Important amides

Amide-Based Sulfonic Acids. The most important amide-based sulfonic acids are the alkenylarnidoalkanesulfoiiic acids. These materials have been extensively described ia the Hterature. A variety of examples are given ia Table 5. Acrylarnidoalkanesulfoiiic acids are typically prepared usiag technology originally disclosed by Lubrizol Corporation ia 1970 (80). The chemistry iavolves an initial reaction of an olefin, which contains at least one aHyhc proton, with an acyl hydrogen sulfate source, to produce a sulfonated intermediate. This intermediate subsequendy reacts with water, acrylonitrile, and sulfuric acid. 

Although, the enzymatic reaction of esters with amines or ammonia have been well documented, the corresponding aminolysis with carboxylic acids are rarer, because of the tendency of the reactants to form unreactive salts. For this reason some different strategies have been used to avoid this problem. Normally, this reaction has been used for the preparation of amides of industrial interest, for instance, one of the most important amides used in the polymer industry like oleamide has been produced by enzymatic amidation of oleic acid with ammonia and CALB in different organic solvents [10]. 

A brief summary of important amide reactions follows reduction... 

Dimethylformamide has become the most important amide for use as solvent. Its most important impurities are dimethylamine, formaldehyde, and water. 

One important amide is caramide (NH2CONH2), or urea, as it is commonly known. Urea is an end product in the metabolic breakdown of proteins in mammals. It is found in the blood, bile, milk, and perspiration of mammals. When proteins are broken down, amino groups (NH2) are removed from the amino acids. The amino groups are then converted to ammonia (NH3) that are toxic to the body. The toxic ammonia is converted to nontoxic urea in the liver. The urea is filtered out of the blood in the kidneys and passed from the body in urine. 

Amides are the least reactive of the common carboxylic acid derivatives. They occur widely in nature. The most important amides are the proteins, whose chemistry we will discuss in Chapter 17. Here we will concentrate on just a few properties of simple amides. 

Asparagine and glutamine are important amide derivatives of the amino acids aspartic acid and glutamic acid. These two amides are also classed as amino acids (Table 4.1) and occur as components of proteins. They also occur as free amides and play an important role in transamination reactions. 

Figure 13.1 Some important amide-containing drugs.

Typical ions produced are MH and M+H3O. Deuterated water appears to offer some advantages in the determination of the number of active hydrogens in a compound (43, 44). Importantly, amide hydrogens can be exchanged, whereas hydrogens a to carbonyl groups are exchanged only in amounts less than 15% (44). 

Alkaloids such as caffeine, nicotine, cocaine, and digitalis, which have powerful physiological activity, are naturally occurring amines obtained from plants. In an amide, the functional group consists of a carbonyl group attached to an amine. Amides, which are derived from carboxylic acids, are important in biology in proteins. In biochemistry, the amide bond that links amino acids in a protein is called a peptide bond. Some medically important amides include acetaminophen (Tylenol) used to reduce fever phenobarbital, a sedative and anticonvulsant medication and penicillin, an antibiotic. 

CO. Alkynes will react with carbon monoxide in the presence of a metal carbonyl (e.g. Ni(CO)4) and water to give prop>enoic acids (R-CH = CH-C02H), with alcohols (R OH) to give propenoic esters, RCH CHC02R and with amines (R NH2) to give propenoic amides RCHrCHCONHR. Using alternative catalysts, e.g. Fe(CO)5, alkynes and carbon monoxide will produce cyclopentadienones or hydroquinols. A commercially important variation of this reaction is hydroformyiation (the 0x0 reaction ). 

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... 

Acid derivatives are made directly from acids or by conversion from other acid derivatives depending on their stabihty. The most important are esters (RCOiEt), amides (RCO2NR2), anhydrides (RCOO COR) and add clilorides (RCOCI). Arrange these in an order of stabilily, the most reactive at the top of the list, the most stable at the bottom. 

Regioselectivity becomes important, if unsymmetric difunctional nitrogen components are used. In such cases two different reactions of the nitrogen nucleophile with the open-chain educt may be possible, one of which must be faster than the other. Hydrazone formation, for example, occurs more readily than hydrazinoLysis of an ester. In the second example, on the other hand, the amide is formed very rapidly from the acyl chloride, and only one cyclization product is observed. 

The phenolic hydroxyl group of tyrosine, the imidazole moiety of histidine, and the amide groups of asparagine and glutamine are often not protected in peptide synthesis, since it is usually unnecessary. The protection of the hydroxyl group in serine and threonine (O-acetylation or O-benzylation) is not needed in the azide condensation procedure but may become important when other activation methods are used. 

Macrocyclic peptides and depsipeptides ( macrocyciic peptides with amide and ester linkages) are important natural compounds. They have been synthesized in low yield from open-chain precursors by DCC treatment at high dilution (E. SchrSder, 1963 M.M. Shemyakin,... 

Aminopalladation and subsequent carbonylation are also facile reactions. The carbonylation of substituted 3-hydroxy-4-pentenylamine as a carbamate (254) proceeds smoothly via the aminopalladation product 255 in AcOH to give 256[228). The protection of the amino group of the carbamate as tosyl amide is important in the carbonylation of 257 to give 258[229],... 

One of the virtues of the Fischer indole synthesis is that it can frequently be used to prepare indoles having functionalized substituents. This versatility extends beyond the range of very stable substituents such as alkoxy and halogens and includes esters, amides and hydroxy substituents. Table 7.3 gives some examples. These include cases of introduction of 3-acetic acid, 3-acetamide, 3-(2-aminoethyl)- and 3-(2-hydroxyethyl)- side-chains, all of which are of special importance in the preparation of biologically active indole derivatives. Entry 11 is an efficient synthesis of the non-steroidal anti-inflammatory drug indomethacin. A noteworthy feature of the reaction is the... 

Thiazolium salts with alkyl (103, 722), arylalkyl (116), aryl (305), or heteroaryl (96) substituents on the nitrogen have been also prepared by this procedure. As in the thiazole series, N-substituted thioamides can be formed directly in the reaction mixture from phosphorus pentasulfide and N-substituted amides (127). These methods are important in the synthesis of thiamine 102 (vitamin Bj) (Scheme 45). 

The chemistry of the carbonyl group is probably the single most important aspect of organic chemical reactivity Classes of compounds that contain the carbonyl group include many derived from carboxylic acids (acyl chlorides acid anhydrides esters and amides) as well as the two related classes discussed m this chapter aldehydes and ketones... 

This difference m reactivity especially toward hydrolysis has an important result We 11 see m Chapter 27 that the structure and function of proteins are critical to life Itself The bonds mainly responsible for the structure of proteins are amide bonds which are about 100 times more stable to hydrolysis than ester bonds These amide bonds are stable enough to maintain the structural integrity of proteins m an aqueous environment but susceptible enough to hydrolysis to be broken when the occasion demands... 

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... 

In this section we turn to a consideration of the experimental side of condensation kinetics. The kind of ab links which have been most extensively studied are ester and amide groups, although numerous additional systems could also be cited. In many of these the carbonyl group is present and is believed to play an important role in stabilizing the actual chemical transition state involved in the reactions. The situation can be represented by the following schematic reaction ... 

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