Acid chloride amides from

Acid chlorides are often used in these syntheses because they are the most electrophilic of all acid derivatives and because they can be made from the acids themselves with PCI5 or SOCI2. The other important acid derivatives can all be made from acid chlorides or from any compound above them in the chart of reactivity. So you can make amides from acid chlorides, anhydrides or esters but it is very difficult to make any other derivatives from amides. All derivatives except amides can easily be made from the acids themselves. 

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 lMaOH. which then does the job of neutralizing the HCI. The trouble is, OH" also attacks acy chlorides to... 

When we made acid anhydrides from acid chlorides plus car-boxylate salts, we used an anionic nucleophile RCO2 but, when we made amides from acid chlorides plus amines, we used a neutral nucleophile NH3, and not NH2. For proper comparisons, we should include in our table ROH (pXaH = -5 in other words, -5 is the pXa of ROH2) and NH3 (pXgH = 9 in other words, 9 is the pKaofNHj). 

Which reactions are useful for a ring-closing reaction In principle, aU reactions can be used. All irreversible reactions may be used in kinetically controlled cyclizations. However, it is advisable to use reactions which possess a decent reaction rate because the dilution and the potentially slow addition of one or more starting material to the reaction mixture lead to long reaction times anyway. Prominent reactions used for kinetically controlled macrocychzations are nucleophilic substitutions as for instance found in Williamson ether syntheses (for an example see the product shown in Figure 7.10) or the formation of amides from acid chlorides and amines (see Figure 7.8). 

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. 

Formation of diastereomeric amides from acid chlorides/imidazoles and chiral amines... 

The high reactivity of chlorides is utilized for the preparation of carboxylic acid derivatives by first converting the acids to chlorides and then allowing them to react with amines or alcohols to give suitable derivatives. For the identification of acid chlorides, reactions described on p. 254 are employed. A simple method of preparation of amides from acid chlorides is illustrated by the preparation of stearoylamide. Other useful amines are aniline or p-toluidine the reaction of amines with chlorides is usually carried out by heating the components in an inert solvent (benzene). 

Amines and ammonia are good nucleophiles and are rather hard to displace, once a tetrahedral intermediate has been formed. The synthesis of amides from acid chlorides and amines has been widely applied (Figure 15.27). Notice in the second example that it is the nitrogen rather than the oxygen of the amino alcohol that acts as the nucleophile, and in the third example that the acid chloride is more reactive toward substitution than the aliphatic bromide. 

Condensa.tlon, This term covers all processes, not previously iacluded ia other process definitions, where water or hydrogen chloride is eliminated ia a reaction involving the combination of two or more molecules. The important condensation reactions are nitrogen and sulfur heterocycle formation, amide formation from acid chlorides, formation of substituted diphenyl amines, and misceUaneous cyclizations. 

Acid anhydride, amides from, 807 eleclrostatic potential map of, 791 esters from, 807 from acid chlorides, 806 from carboxylic acids, 795 1R spectroscopy of, 822-823 naming, 786... 

Amides prepared from carboxylic acids and primary amines using azolides obtained from acid chloride/imidazolea) or ketene/imidazole systems.b)... 

The cyclization of IV-allyl-o-haloanilines was adapted to the solid phase for both indoles [332, 333] and oxindoles [334]. For example, as illustrated below, a library of l-acyl-3-aIkyl-6-hydroxyindoles is readily assembled from acid chlorides, allylic bromides, and 4-bromo-3-nitroanisole [332], Zhang and Maryanoff used the Rink amide resin to prepare Af-benzylindole-3-acetamides and related indoles via Heck cyclization [333], and Balasubramanian employed this technology to the synthesis of oxindoles via the palladium cyclization of o-iodo-N-acryloylanilines [334], This latter cyclization route to oxindoles is presented later in this section. 

Amides generally are formed from acid chlorides, acid azides, acid anhydrides, and esters. It is not practical to prepare them directly from an amine and a carboxylic acid without strong heating or unless the reaction is coupled to a second reaction that activates the acid (see Exercise 15-25). Notice that esters of phenols are more reactive toward amines than esters of alcohols because phenols are stronger acids than alcohols. 

Amines are at the same low oxidation level as alcohols and consequently are easily prepared by reduction. Amides and nitriles are reduced efficiently by LAH to amines. Nitriles give only primary amines while amides give 1°, 2°, or 3° amines depending on the number of carbon substituents on the amide nitrogen. The advantage of this method is that amides are easy to prepare from acid chlorides and amines while nitriles are available by displacement reactions. 

Amides can be prepared from acid chloride by nucleophilic substitution. When ammonia is treated with acid chlorides it gives a primary amide. Acid chloride on treatment with a primary amine gives a secondary amide, and on treatment with a secondary amine gives a tertiary amide. Tertiary amines cannot be used on this reaction because they do not form a stable product. 

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. ... 

Amides are much more easily prepared from acid chlorides and anhydrides, as discussed in Sections 22.8 and 22.9. 

The requisite W-methoxy-W-methylamides may be pre >ared from acid chlorides by employing a slight excess of the commercially available W,G-dimetiiylhydroxylamine hydrochloride in the presence of pyridine. They have also been pre >ared from acylimidazoles and from mixed anhydrides of carboxylic acids. Once prepared, these systems X)ssess stability equivalent to that of most tertiary amides and, in... 

RCO2H, R OH, (Chlorophenylthiomethylene)dimethylammonium chloride, DIPEA, CH2CI2, 75-100% yield. This coupling reagent can also be used to prepare amides from acids."... 

Amides can be prepared from acid chlorides + ammonia. 

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