid derivative determines the product produced in the subsequent steps. 

Other organometallic reagents can be used to convert alkyl halides to carboxylic acid derivatives. Benzylic halides were converted to carboxylic esters with CO in the presence of a rhodium complex, ether a borate ester B(OR )3,... 

This chapter will discuss methods for the preparation of esters, acid chlorides, anhydrides, and amides from carboxylic acids, based on acyl substitution reactions. Acyl substitution reactions of carboxylic acid derivatives will include hydrolysis, interconversion of one acid derivative into another, and reactions with strong nucleophiles such as organometallic reagents. In addition, the chemistry of dicarboxylic acid derivatives will be discussed, as well as cyclic esters, amides, and anhydrides. Sulfonic acid derivatives will be introduced as well as sulfate esters and phosphate esters. Finally, nitriles will be shown to be acid derivatives by virtue of their reactivity. 

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