Amides, from acid derivatives hydrolysis

Amides are the least reactive of the carboxylic acid derivatives they can be prepared from any of the other acid derivatives. Hydrolysis, either acid- or base-catalyzed, to form acids is the only nucleophilic acyl substitution reaction. 

Apart from valpromide derivatives, there are only few other drugs with a primary amide group that undergo metabolic hydrolysis. One example is that of metopimazine (4.23), a phenothiazine with antiemetic properties. Its carboxylic acid 4.24 was the major urinary metabolite in rabbits, but was not formed in dogs [8],... 

By analogy with the synthesis of a-hydroxy acids one can envisage a one-pot synthesis of a-hydroxy amides from aldehydes via hydrocyanation and in situ NHase-catalyzed hydrolysis to the amide. Since enantioselective NHases are very rare, the enantioselectivity should be derived from HnL-catalyzed hydrocyanation. The second step has been described for the Rhodococcus erythropolis NHase-catalyzed hydration of (R)-mandelonitrile to give the (R)-amide with retention of enantiopurity [43]. 

Amides are the least reactive of the carboxylic acid derivatives, and undergo acid or base hydrolysis to produce the parent carboxylic acids, and reduction to appropriate amines (see Section 4.3.10). They can also be dehydrated to nitriles, most commonly with boiling acetic anhydride, (AcO)20, sulphonyl chloride (SOCI2) or phosphoms oxychloride (POCI3) (see Section 4.3.18). Amines (with one less carbon) are prepared from amides by the treatment of halides (Br2 or CI2) in aqueous NaOH or KOH. This reaction is known as Hofmann rearrangement (see Section 4.3.10). 

In the case of amino acid ester and amide complexes, the intramolecular hydrolysis reaction was not observed directly, but was deduced from the results of lsO tracer studies. However, recently the cis-hydroxo and cis-aqua complexes derived from the bis(ethylenediamine)cobalt(III) system, containing glycinamide, glycylglycine and isopropylglycylglycinate, have been isolated and their subsequent cyclization studied over the pH range 0-14.160,161... 

The resistance of the furoxan ring to chemical attack allows derivatives to be prepared via the reactions of the substituents (Section 4.22.3.4). Carboxylic acids are available by permanganate oxidation of methyl derivatives or by hydrolysis of the corresponding esters reaction with ammonia affords carboxamides. Acylfuroxans provide a source of hydroxyalkyl compounds by reduction, and oximes, for example, via nucleophilic addition. Acylation and oxidation of aminofuroxans allows the amide and nitro derivatives to be prepared. Nucleophilic displacements of nitro substituents can take place, but can be somewhat hazardous on account of the explosive nature of these compounds. Alkoxy derivatives are formed with sodium alkoxide, while reaction with thiolate anions yields sulfides, from which sulfones can be synthesized by peracid oxidation. Nitrofuroxans have also been reduced to... 

All acid derivatives hydrolyze to give carboxylic acids. In most cases, hydrolysis occurs under either acidic or basic conditions. The reactivity of acid derivatives toward hydrolysis varies from highly reactive acyl halides to relatively unreactive amides. 

Synthesis of Amides Amides are the least reactive acid derivatives, and they can be made from any of the others. In the laboratory, amides are commonly synthesized by the reaction of an acid chloride (or anhydride) with an amine. The most common industrial synthesis involves heating an acid with an amine (at high temperatures, in the absence of oxygen) to drive off water and promote condensation. This simple industrial technique rarely works well in the laboratory, but it may succeed with the use of a coupling reagent (Section 24-11). Esters react with amines and ammonia to give amides, and the partial hydrolysis of nitriles also gives amides. 

Alternatively, biological methods of rvsulutioamide formed from an S amino acid, while leaving the relnted amide from an R amino acid untouched. We can therefore resolve ar. R.8 mixture of an amino acid by forming an AT-ace-tyl derivative, carrying out an enzyme-catalyzed hydrolysis, and separating the S amino acid from unreacted R amide. 

In living cells, proteins account for a major fraction of the cellular C and most of the N. We therefore expect that DON released from living organisms will contain proteins. In addition, the prominent amide resonance in the N-NMR spectrum of HMWDON could be derived from peptides and therefore, it is reasonable to hypothesize that proteins dominate the DON reservoir. Direct quantification of proteins in DOM has proven to be difficult (as seen later), so to test the above hypothesis many studies have focused on identifying and quantifying total hydro-lysable amino acids (THAA) in DOM. Amino acids are released from DOM following hydrolysis of peptides and proteins, and most marine DOM studies have used similar methods of hydrolysis and subsequent quantification (i.e., 6M HCl hydrolysis with variable temperature and hydrolysis times, followed by HPLC... 

The amide must be made from the amine and an acid derivative and any of the methods described in the chapter could be used though we must be sure that the amine will attack the carbonyl group and not do conjugate addition. The acid can be made by a Wittig reaction (Chapter 14) from the available aldehyde piperonal . If the amine does conjugate addition to the ester, change to the add chloride by hydrolysis to the acid and treatment with SOCI2 first. 

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