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Urea

UREA, or CARBAMIDE, CO(NH 2 ) 2 , the amide of carbonic acid, discovered in 1773 by H. M. v. Rouelle, is found in the urine of mammalia, birds and some reptiles; human urine contains approximately 2-3%, a grown man producing about 30 grammes daily. It is also a constituent of the blood, of milk, and other animal fluids. Its synthesis in 1828 by F. Wohler (Fogg. Ann., 1828, 12, p. 253) is of theoretical importance, since it was the first organic compound obtained from inorganic materials. Wohler oxidized potassium ferrocyanide to potassium cyanate by fusing it with lead or manganese dioxide, converted this cyanate into ammonium cyanate by adding ammonium sulphate, and this on evaporation gives urea, thus:

K 4 Fe(NC) r -*KCNO-NH 4 CNO->CO(NHi)i- It may also be prepared by the action of ammonia on carbonyl chloride, diethyl carbonate, chlorcarbonic ester or urethane; by heating ammonium carbamate in a sealed tube to 130-140 C; by oxidizing potassium cyanide in acid solution with potassium permanganate (E. Baudrimant, Jahresb., 1880, P- 393); by the action of 50 % sulphuric acid on cyanamide: CN-NH 2 +H 2 0=CO(NH 2 ) 2 ; by the action of mercuric oxide on oxamide (A. Williamson): (CONH 2 ) 2 +HgO=CO(NH 2 ) 2 + Hg+CGy, by decomposing potassium cyanide with a dilute solution of sodium hypochlorite, followed by adding ammonium sulphate (A. Reychler, Bull. Soc. Chim., 1893 [3], 9, p. 427); and by oxidation of uric acid. It may be obtained from urine by evaporating to dryness on the water bath, taking up the residue in absolute alcohol and evaporating the alcoholic solution to dryness again. The residue is then dissolved in water, decolorized by animal charcoal and saturated at 50 C. with oxah'c acid. The urea oxalate is recrystallized and decolorized and finally decomposed by calcium carbonate (J. J. Berzelius, Pogg. Ann., 1830, 18, p. 84). As an alternative method, A. N. E. Millon (Ann. Mm. phys [2], 8, p. 235) concentrates the urine and precipitates the urea by nitric acid. The precipitate is dissolved in boiling water, decolorized by potassium permanganate and decomposed by barium carbonate. The solution is then evaporated to dryness and extracted by alcohol. Urea crystallizes in long needles or prisms which melt at 132 C. and sublime when heated in vacua. It is readily soluble in water and in alcohol, but is insoluble in chloroform and ether. When heated above its melting-point, it yields ammonia, cyanuric acid, biuret and ammelide. On. warming with sodium, it yields cyanamide. Dry chlorine gas passed into melted urea decomposes it with formation of cyanuric acid and ammonium chloride, nitrogen and ammonia being simultaneously liberated. Alkaline hypobromites or hypochlorites or nitrous acid decompose urea into carbon dioxide and nitrogen. It is also decomposed by warm aqueous solutions of caustic alkalis, with evolution of ammonia and carbon dioxide. When heated with alcohol in sealed tubes, it yields carbamic esters; with alcohol and carbon bisulphide at 100 C., carbon dioxide is liberated and ammonium sulphocyanide is formed. Acid potassium permanganate oxidizes it to carbon dioxide and nitrogen. It acts as a monacid base.

Urea may be recognized by its crystalline oxalate and nitrate, which are produced on adding oxalic and nitric acids to concentrated solutions of the base; by the white precipitate formed on adding mercuric nitrate to the neutral aqueous solutions of urea; and by the so-called " biuret " reaction. In this reaction urea is heated in a dry tube until it gives off ammonia freely; the residue is dissolved in water, made alkaline with caustic soda, and a drop of copper sulphate solution is added, when a fine violet-red coloration is produced. Several methods are employed for the quantitative estimation of urea. R. Bunsen (Ann., 1848, 65, p. 875) heated urea with an ammoniacal solution of barium chloride to 220 C., and converted the barium carbonate formed into barium sulphate, which is then weighed (see also E. Pfltiger and K. Bphland, Zeit. f. anal. Ghent., 1886, 25, p. 599; K. A. H. Morner, ibid., 1891, 30, p. 389). Among the volumetric methods used, the one most commonly employed is that of W. Knop (ibid., 1870, 9, p. 226), in which the urea is decomposed by an alkaline hypobromite and the evolved nitrogen is measured (see A. H. Allen, Commercial Organic Analysis'). J. v. Liebig (Ann., 1853, 85, p. 289) precipitates dilute solutions of urea with a dilute standard solution of mercuric nitrate, using alkaline carbonate as indicator. In this process phosphates must be absent, and the nitric acid liberated during the reaction should be neutralized as soon as possible. Chlorides also prevent the formation of the precipitate until enough of the mercury solution has been added to convert them into mercuric chloride (see also E. Pfluger, Zeit. f. anal. Chem., 1880, 19, p. 378). E. Riegler (ibid., 1894, 33, p. 49) decomposes urea solutions by means of mercury dissolved in nitric acid, and measures the evolved gas.

