Acid anhydride reaction with amines

Chemical Properties The formation of salts with acids is the most characteristic reaction of amines. Since the amines are soluble in organic solvents and the salts are usually not soluble, acidic products can be conveniendy separated by the reaction with an amine, the unshared electron pair on the amine nitrogen acting as proton acceptor. Amines are good nucleophiles reactions of amines at the nitrogen atom have as a first step the formation of a bond with the unshared electron pair of nitrogen, eg, reactions with acid anhydrides, haUdes, and esters, with carbon dioxide or carbon disulfide, and with isocyanic or isothiocyanic acid derivatives. 

When water is chemically removed, a basic catalyst, such as triethyl-amine, pyridine, jS-picoline, or isoquinoUne, and acetic anhydride is added. Water produced in the imidization is chemically removed by the reaction with acid anhydride. However, this method, requires a process for purification of a reaction mixture to remove the residue, such as tertiary amines and acetic anhydrides, out of the system. 

Carboxyhc acids react with aryl isocyanates, at elevated temperatures to yield anhydrides. The anhydrides subsequently evolve carbon dioxide to yield amines at elevated temperatures (70—72). The aromatic amines are further converted into amides by reaction with excess anhydride. Ortho diacids, such as phthahc acid [88-99-3J, react with aryl isocyanates to yield the corresponding A/-aryl phthalimides (73). Reactions with carboxyhc acids are irreversible and commercially used to prepare polyamides and polyimides, two classes of high performance polymers for high temperature appHcations where chemical resistance is important. Base catalysis is recommended to reduce the formation of substituted urea by-products (74). 

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. 

The most important group of derivatives for the amino function (Fig. 7-4) is the carbamate group, which can be formed by reactions with acids, acid chlorides or acid anhydrides. A series of chlorides as 2-chloroisovalerylchloride [1], chrysanthe-moylchloride [2] and especially chloride compounds of terpene derivatives (cam-phanic acid chloride [3], camphor-10-sulfonyl chloride [4]) are used. The a-methoxy-a-trifluoromethylphenylacetic acid or the corresponding acid chloride introduced by Mosher in the 1970s are very useful reagents for the derivatization of amines and alcohols [5]. 

There is no obvious advantage of purifying mixed anhydrides of /V-alkoxycar-bonylamino acids before reacting them with an /V-nuclcophilc to form a peptide bond. However, there are a few reports of success with the reaction of a purified mixed anhydride after the reaction with the anhydride in the presence of tertiary-amine salt had failed. It would seem that the prudent course of action is to try the reaction using both the crude and purified anhydrides in case one approach is better.18-19... 

The classes of compounds which are conveniently considered together as derivatives of carboxylic acids include the carboxylic acid anhydrides, acyl chlorides, esters, and amides. In the case of simple aliphatic and aromatic acids, synthetic transformations among these derivatives are usually a straightforward matter involving such fundamental reactions as ester saponification, formation of acyl chlorides, and the reactions of amines with acid anhydrides or acyl chlorides ... 

A series of solid-state reactions has been explored by Kaupp et al., in which gaseous amines were reacted with aldehydes to give imines. Analogous reactions with solid anhydrides, imides, lactones or carbonates, and isothiocyanates were used to give, respectively, diamides or amidic carboxylic salts or imides, diamides, carbamic acids, and thioureas [24]. In general the yields were found to be quantitative. Ammonia and other gaseous amines, in particular methyl-amine, have also been shown to aminolyse thermoplastic polycarbonates [25]. 

The enantioselective synthesis of the jS-amino acid ester shown in Figure 1.6 has recently been reported by Kubryk and Hansen (Merck) where good ees were obtained by asymmetric hydrogenation. Using an in-situ reaction with diBoc-anhydride to protect the amine group a crystalline product was obtained that was recrystallized to the required 99 % + ee purity very easily. 

