Formation of Acid Chlorides

The hydroxyl group of carboxylic acids is replaced by chloride upon reaction with PC13, PC15 or SOCl2. To obtain the name of the acid chloride, the suffix -oic acid is replaced by -oyl chloride. 

When acid chlorides hydrolyse in water, carboxylic acids form. 

Write down the reactions of propanoic acid with the given compounds under suitable conditions. 

Attempted preparations of the acid chloride from 2,6-diamino-3-carboxy-5-chloropyrazine under a variety of conditions were unsuccessful (1331) and in that respect it resembled anthranilic acid. 

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The use of DMF to accelerate the formation of acid chlorides from carboxylic acids has been reviewed previously,4 and is believed to occur via an imidoyl chloride intermediate.5... 

Preparation of acid chlorides The best way to make acid chlorides is the reaction of a carboxylic acid with either thionyl chloride (SOCI2) or oxalyl chloride (COCl)2 in the presence of a base (pyridine). The mechanism of formation of acid chloride is similar to the reaction of alcohol with SOCI2. 

If care is taken to avoid ring cleavage, 5-aryl-l,3,4-oxadiazole-2-carboxylic acids will undergo typical reactions such as the formation of acid chlorides, amides and esters. Decarboxylation may occur on heating, for example with 5-amino-l,3,4-oxadiazole-2-carboxylic acids (77JHC1385), and an amide has been dehydrated to a nitrile (78GEP2808842). 

Amidation reactions are some of the most widely utilized in organic chemistry however, several of the commonly used amidation conditions are not suitable for large-scale manufacture. For instance, the use of carbodiimides poses a problem in that the reagents are potent sensitizers and the by-product ureas are not easily removable by nonchromatographic methods. Several other activation conditions such as formation of acid chlorides followed by amidation were explored in the laboratory and met with moderate success at best. Activation of 9 with iso-butyl chloroformate gave the desired mixed carbonic anhydride (Scheme 4.4), but subsequent reaction of the amine 8 occurred at the carbonate center to afford 9 and the isobutyl carbamate of 8 (via pathway b ), instead of amide 4 (pathway a ). 

Over the last decade, a considerable number of reactions has been studied (11,35) (i) olefins oxidation (38,39), hydroboration, and halogenation (40) (ii) amines silylation (41,42), amidation (43), and imine formation (44) (iii) hydroxyl groups reaction with anhydrides (45), isocyanates (46), epichloro-hydrin and chlorosilanes (47) (iv) carboxylic acids formation of acid chlorides (48), mixed anhydrides (49) and activated esters (50) (v) carboxylic esters reduction and hydrolysis (51) (vi) aldehydes imine formation (52) (vii) epoxides reactions with amines (55), glycols (54) and carboxyl-terminated polymers (55). A list of all the major classes of reactions on SAMs plus relevant examples are discussed comprehensively elsewhere (//). The following sections will provide a more detailed look at reactions with some of the common functional SAMs, i.e hydroxyl and carboxyl terminated SAMs. 

Some reactions of the first class of compounds to be considered as derived from carboxylic acids, the acid chlorides, are presented in Table 9.7. The formation of acid chlorides from carboxylic acids is shown, specifically for a cyclohexanecarboxylic acid, in Scheme 9.118. 

In peptide synthesis it is necessary to activate the carboxyl group (COOH-group) during the reaction involving amide bond formation. Earlier methods of COOH-activation were based on the formation of acid chlorides, anhydrides (either mixed or symmetrical carboxyanhydrides, as well as mixed anhydrides of inorganic acids such as sulfuric or phosphorous acids), and azides (Schroder and Lubke, 1965). It was soon... 

The classes of compounds which are conveniently considered together as derivatives of carboxylic acids include the carboxylic acid anhydrides, acid chlorides, esters, and amides. In the case of simple aliphatic and aromatic acids, synthetic transformations among these derivatives is usually a straightforward matter involving such fundamental reactions as ester saponification, formation of acid chlorides, and the reaction of amines with acid anhydrides or acid chlorides. When a multistep... 

Treatment of the toluene solution of bromide 12 with oxalyl chloride and catalytic DMF at room temperature led to the formation of acid chloride 13. This acid chloride was stable in toluene at room tenq)erature. The toluene solution was concentrated to half volume under reduced pressure in order to remove excess oxalyl chloride. This was necessary to avoid formation of oxamide 16, a result of the addition of methionine methyl ester to oxalyl chloride. Because 16 proved difficult to remove, it was necessary to verify that the toluene concentration had completely removed the excess oxalyl chloride. This was accon5)lished by quenching an aliquot of the reaction mixture into a dilute solution of phenethylamine and assaying for the amounts of... 

FIGURE 15.33 Formation of acid chlorides using PCI5... 

N,N-Dimethylformamide is a particularly effective catalyst for the formation of acid chlorides with SOCI2 and is now commonly the catalyst of choice. The chloromethyleneiminium chloride intermediate is the active chlorinating species (see Dimethylchloromethyleneammonium Chloride). 

For the formation of acid chlorides, the competing reactions of concern are a-oxidation and acid-catalyzed degradation. The use of solid Sodium Carbonate in the reaction mixture can minimize the latter for some compounds. As shown in eq 7, even simple carboxylic acids with enolizable hydrogens a to the carboxylic functionality are subject to oxidation under standard chlorinating conditions. Since the unoxidized acid chloride is the precursor to the sulfenyl chloride, careful attention to stoichiometry and reaction time can effectively minimize this problem. 

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