Amines reaction + acid chlorides

Additional work was carried out by the GE group on optimization of the reaction yield and to eliminate unwanted linear oligomers [14], Three side reactions which interfere with synthesis of cyclics were identified reaction of the amine with acid chloride to form an acyl ammonium salt, followed by decomposition to an amide (Equation (3.2)) reaction with CH2CI2 to form a salt (Equation (3.3)) hydrolysis of the acid chloride, forming carboxylate via catalysis... 

Quantitative stoichiometric gas-solid or solid-solid (these at 0 °C) acylations of amines with acid chlorides are varied (Scheme 32). However, for a clean reaction the liberated hydrochloric acid has to be neutralized by an additional gaseous or solid base that may also be a second mole of the amine. The reactions are performed in an evacuated flask or in a ball-mill, respectively. There are only minimal losses of the amides or sulfonamides upon removal of the stoichiometric coproduct with water [91]. The solid-solid reactions can be turned into sustainable 100% yield processes with optimal atom efficiency by milling stoichiometric 1 1 1 mixtures of acid chloride, aniline derivative, and K2CO3... 

Similarly, a monolithic polymer of PolyHIPE functionalized with tris(aminoethyl)amine captures acid chlorides in solution with high efficiency (entry 36).42 Contrary to suspensions of polymer beads, the porous polymer monolith is used in a flow-through reaction format. 

More information can be gained on the mechanism of the reaction if two separate experiments can be carried out with the mechanistic probe inserted at two different sites on the reagents. If we are studying a reaction between a nucleophile and an electrophile, it may be possible to make Hammett plots from the variation of substituents on both reagents. The acylation of amines with acid chlorides is an example. 

The product is a N,jV-disubstituted amine, which can be formed by reduction of an amide. The amide results from treatment of an acid chloride with the appropriate amine. The acid chloride is the product of the reaction of SOCI2 with a carboxylic acid that is formed by carboxylation of the Grignard reagent synthesized from the starting material. 

With the structure known, synthesis of a peptide can then be undertaken— perhaps to obtain larger amounts for biological evaluation. Although simple amides are usually formed by reaction between amines and acid chlorides (Section 21.7), peptide synthesis is more difficult becau.se many different amide bonds must he formed in a specific order rather than at random. 

Synthesis of new imide-containing monomers bearing amine or acid chloride functional groups starting from DPTA, followed by the reaction of the resultant monomers with the appropriate compounds [6-8]. 

Hydrogen chloride, the product of the fast reaction between amine and acid chloride, diffuses to the aqueous phase. Any amine hydrochloride that might be formed is usually very insoluble in the organic phase but is soluble in the aqueous phase. Both hydrogen chloride and amine hydrochloride have to be neutralized in the aqueous phase with inorganic bases. 

Substituted amides are formed by the reaction of amines with acid chlorides or anhydrides ... 

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. 

Anhydrides are formed from the reaction of acid chlorides with acids, and an ester is formed from the reaction of acid chlorides or anhydrides with alcohols. Amides may be formed by the reaction of ammonia or an amine with acid chlorides, acid anhydrides, or esters. The nitrogen atom of ammonia or an amine is a good nucleophile, and it attacks the acyl carbon of an acid derivative in a now familiar sequence (see 60 62) to give the amide. A typical example reacts... 

Anhydrides generally react more slowly with an amine than acid chlorides, though both reactions produce amides. Explain this observation. 

Amides can be synthesized by reaction of amines with acid chlorides, anhydrides, or esters. Acid chlorides can be prepared from carboxylic acids using thionyl chloride, SOCIj, oxalyl chloride (COCOj, or PCI5. 

