Acyl amides acid halide synthesis

Acid halides, also called acyl halides, are activated derivatives used for the synthesis of other acyl compounds such as esters, amides, and acylbenzenes (in the Friedel-Crafts acylation). The most common acyl halides are the acid chlorides (acyl chlorides), and we will generally use acid chlorides as examples. 

At oxidation level 3, acid chlorides occupy a key position, since they may serve as a nearly universal substrate for an isohypsic transformation into any kind of carboxylic acid derivative. Acid halides are electrophiles that are synthetically equivalent to acyl cations (RCO ). In this capacity they are used for the synthesis of such important compounds as esters, amides (and hence, nitriles), thioesters, etc. (see Scheme 2.57), and for the formation of C-C bonds in the Friedel-Crafts reaction (see above). Acid chlorides may readily lose HCl upon treatment with triethylamine. This isohypsic conversion leads to ketenes, important reagents widely employed in [2 + 2] cycloadditions, as we will see later. 

Conductivity measurements have revealed that DMF and carboxylic acid chlorides form salt-like adducts (22) in an equilibrium reaction (equation 12). Such adducts can be prepared either from DMF and acid halides (chlorides and bromides) or from chloromethyleneiminium salts and salts of carboxylic acids. Acyloxyiminium salts (23) can be prepared in the pure state by reacting acid amides with carboxylic acid chlorides in the presence of silver trifluoromethanesulfonate (equation 13). Salts of type (24 equation 14) are regarded as being intermediates in the synthesis of ketones from carboxylic acids and Grignard reagents in the presence of a-chloroenamines as well as in the preparation of acyl halides (F, Cl, Br, I) by action of a-haloenamines on carboxylic acids. ... 

Less reactive than acyl halides, but still suitable for difficult couplings, are symmetric or mixed anhydrides (e.g. with pivalic or 2,6-dichlorobenzoic acid) and HOAt-derived active esters. HOBt esters smoothly acylate primary or secondary aliphatic amines, including amino acid esters or amides, without concomitant esterification of alcohols or phenols [34], HOBt esters are the most commonly used type of activated esters in automated solid-phase peptide synthesis. For reasons not yet fully understood, acylations with HOBt esters or halophenyl esters can be effectively catalyzed by HOBt and HOAt [3], and mixtures of BOP (in situ formation of HOBt esters) and HOBt are among the most efficient coupling agents for solid-phase peptide synthesis [2]. In acylations with activated amino acid derivatives, the addition of HOBt or HOAt also retards racemization [4,12,35]. 

Peptide synthesis requires the formation of amide bonds between the proper amino acids in the proper sequence. With simple acids and amines, we would form an amide bond simply by converting the acid to an activated derivative (such as an acyl halide or anhydride) and adding the amine. 

Carboxyl Activation Synthesis of Esters and Amides from Carboxylic Acids. 4-(Dimethylamino)pyridinium chlorosulfite chloride is more reactive than either thionyl chloride or thionyl chloride/pyridine for carboxyl activation. Aliphatic and aromatic, as well as amino acids (in racemic form), undergo activation (via the acyl halide) and subsequent esterification by reaction with an alcohol at — 20 °C (eq 1). The esterification step requires the addition of a second equivalent of DMAP and this method has been applied to a range of functionalized carboxylic acids. 

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