The Amides

Examples Lignocaine Hydrochloride Prilocaine Hydrochloride Mepivacaine Hydrochloride Bupivacaine Hydrochloride Pyrrocaine Hydrochloride Diperodon. 

Lignocaine Hydrochloride BAN, Lidocaine INN, Lidocaine Hydrochloride USAN. 

2-(Diethylamino)-2, 6 -acetoxylidide monohydrochloride monohydrate Aeetamide, 2-(diethylamino)-N-(2,6-dimethyl-phenyl-, monohydroehloride, monohydrate  

Lidoeaine Hydrochloride U.S.P., Eur. R, Lignocaine Hydroehloride B.R, Int. R, Ind. R. Xyloeaine (Astra) Dolicaine (Reid-Provident)  

Chloroacetoxylidide is prepared by the interaetion of 2, 6-xylidine with chloroacetyl chloride which on treatment with diethylamine yields the lignoeaine base. This when treated with an equimolar quantity of hydrochloric acid gives the respeetive lignocaine hydrochloride. 

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C2H4N2O3, NH2CONHCOOH. Unknown in the free state as it breaks down immediately to urea and COi- The NH4, Ba, Ca, K and Na salts are known and are prepared by treating ethyl allophanate with the appropriate hydroxide. The esters with alcohols and phenols are crystalline solids, sparingly soluble in water and alcohol. They are formed by passing cyanic acid into alcohols or a solution of an alcohol or phenol in benzene. The amide of allophanic acid is biuret. Alcohols are sometimes isolated and identified by means of their allophanates. 

The alkali amides are stable, crystalline salts the heavy metal amides are often explosive. The amides are the bases of the ammonia system. 

Additives acting on the pour point also modify the crystal size and, in addition, decrease the cohesive forces between crystals, allowing flow at lower temperatures. These additives are also copolymers containing vinyl esters, alkyl acrylates, or alkyl fumarates. In addition, formulations containing surfactants, such as the amides or fatty acid salts and long-chain dialkyl-amines, have an effect both on the cold filter plugging point and the pour point. 

In some extremely iimovative recent experiments, Hochstrasser and co-workers [ ] have described IR transient hole-burning experiments focused on characterizing inliomogeneous broadening in the amide 1... 

Hamm P, Urn M and Hochstrasser R M 1998 Structure of the amide I band of peptides measured by femtosecond nonlinear-infrared spectroscopy J. Phys. Chem. B 102 6123-38... 

Reactions with electropositive metals. Ammonia gas reacts with strongly electropositive metals to form the amide, for example... 

With RAMSES, the conjugation between the C=0 rr-system and the lone pair of the nitrogen atom in the amide group is taken into account (see Figure 2-51b). 

Hagler A T and S Lifson 1974. Energy Functions for Peptides and Proteins. II. The Amide Hydrogen Bond and Calculation of Amide Crystal Properties. Journal of the American Chemical Society 96 5327-5335. 

Fig. 12.20 4-Acetamido benzoic acid. Triangle smoothing predicts that the lower bound distance between the amide nitrogen and the carbonyl oxygen is equal to the sum of the van der Waals radii. The actual distance is about 6.4A.

Method (1) is most frequently used for aliphatic acid amides, while Methods (2a), (2b) and (zc) are used most frequently for aromatic acid amides. Of the last three methods, the Acid Chloride Method (zb) is the most rapid and certain. The Ester Method (za) is practicable only when the amide is insoluble in water, and even then is often very slow unless the ester itself is appreciabb soluble in the aqueous ammonia solution. 

Acid amides have weakly amphoteric properties, and thus give salts such as CjHsCONHj.HCl with strong acids, and salts of the type C HsCONHNa with strong bases. These compounds have to be prepared at low temperatures to avoid hydrolysis, and are difficult to isolate. The mercury derivatives can, however, usually be readily prepared, because mercuric oxide is too feebly basic to cause hydrolysis of the amide, and the heavy mercuric derivatives crystallise well. 

Ethyl oxalate is the only liquid ester which gives this rapid separation of the amide, which is therefore characteristic. Methyl and ethyl formate react rapidly with ammonia, but the soluble formamide does not separate methyl succinate gives crystalline succinamide after about I hour s standing, other esters only after a much longer time. The solid esters, other than methyl oxalate, are either soluble in water and remain so when treated with ammonia, or alternatively are insoluble in water and hence clearly not methyl oxalate. 

The evolution of nitrogen is not always entirely satisfactory as a test owing to the possible evolution of gaseous decomposition products of nitrous acid itself. The test may be performed as follows. To i ml. of chilled concentrated sodium nitrite solution add i ml. of dilute acetic acid. Allow any preliminary evolution of gas to subside, and then add the mixed solution to a cold aqueous solution (or suspension) of the amide note the brisk effervescence. 