Method 2. Place a 3 0 g. sample of the mixture of amines in a flask, add 6g. (4-5 ml.) of benzenesulphonyl chloride (or 6 g. of p-toluenesulphonyl chloride) and 100 ml. of a 5 per cent, solution of sodium hydroxide. Stopper the flask and shake vigorously until the odour of the acid chloride has disappeared open the flask occasionally to release the pressure developed by the heat of the reaction. AUow the mixture to cool, and dissolve any insoluble material in 60-75 ml. of ether. If a solid insoluble in both the aqueous and ether layer appears at this point (it is probably the sparingly soluble salt of a primary amine, e.g., a long chain compound of the type CjH5(CH2) NHj), add 25 ml. of water and shake if it does not dissolve, filter it off. Separate the ether and aqueous layers. The ether layer will contain the unchanged tertiary amine and the sulphonamide of the secondary amine. Acidify the alkaline aqueous layer with dilute hydrochloric acid, filter off the sulphonamide of the primary amine, and recrystaUise it from dilute alcohol. Extract the ether layer with sufficient 5 per cent, hydrochloric acid to remove all the tertiary amine present. Evaporate the ether to obtain the sulphonamide of the secondary amine recrystaUise it from alcohol or dilute alcohol. FinaUy, render the hydrochloric acid extract alkaline by the addition of dilute sodium hydroxide solution, and isolate the tertiary amine. 

Feebly basic amines, e.g., the nitroanilines, generally react so slowly with benzenesulphonyl chloride that most of the acid chloride is hydrolysed by the aqueous alkali before a reasonable yield of the sulphonamide is produced indeed, o-nitroaniline gives little or no sulphonamide under the conditions of the Hinsberg test. Excellent results are obtained by carrying out the reaction in pyridine solution ... 

Most aromatic acid chlorides impart a strongly acid reaction when shaken with water (compare Section 111,88). All are completely hydrolysed by boiling with solutions of caustic alkalis and yield no product volatile from the alkaline solution (compare Eaters, Sections 111,106 and IV, 183). They may be distinguished from acids by their facile reactions with alcohols (compare Section 111,27), phenols (compare Section IV,114), and amines (compare Sections 111,123 and IV.lOO). 

Primary and secondary amines also react with epoxides (or in situ produced episulfides )r aziridines)to /J-hydroxyamines (or /J-mercaptoamines or 1,2-diamines). The Michael type iddition of amines to activated C—C double bonds is also a useful synthetic reaction. Rnally unines react readily with. carbonyl compounds to form imines and enamines and with carbo-tylic acid chlorides or esters to give amides which can be reduced to amines with LiAlH (p. Ilf.). All these reactions are often applied in synthesis to produce polycyclic alkaloids with itrogen bridgeheads (J.W. Huffman, 1967) G. Stork, 1963 S.S. Klioze, 1975). 

Refluxing linoleic acid and a primary or secondary alkyl amine with -toluenesulfonic acid in toluene for 8—18 h also yields the substituted amides (32—34). The reaction of methyl esters with primary or secondary amines to make substituted amides is catalyzed with sodium methoxide. Reactions are rapid at 30°C under anhydrous conditions (35). Acid chlorides can also be used. Ai,A/-dibutyloleamide [5831-80-17 has been prepared from oleoyl chloride and dibutyl amine (36). 

Primary cycloaUphatic amines react with phosgene to form isocyanates. Reaction of isocyanates with primary and secondary amines forms ureas. Dehydration of ureas or dehydrosulfuri2ation of thioureas results in carhodiimides. The nucleophilicity that deterrnines rapid amine reactivity with acid chlorides and isocyanates also promotes epoxide ring opening to form hydroxyalkyl- and dihydroxyalkylaniines. Michael addition to acrylonitrile yields stable cyanoethylcycloalkylarnines. 

Acylation. Aromatic amines react with acids, acid chlorides, anhydrides, and esters to form amides. In general, acid chlorides give the best yield of the pure product. The reaction with acetic, propionic, butanoic, or benzoic acid can be catalyzed with phosphoms oxychloride or trichloride. 

Chloroformates are reactive intermediates that combine acid chloride and ester functions. They undergo many reactions similar to those of acid chlorides however, the rates are usually slower (4—8). Those containing smaller organic (hydrocarbon) substituents react faster than those containing large organic (hydrocarbon) substituents (3). Reactions of chloroformates and other acid chlorides proceed faster with better yields when alkaU hydroxides or tertiary amines are present to react with the HCl as it forms. These bases act as stoichiometric acid acceptors rather than as tme catalysts. 

Reactions of the carboxyl group include salt and acid chloride formation, esterification, pyrolysis, reduction, and amide, nitrile, and amine formation. Salt formation occurs when the carboxyUc acid reacts with an alkaline substance (22)... 

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