Amidation mechanism

Once again, the nitrile is first converted to an amide (Mechanism 21.15), which is then converted to a carboxylic acid (see Mechanism 21.12). 

Place 125 ml. of concentrated ammonia solution (sp. gr. 0-88) in a 600 ml. beaker and surround the latter with crushed ice. Stir the ammonia solution mechanically, and introduce the n-caproyl chloride slowly by means of a suitably supported separatory funnel with bent stem. The rate of addition must be adjusted so that no white fumes are lost. The amide separates immediately. Allow to stand in the ice water for 15 minutes after all the acid chloride has been introduced. Filter oflF the amide at the pump use the flltrate to assist the transfer of any amide remaining in the beaker to the Alter (2). Spread the amide on sheets of Alter or drying paper to dry in the air. The crude n-capro-amide (30 g.) has m.p. 98-99° and is sufficiently pure for conversion into the nitrile (Section 111,112) (3). Recrystallise a small quantity of the amide by dissolving it in the minimum volume of hot water and allowing the solution to cool dry on filter paper in the air. Pure n-caproamide has m.p. 100°. 

The mechanism of the reaction probably involves the production of bivalent carbon during the initial loss of nitrogen the group R shifte from an adjacent position to this carbon leading to the production of a keten the latter then reacts with the solvent to give an acid, an amide or an ester. 

Perhaps the most extensively studied catalytic reaction in acpreous solutions is the metal-ion catalysed hydrolysis of carboxylate esters, phosphate esters , phosphate diesters, amides and nittiles". Inspired by hydrolytic metalloenzymes, a multitude of different metal-ion complexes have been prepared and analysed with respect to their hydrolytic activity. Unfortunately, the exact mechanism by which these complexes operate is not completely clarified. The most important role of the catalyst is coordination of a hydroxide ion that is acting as a nucleophile. The extent of activation of tire substrate througji coordination to the Lewis-acidic metal centre is still unclear and probably varies from one substrate to another. For monodentate substrates this interaction is not very efficient. Only a few quantitative studies have been published. Chan et al. reported an equilibrium constant for coordination of the amide carbonyl group of... 

Apparatus 3-1 round-bottomed, three-necked flask, provided with a mechanical stirrer- During the addition of the sodium amide suspension the other necks were open. 

The o-keto ester 513 is formed from a bulky secondary alcohol using tricy-clohexylphosphine or triarylphosphine, but the selectivity is low[367-369]. Alkenyl bromides are less reactive than aryl halides for double carbonyla-tion[367], a-Keto amides are obtained from aryl and alkenyl bromides, but a-keto esters are not obtained by their carbonylation in alcohol[370]. A mechanism for the double carbonylation was proposed[371,372],... 

Oxidative dimerization of various 2-benzyloxy-2-thiazoline-5-ones (222) catalyzed by iodine and triethylamine is another example of the nucleophilic reactivity of the C-4 atom (469) (Scheme 112). Treatment of 212 with pyrrolidinocyclohexene yields the amide (223) (Scheme 113). The mechanism given for the formation of 223 is proposed by analogy with the reactivitx of oxazolones with enamines (4701. 4-Substituted 2-phenylthiazol-5(4Hi-ones react with A -morphoiino-l-cyclohexene in a similar manner (562j. Recently. Barret and Walker have studied the Michael addition products... 

FIGURE 20 6 Mechanism of amide formation in the reac tion of a secondary amine with an ethyl ester... 

Mechanistically amide hydrolysis is similar to the hydrolysis of other carboxylic acid derivatives The mechanism of the hydrolysis m acid is presented m Figure 20 7 It proceeds m two stages a tetrahedral intermediate is formed m the first stage and disso ciates m the second... 

A solution to the question of the mechanism of these reactions was provided by John D Roberts m 1953 on the basis of an imaginative experiment Roberts prepared a sample of chlorobenzene m which one of the carbons the one bearing the chlorine was the radioactive mass 14 isotope of carbon Reaction with potassium amide m liquid... 

Nucleophilic aromatic substitution can also occur by an elimination-addition mechanism This pathway is followed when the nucleophile is an exceptionally strong base such as amide ion m the form of sodium amide (NaNH2) or potassium amide (KNH2) Benzyne and related arynes are intermediates m nucleophilic aromatic substitutions that pro ceed by the elimination-addition mechanism... 

In each of the following reactions an amine or a lithium amide derivative reacts with an aryl halide Give the structure of the expected product and specify the mechanism by which it is formed... 

The mechanism by which DCCI promotes the condensation of an amine and a carboxylic acid to give an amide is outlined m Figure 27 13... 

FIGURE 27 13 The mechanism of amide bond formation by W W dicyclohexylcarbodiimide promoted condensation of a carboxylic acid and an amine... 

Hydrazine cleaves amide bonds to form acylhydrazides according to the general mechanism of nucleophilic acyl substitution discussed in Chapter 20... 

In addition to illustrating the mechanics of translation Figure 28 12 is important m that It shows the mechanism of peptide bond formation as a straightforward nude ophilic acyl substitution Both methionine and alanine are attached to their respective tRNAs as esters The ammo group of alanine attacks the methionine carbonyl displac mg methionine from its tRNA and converting the carbonyl group of methionine from an ester to an amide function... 

Some amorphous copoly(ether—sulfone) fkms have been prepared (117) with Ts around 130°C with no loss in weight up to 400°C in ak or N2. Other backbones iavestigated in this class of polymers are copoly(ether—amides) (118) and copoly(ether—ketones) (119). These polymers show good mechanical properties, flow characteristics, and abrasion resistance. 

Grafting can also occur in the amide nitrogen, either through an anionic-type mechanism which is beheved to operate when ethylene oxide [75-21 -8] and similar copolymers are grafted to polyamides, or through a polycondensation mechanism when secondary amides are formed as graft copolymers (70). 

The mechanism for photodegradation at short wavelengths is generaUy beUeved to be initiated by the photolytic cleavage of the amide bond (eq. 17), which has the lowest bond strength in aUphatic polyamides (220 kj/mol (53 kcal/mol))... 

Hydrolysis of esters and amides by enzymes that form acyl enzyme intermediates is similar in mechanism but different in rate-limiting steps. Whereas formation of the acyl enzyme intermediate is a rate-limiting step for amide hydrolysis, it is the deacylation step that determines the rate of ester hydrolysis. This difference allows elimination of the undesirable amidase activity that is responsible for secondary hydrolysis without affecting the rate of synthesis. Addition of an appropriate cosolvent such as acetonitrile, DMF, or dioxane can selectively eliminate undesirable amidase activity (128). 

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