If the amide is an N-(mono- or di)-substituted amide, or the imide an N-substituted imide, the above alkaline hydrolysis will give a solution... 

The by-products are both gaseous and the excess of thiouyl chloride (b.p. 78°) may be readily removed by distillation. Interaction of the acid chloride with ammonia solution, aniline or p-toluidiiie yields the amide, anilide or p-toluidide respectively ... 

Alternatively, dissolve or suspend the acid chloride in 5-10 ml. of dry ether or dry benzene, and pass in dry ammonia gas. If no solid separates, evaporate the solvent. Recrystallise the amide from water or dilute alcohol. 

The reaction commences at about 120° the carbamic acid formed decomposes immediately into carbon dioxide and ammonia. The latter may form the ammonium salt with unreacted acid the ammonium salt also reacts with urea at temperatures above 120° to yield the amide ... 

By the action of concentrate aqueous ammonia solution upon esters. This process is spoken of as ammonolysls of the ester, by analogy with hydrolysis applied to a similar reaction with water. If the amide is soluble in water, e.g., acetamide, it may be isolated by distillation, for example ... 

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°. 

Xanthylamides. Dissolve 0 25 g. of xanthhydrol in 3-5 ml. of glacial acetic acid if an oil separates (as is sometimes the case with commercial material), allow to settle for a short time and decant the supernatant solution. Add 0-25 g. of the amide, shake and allow to stand. If a crystalline derivative does not separate in about 10 minutes, warm on a water bath for a period not exceeding 30 minutes, and allow to cool. Filter oflF the solid xanthylamide (9-acylamidoxanthen) and recrystallise it from dioxan - water or from acetic acid - water, dry at 80° for 15 minutes and determine the m.p. 

For those nitriles which yield water-insoluble amides e.g., the higher alkyl cyanides), hydrolysis to the amide often leads to a satisfactory derivative. The hydration is eflfected by warming a solution of the nitrile in concentrated sulphuric acid for a few minutes, cooling and pouring... 

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 ... 

Nitriles may often be hydrolysed (hydrated) to the amides (RCN— RCONHj) by concentrated sulphuric acid or by concentrated hydrochloric acid, usually in the cold or at 40° (see Sections III,115 and IV,160). The resulting amide is, of course, a useful derivative. 

Nicotinamide. Place 50 g. of pure ethyl nicotinate (Section V,23) in a 350 ml. bolt-head flask and add 75 ml. of concentrated aqueous ammonia saturated at 0°. Keep the flask loosely stoppered for 18 hours, after w)iich time the lower layer generally dissolves on shaking. Saturate the solution with ammonia and allow it to stand for a further 4 hours. Repeat the saturation with ammonia crystals of the amide commence to appear in the solution. Evaporate to drjmess in a dish on the steam bath and dry at 120°. The yield of nicotinamide, m.p. 130°, is usuallj quantitative. 

A solution of sodamide in liquid ammonia (essentially the amide NHj ion) is a very powerful alkylation catalyst, enabling condensations to be carried out with ease and in good yield which are otherwise either impossible or proceed with difficulty and are accompanied by considerable by-products. Thus 3-alkylpjTidines, otherwise inaccessible, are easily prepared from 3-picoline (see 3-n-amylpyridine in Section V,20). Also benzyl cyanide (I) and cyclohexyX bromide give a- r/ohexylphenylacetonitrile (II) ... 

When an alkyl aryl ketone is heated with yellow ammonium polysulphide solution at an elevated temperature, an aryl substituted aliphatic acid amide is foimed the product actually isolated is the amide of the ci-aryl carboxylic acid together with a smaller amount of the corresponding ammonium salt of the oarboxylio acid. Thus acetophenone affords phenylacetamide (50 per cent.) and ammonium phenylacetate (13 per cent.) ... 

The lower members of other homologous series of oxygen compounds— the acids, aldehydes, ketones, anhydrides, ethers and esters—have approximately the same limits of solubility as the alcohols and substitution and branching of the carbon chain has a similar influence. For the amines (primary, secondary and tertiary), the limit of solubility is about C whilst for the amides and nitriles it is about C4. 

Nitriles and simple amides differ in physical properties the former are liquids or low-melting Solids, whilst the latter are generally solids. If the amide is a solid and insoluble in water, it may be readily prepared from the nitrile by dissolving in concentrated sulphuric acid and pouring the solution into water ... 

Hydrolysis of a nitrile to an amide. Warm a solution of 1 g. of the nitrile benzyl cyanide) in 4 ml. of concentrated sulphuric acid to 80-90°, and allow the solution to stand for 5 minutes. Cool and pour the solution cautiously into 40 ml. of cold water. Filter oflT the precipitate stir it with 20 ml. of cold 5 per cent, sodium hydroxide solution and filter again. RecrystaUise the amide from dilute alcohol, and determine its m.p. Examine the solubility behaviour and also the action of warm sodium hydroxide solution upon the amide. 

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