Many such activated acyl derivatives have been developed, and the field has been reviewed [7-9]. The most commonly used irreversible acyl donors are various types of vinyl esters. During the acylation of the enzyme, vinyl alcohols are liberated, which rapidly tautomerize to non-nucleophilic carbonyl compounds (Scheme 4.5). The acyl-enzyme then reacts with the racemic nucleophile (e.g., an alcohol or amine). Many vinyl esters and isopropenyl acetate are commercially available, and others can be made from vinyl and isopropenyl acetate by Lewis acid- or palladium-catalyzed reactions with acids [10-12] or from transition metal-catalyzed additions to acetylenes [13-15]. If ethoxyacetylene is used in such reactions, R1 in the resulting acyl donor will be OEt (Scheme 4.5), and hence the end product from the acyl donor leaving group will be the innocuous ethyl acetate [16]. Other frequently used acylation agents that act as more or less irreversible acyl donors are the easily prepared 2,2,2-trifluoro- and 2,2,2-trichloro-ethyl esters [17-23]. Less frequently used are oxime esters and cyanomethyl ester [7]. S-ethyl thioesters such as the thiooctanoate has also been used, and here the ethanethiol formed is allowed to evaporate to displace the equilibrium [24, 25]. Some anhydrides can also serve as irreversible acyl donors. 

This type of duality of action is presumably present in other situations, such as the Fries rearrangement (78), the Friedel-Crafts reaction with acid chlorides (65) or acid anhydrides (21), and the catalytic chlorination of nitrobenzene (17). In these reactions it appears that the uncoordinated Lewis acid is the effective catalyst. The same situation is illustrated by recent work on aromatic amination (32, 33) and halogenation (57, 58, 71) and seems to be general feature of Lewis acid-catalyzed electrophilic reactions of aromatic compounds containing suitable donor groups. 

Exercise 23-24 Show how a mixture of amines prepared from 1-bromobutane and an excess of butanamine may be resolved into its components by reaction with the anhydride of 1,4-butanedioic acid, (CH2)2(CO)20, separation of the products through advantage of their solubility properties in acid or base, and regeneration of the corresponding amines (Section 18-10C). Write equations for the reactions involved. 

These may be prepared from a primary amine by reaction with phthalic anhydride. The general procedure described in Section 9.6.21, p. 1276 uses glacial acetic acid reaction conditions using chloroform as the solvent medium have been reported.235 Deprotection using hydrazine is described in Expt 5.198. 

Trifluoromethyl derivatives of thiochromone are also available from thiosalicylic acid by conversion to alkyl 2-mercaptophenyl ketones followed by a Baker-Venkataraman reaction with trifluoroacetic anhydride in triethyl-amine (Scheme 205) <2005PS(180)1315>. 

Amino acids exhibit chemical reactions that are typical of both amines and carboxylic acids. For example, the acid can be converted to an ester by the Fischer method. This reaction requires the use of an excess of acid because one equivalent is needed to react with the amino group of the product. As another example, the amine can be converted to an amide by reaction with acetic anhydride. Additional examples are provided by the reactions that are used in the preparation of peptides from amino acids described in Section 26.7 ... 

These compounds do not readily react with epoxy resins except in the presence of water, alcohol, or some other base, called an accelerator. Tertiary amines, metallic salts, and imidazoles often act as accelerators for anhydride cured epoxy systems. The reaction between acid anhydride and epoxy resins is illustrated in Fig. 5.7. 

Other experimental reproductive effects. A skin and severe eye irritant. A narcotic. Human mutation data reported. A common air contaminant. Highly flammable liquid. NCxmres of 30-60% of the vapor in air ignite above 100°. It can react violently with acid anhydrides, alcohols, ketones, phenols, NH3, HCN, H2S, halogens, P, isocyanates, strong alkalies, and amines. Reactions with cobalt chloride, mercury(II) chlorate, or mercury(II) perchlorate form violendy in the presence of traces of metals or acids. Reaction with oxygen may lead to detonation. When heated to decomposition it emits acrid smoke and fumes. 

Acetyl derivatives of primary and secondary amines are usually solids suitable for melting point characterization and are readily prepared by reaction with acetic anhydride, even in the presence of water. Benzoyl and benzenesulfonyl derivatives are made by reaction of the amine with the appropriate acid chloride in the presence of alkali, as in Section 2 (the benzenesulfonamides of aniline and of A-methylaniline melt at 110°C and 79°C, respectively). 

We ve already studied the two most general reactions of amines—alkylation and acylation. As we saw earlier in this chapter, primary, secondare and tertiary amines can be alkylated by reaction with a primary alkyl halide. Alkylations of primary and secondary amines are difficult to conind and often give mixtures of products, but tertiary amines are cleanly allqd-ated to give quaternary ammonium salts. Primary and secondary (bat not tertiary) amines can also be acylated by reaction with acid chlorides or add anhydrides to yield amides (Sections 21.4 and 21.5). 

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