Amides from acyl chlorides

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

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

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. 

These thermal methods for preparing amides are limited m their generality Most often amides are prepared m the laboratory from acyl chlorides acid anhydrides or esters and these are the methods that you should apply to solving synthetic problems... 

As a dibasic acid, malic acid forms the usual salts, esters, amides, and acyl chlorides. Monoesters can be prepared easily by refluxing malic acid, an alcohol, and boron trifluoride as a catalyst (9). With polyhydric alcohols and polycarboxyUc aromatic acids, malic acid yields alkyd polyester resins (10) (see Alcohols, polyhydric Alkyd resins). Complete esterification results from the reaction of the diester of maUc acid with an acid chloride, eg, acetyl or stearoyl chloride (11). 

From acyl chlorides and ammonia or amines Most amides are prepared by this... 

This reaction represents the best general method for amide preparation. Cold, concentrated aqueous ammonia is used as in the preparation of iso-butyramide (83%),or the reaction may be carried out by passing dry ammonia into a solution of the acyl halide in anhydrous ether as in the formation of cyclopropanecarboxamide (91%). Separation of the amide from ammonium chloride is usually accomplished by extraction of the amide by organic solvents. Aqueous sodium hydroxide is employed to take up the hydrogen chloride when amine hydrochlorides are used in place of the free amines as in the preparation of N-methylisobutyramide (75%). When phosphorus trichloride is added to a mixture of an amine and a carboxylic acid, phosphazo compounds, RN=PNHR, rather than acyl halides, are believed to be intermediates. These compounds have been shown to react with carboxylic acids to give amides. ... 

Carboxylic acids contain a carbonyl group, but it does not undergo the type of addition reactions that occur with the aldehydes and ketones. The carbonyl group in carboxylic acids, esters, amides or acyl chlorides has the electronegative atoms O, N or Cl next to the C=0, and these stop it from acting as a proper C=0 group should (Figure 7.2.15). 

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. 

Because acylation of amines with acyl chlorides and anhydrides yields an acid as one of the products (HCl from acyl chlorides, a carboxylic acid from an anhydride), the efficient synthesis of amides requires some attention to stoichiometry. 

The reaction of an amine with an acyl chloride is one of the most widely used laboratory methods for the synthesis of amides, because acyl chlorides are themselves easily prepared from carboxylic acids. 

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. 

Trifluoromethylated pyrones can also be prepared from acyl chlorides by reaction with pyridine and trifluoroacetic anhydride followed by capture of the intermediate trifluoroacyl ketene 8 with suitable reagents. Thus, addition of A -cyclohexenyl-morpholine to the intermediate from palmitoyl chloride gave pyrone 9 as the major product, accompanied by amide 10. Ethyl vinyl ether yielded pyrones 11a and 11b (through p-elimination of ethanol) [9] (Scheme 5). 

Mechanism of Amide Formation from Acyl Chlorides... 

In synthetic target molecules esters, lactones, amides, and lactams are the most common carboxylic acid derivatives. In order to synthesize them from carboxylic acids one has generally to produce an activated acid derivative, and an enormous variety of activating reagents is known, mostly developed for peptide syntheses (M. Bodanszky, 1976). In actual syntheses of complex esters and amides, however, only a small selection of these remedies is used, and we shall mention only generally applicable methods. The classic means of activating carboxyl groups arc the acyl azide method of Curtius and the acyl chloride method of Emil Fischer. 

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. 

The chemistry of the carbonyl group is probably the single most important aspect of organic chemical reactivity Classes of compounds that contain the carbonyl group include many derived from carboxylic acids (acyl chlorides acid anhydrides esters and amides) as well as the two related classes discussed m this chapter aldehydes and ketones... 

IS general for nucleophilic acyl substitution and well worth remembering The range of reactivities is quite large a factor of about 10 m relative rate separates acyl chlorides from amides... 

Section 20 21 Acyl chlorides anhydrides esters and amides all show a strong band for C=0 stretching m the infrared The range extends from about 1820 cm (acyl chlorides) to 1690 cm (amides) Their NMR spectra are characterized by a peak near 8 180 for the carbonyl carbon H NMR spectroscopy is useful for distinguishing between the groups R and R m esters (RCO2R ) The protons on the carbon bonded to O m R appear at lower field (less shielded) than those on the carbon bonded to C=0... 

FIGURE 20.1 Structure, reactivity, and carbonyl-group stabilization in carboxylic acid derivatives. Acyl chlorides are the most reactive, amides the least reactive. Acyl chlorides have the least stabilized carbonyl group, amides the most. Conversion of one class of compounds to another is feasible only in the direction that leads to a more stabilized carbonyl group that is, from more reactive to less reactive. 

---