Acyl chlorides amide formation from

As a catalyst for ester and amide formation from acyl chlorides or anhydrides, 4-(di-methylamino)pyridine has been recommended (DMAP G. Hdfle, 1978). In the presence of this agent highly hindered hydroxyl groups, e.g. of steroids and carbohydrates, are acylated under mild conditions, which is difficult to achieve with other catalysts. 

Cyanuric chloride has been used for the preparation of acyl chlorides, amides, and peptides. Conversion of cyanuric chloride into 2-chloro-4,6-dimethoxy-l,3,5-triazine (CDMT, 6) leads to a reagent that upon reaction with carboxylic acids produces the highly reactive 2-acyloxy-4,6-dimethoxy-l,3,5-triazines.P l The resulting active ester is a powerful acylating agent for alcohols and amines. The activation is performed in presence of a base, preferentially NMM, which leads to intermediate formation of 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM, 7)P l (Scheme 5). This addition product is readily prepared from the commercially available CDMT (6) and NMM in THF and can be stored as solid compound in the cold.P P l It offers the advantage that it can be used in a one-... 

The Stolle reaction is thought to occur via a typical mechanism for amide formation from an amine and acid chloride, followed by Friedel-Crafts alkylation or acylation. No definitive mechanistic work has been performed on this reaction, but incorporating the mechnistic understandings of two steps provides a firm basis for understanding the mechanism of this reaction. Formation of the mono-amide from oxalyl chloride and aniline provides intermediate 4, which in the presence of AICI3 undergoes intramolecular electrophilic aromatic substitution to the desired 2,3-dioxindole (isatin) 7 via intermediates 5 and 6. 

Mechanism of Amide Formation from Acyl Chlorides... 

Regioselectivity becomes important, if unsymmetric difunctional nitrogen components are used. In such cases two different reactions of the nitrogen nucleophile with the open-chain educt may be possible, one of which must be faster than the other. Hydrazone formation, for example, occurs more readily than hydrazinoLysis of an ester. In the second example, on the other hand, the amide is formed very rapidly from the acyl chloride, and only one cyclization product is observed. 

However, in the presence of a catalytic amount of tris(dimethylamino)sulfonium difluorotrimethylsilicate ( TASF ), pivaldehyde imine yields the N-unsubstituted adduct, whereas acetone imine leads to the corresponding BSMA amides accompanied with the addition product of THF to DMAD. Formation of amides might be explained by the loss of HC1 from the iminium resulting from condensation of acyl chloride with imine, leading to a vinyl amide which is easily hydrolyzed. No explanation was presented for the formation of the THF adduct.241... 

Acyl or acid chlorides are used frequently in amide formation as activated forms of the corresponding carboxylic acid. A wide selection of acyl chlorides is available commercially. Otherwise, they can be prepared readily from the corresponding carboxylic acid in the presence of reagents such as thionyl chloride (9), oxalyl chloride 5 (10), phosphorus trichloride (11), and phosphorus pentachloride (12). Reactions that use oxalyl chloride or thionyl chloride are promoted by the addition of a catalytic amount of DMF (13) (see Fig. 3). 

As these mechanisms show, the formation of am ides from acid chlorides and amines is accompanied by production of one equivalent of HCI, which needs to be neutralized by a second equivalent of amine. An alternative method for making amides is to carry out the reaction in the presence of another base, such as NaOH, which then doesthejob of neutralizing the HCI. The trouble Is, OH" also attacks acyl chlorides to... 

The ammonolysis of acyl chlorides is commonly employed whenever the preparation of an amide is desired for the identification of a carboxylic acid. The acyl chloride is prepared and treated with aqueous ammonia, or, if the amide is very soluble in water, with ammonia in benzene. In the latter case the ammonium chloride is filtered off, and the amide obtained by evaporation of the benzene with powdered ammonium carbonate. The preparation of amides from carboxylic acids is based upon the formation of an equilibrium mixture when the ammonium salts of the acid are heated ... 

