Imides, hydrolysis reactions amines

Another alternative for preparing a primary amine from an alkyl halide is the Gabriel amine synthesis, which uses a phthalimide alkylation. An imide (—CONHCO—) is similar to a /3-keto ester in that the acidic N-H hydrogen is flanked by two carbonyl groups. Thus, imides are deprotonated by such bases as KOH, and the resultant anions are readily alkylated in a reaction similar to the acetoacetic ester synthesis (Section 22.7). Basic hydrolysis of the N-alkylated imide then yields a primary amine product. The imide hydrolysis step is analogous to the hydrolysis of an amide (Section 21.7). 

Traut s reagent is fully water-soluble and reacts with primary amines in the pH range 7—10. The cyclic imidothioester is stable to hydrolysis at acid pH values, but its half-life in solution decreases as the pH increases beyond neutrality. However, even at pH 8 in 25 mM triethanolamine the rate of sulfhydryl formation without added primary amine was found to be negligible. On addition of dipeptide amine, the reagent reacted quickly as evidenced by the production of Ellman s reagent color. The rate of reaction also can be followed by 2-iminothiolane s absorbance at 248 nm (Xmax e = 8 840 M 1 cm 1). As the cyclic imidate reacts with amines, its absorbance at... 

Acidity of Amides, Imides, and Sulfonamides Characteristic Reactions Reaction with Water Hydrolysis Reaction with Alcohols Reactions with Ammonia and Amines Reaction of Acid Chiorides with Salts of Carboxylic Acids Interconversion of Functional Derivatives Reactions with Organometallic Compounds 18.10 Reduction... 

The sodium salt of succinimide reacts with a,o)-dibromide such as 4.93 to give 4.94. In a second step, the enolate of a-phenyl nitrile displaced the bromide moiety in 4.94 to give 4.95. Acid hydrolysis converted the nitrile to an acid and the imide to an amine, leading to 4.96. Reaction of 4.94 (n = 4) with the indicated nitrile (R = H) led to a 57% yield of 2-phenyl-6-aminohexanoic acid (4.96a). Similarly prepared were 2-phenyl-7-aminoheptanoic acid 4.96b) in 68% yield 2-phenyl-8-amino-octanoic acid 4.96c) in 68% yield 2-phenyl-10-aminodecanoic acid 4.96d) in 44% yield and, 2-phenyl-12-aminododecanoic acid 4.96e) in 26% yield, all with R = H.45 Many other nitriles were used in this sequence to give a wide variety of phenyl... 

Recall that A-alkylation of 1,2-benzenedicarboxylic imide (phthalimide) anion followed by acid hydrolysis furnishes amines (Section 21-5). To prepare an amino acid instead, we can use diethyl 2-bromopropanedioate (diethyl 2-bromomalonate) in the first step of the reaction sequence. This alkylating agent is readily available from the bromination of diethyl propanedioate (malonate). Now the alkylation product can be hydrolyzed and decarboxylated (Section 23-2). Hydrolysis of the imide group then furnishes an amino acid. 

The reaction is applicable to the preparation of amines from amides of aliphatic aromatic, aryl-aliphatic and heterocyclic acids. A further example is given in Section IV,170 in connexion with the preparation of anthranilic acid from phthal-imide. It may be mentioned that for aliphatic monoamides containing more than eight carbon atoms aqueous alkaline hypohalite gives poor yields of the amines. Good results are obtained by treatment of the amide (C > 8) in methanol with sodium methoxide and bromine, followed by hydrolysis of the resulting N-alkyl methyl carbamate ... 

Initially, water can cause the hydrolysis of the anhydride or the isocyanate, Scheme 28 (reaction 1 and 2), although the isocyanate hydrolysis has been reported to occur much more rapidly [99]. The hydrolyzed isocyanate (car-bamic acid) may then react further with another isocyanate to yield a urea derivative, see Scheme 28 (reaction 3). Either hydrolysis product, carbamic acid or diacid, can then react with isocyanate to form a mixed carbamic carboxylic anhydride, see Scheme 28 (reactions 4 and 5, respectively). The mixed anhydride is believed to represent the major reaction intermediate in addition to the seven-mem bered cyclic intermediate, which upon heating lose C02 to form the desired imide. The formation of the urea derivative, Scheme 28 (reaction 3), does not constitute a molecular weight limiting side-reaction, since it too has been reported to react with anhydride to form imide [100], These reactions, as a whole, would explain the reported reactivity of isocyanates with diesters of tetracarboxylic acids and with mixtures of anhydride as well as tetracarboxylic acid and tetracarboxylic acid diesters [101, 102]. In these cases, tertiary amines are also utilized to catalyze the reaction. Based on these reports, the overall reaction schematic of diisocyanates with tetracarboxylic acid derivatives can thus be illustrated in an idealized fashion as shown in Scheme 29. 

Other model compound hydrolysis experiments confirmed this generic behavior. The dependence of hydrolysis on chemical structure of the model compounds was observed between the 4-FA imide compounds of SDA and ODPA. Under the same hydrolysis conditions, the highly electron-withdrawing sulfone group induced much more reaction of both the imide and the amic acid species than the ODPA analogue, as shown in Figure 17.14. Also, amines that... 

Acrylamide polymers in aqueous solution undergo thermal hydrolysis and cyclic imide formation. Acrylate, acrylamide and cyclic imide functional groups were detected when a poly(acrylamide) is heated at 150°C in water. The formation of intramolecular imide has been reported in literature. Moradi-Araghi, Hsieh and Westerman reported the formation of cyclic imide in acid, neutral and slightly basic media at 90° C.7 In acidic media, imide formation is favored. In neutral and basic media, both hydrolysis to acrylate and imide formation do occur, but hydrolysis is the dominant reaction. We speculate the high conversion of amine to amide is the result of transamidation, amidation and the nucleophilic addition of the amine to the glutarimide intermediate (Reaction 1). 

Hydrolysis of peptides,84 amides,85 phosphate esters,86 sulfonate esters87 and acetals88 can also be metal catalyzed. The hydrolysis of a phosphate ester coordinated to cobalt(III) also occurs at an increased rate (Scheme 19).89 A rather similar reaction occurs in the amine exchange of coordinated dithiocarbamates (equation 21).90 The conversion of imidates to amidines has been mentioned previously and is a similar type of reaction (see Section 7.4.2.2.1). 

The hydrolysis of imidate salts is a technique to generate in situ hemi-orthoamide tetrahedral intermediates (44), and to observe their breakdown to yield the reaction products under kinetically controlled conditions. Such conditions can be ascertained by verifying that the reaction products are not ihterconverted (amide + alcohol ester +amine) during the reaction. This technique can therefore be used to test the principle of stereoelec-tronic control in the cleavage of tetrahedral intermediates derived from amides. 

As electron-rich olefins are more reactive, vinyl-sulfones are the most reactive species and are capable of reacting with thiols, amines, and even with small nucleophilic alcohol groups. Less reactive are acrylamides and acrylates, which are reactive towards amines and thiols. Maleimides are the least reactive of the mentioned species and allow selective addition of thiols in the presence of amines in the pH range 6.5-7.5. However, hydrolysis of the imide, especially at elevated pH values [35], may be a concern for certain applications. The mentioned Michael addition reactions do not require organic solvents and can be carried out at physiological temperature and pH [36], In acidic conditions, the reaction is either very slow or does not proceed because protonation removes the nucleophilic form in the case of amines, and the thiolate anion is usually the active species in Michael additions involving thiols [25],... 

An acid—base reaction forms a nucleophilic anion that can react with an unhindered alkyl halide— that is, CH3X or RCH2X—in an 5 2 reaction to form a substitution product. This alkylated imide is then hydrolyzed with aqueous base to give a 1° amine and a dicarboxylate. This reaction is similar to the hydrolysis of amides to afford carboxylate anions and amines, as discussed in Section 22.13. The overall result of this two-step sequence is nucleophilic substitution of X by NH2, so the Gabriel synthesis can be used to prepare 1° amines only. 

---