The common synthetic route3 to N,N-dimethylhomoveratrylamine involves acyl chloride formation from (3,4-dimethoxyphenyl)acetic acid with thionyl chloride (84%),7 followed by amide formation with dimethylamine (99%),8 and reduction with lithium aluminum hydride (71%).9 The procedure provides N.N-dimethylhomoveratrylamine in 59% overall yield, requires three steps and more expensive substrates and reagents. 

Acylation of amides is naturally much harder to achieve, because of their lower basicity, but it is very greatly facilitated by the presence of pyridine.583 617 618 The reason for this effect is, of course, the intermediate formation of 1-acylpyridinium salts as mentioned above.619 For instance, dibenzamide is formed almost quantitatively from benzoyl chloride and benzamide in pyridine solution even at room temperature, whereas there is no reaction in the absence of pyridine.620 Also, by the action of aromatic acid halides on aliphatic or aromatic amides in the presence of pyridine at temperatures as low as —60° to —70° Thompson617 obtained high yields of triacyl derivatives. 

Structure of Amides.—The formation of amides from acyl chlorides, esters, and cyanides can best be interpreted by... 

During our attempts to improve the overall convergency of the original route, we explored several options for installation of the side chain. For example, we attempted to isolate and utilize acyl chloride 109, which resulted from the prior coupling of the piperazine to oxalyl chloride (Scheme 25). This approach would have eliminated the need for the hydrolysis of 15 and amide coupling. While 109 was isolatable on lab scale, the preparation of this reagent was complicated by the formation of VUsmeier intermediate 110. Furthermore,... 

As these mechanisms show, the formation of amides from acid chlorides and amines is accompanied by production of one equivalent of HCI, which needs to be neutralized by a second equivalent of amine. An alternative method for making amides is to carry out the reaction in the presence of another base, such as NaOH, which then does the job of neutralizing the HCI. The trouble is, OH- also attacks acyl chlorides to give carboxylic acids. Schotten and Baumann, in the late nineteenth century, published a way round this problem by carrying out these reactions in two-phase systems of immiscible water and dichloromethane.The organic amine (not necessarily ammonia) and the acyl chloride remain in the (lower) dichloromethane layer, while the base (NaOH) remains in the (upper) aqueous layer. Dichloromethane and chloroform are two common organic solvents that are heavier (more dense) than water. The acyl chloride reacts only with the amine, but the HCI produced can dissolve in, and be neutralized by, the aqueous solution of NaOH. 

The main applications of oxalyl chloride, as described in Chapter 4, are the formation of aryl isocyanates and chloroformates (by reactions with amines and hydroxylic substrates, respectively), and the formation of acyl chlorides from carboxylic acids under very mild conditions. Oxalyl chloride reacts with amides to give acyl isocyanates, and it is used with dimethyl sulfoxide as a mild reagent for the oxidation of alcohols (Swern-type oxidation). It is also used with N,N-dimethylformamide as a mild reagent for chlorination and formylation. Oxalyl chloride is widely used in commercial formulations of speciality polymers, antioxidants, photographic chemicals, X-ray contrasting agents, and chemiluminescent materials. Other physical properties are presented in Chapter 3. 

Formation of amides from acyl chlorides is introduced in Section 9.5, while amide hydrolysis is discussed in Section 9.8... 

Notice that salt formation, though very favorable, is nonetheless reversible. Upon heating, a slower but thermodynamically favored reaction between the acid and the amine can take place. The acid and the amine are removed from the equilibrium, and eventually salt formation is completely reversed. In this second mode of reaction, the nitrogen acts as a nucleophile and attacks the carbonyl carbon. Completion of an addition-elimination sequence leads to the amide. Although it is convenient, this method suffers from the high temperatures required to reverse ammonium carboxylate formation. Therefore, better procedures rely on the use of activated carboxylic acid derivatives, such as acyl chlorides (Chapter 20). 

---