Urea chlorides are formed by the action of carbonyl chloride - on ammonium chloride (at 400 C.), or on salts of primary amines. They are readily hydrolysed by water, and combine with bases to form a'.kyl ureas, and with alcohols to form carbamic esters. Substituted urea chlorides are formed by the direct action of chlorine (F. D. Chattaway and D. F. S. Wunsch, Jour. Chem. Soc., 1909, 95, p. 129). Urea chloride, NH 2 -COC1 (L. Gattermann, Ann., 1888, 244, p. 30), melts at 50 C. and boils at 61-62 C. In the presence of anhydrous aluminium chloride it reacts with aromatic hydrocarbons to form the amides of aromatic acids. Nitrourea, H 2 N-CO-NH-NO 2 , prepared by adding urea nitrate to wellcooled concentrated sulphuric acid (J. Thiele and A. Lachmann, Ann., 1895, 288, p. 281), is a crystalline powder, soluble in water, and which decomposes on heating. It is a strong acid and is stable towards oxidizing agents. Diazomethane converts it into the methyl derivatives of isocyanic acid, and nitramide, NH 2 NO 2 . Amidourea, or semicarbazide, NH 2 'CONH-NH 2 , is best prepared from hydrazine sulphate and potassium cyanate (J. Thiele and O. Stange, Ber., 1894, 27, p. 31). It may also be obtained by reducing nitrourea in acid solution with zinc dust. It crystallizes in prisms, which melt at 96 C., and are easily soluble in water. It reduces Fehling's solution in the cold. It reacts with carbonyl compounds, giving semi-carbazones, and in consequence is frequently used for characterizing such substances. Hydroxy-urea, NH 2 -CO-NH-OH, is produced from hydroxylamine and cyanic acid (W. F. Dresler and R. Stein, Ann., 1869, 150, p. 242), or from ammonium hypochlorite and potassium cyanate (A. Hantzsch, Ann., 1898, 299, p. 99). It crystallizes in needles, which melt at 128-130 C., and is decomposed on long heating. It is readily soluble in water and reduces warm silver solutions. Hyponitrous acid is formed by passing nitrous fumes into its methyl alcohol solution.

Alkyl ureas are formed by the action of primary or secondary amines on isocyanic acid or its esters: CONH+NH 2 R = R-NHCONH 2 ; CONR+NHR 2 = NR 2 -CO-NHR; by the action of carbonyl chloride on amines: COC1 2 +2NHR 2 = CO(NR 2 ) 2 +2HC1; and in the hydrolysis of many ureides. The tetra-alkyl derivatives are liquids, the remainder being solids. Hydrolysis by alkalis decomposes them into carbon dioxide, amines and ammonia. The symmetrically substituted ureas are generally tasteless, while the asymmetrical derivatives are sweet. For example, oa-dimethyl urea is sweet, o/3-dimethyl urea is tasteless; p-phenetol carbamide ordulcin, NH 2 -CO-NH-C 6 H 4 -OC 2 H 6 , is sweet, while the di-p-phenetol carbamide, COCNH-CeHi-OCjHs)^, is tasteless.

The derivatives of urea containing acid radicles are known as ureides. Those derived from monobasic acids, obtained by the action of acid chlorides or anhydrides on urea, decompose on heating and do not form salts. Those containing more than one acyl group are formed by the action of carbonyl chloride on acid amides :

COC1 2 +2CH 3 CONH 2 = CO(NHCOCH 3 ) 2 +2HC1.

Acetyl urea, NH 2 -CONH-COCH 8 , formed by the action of acetic anhydride on urea, crystallizes in needles which melt at 212 C. and, on heating, strongly decomposes into acetamide and cyanuric acid. Methyl acetyl urea, CH 3 NH-CO-NHCOCH 3 , is formed by the action of potash on a mixture of bromine (l mol.) and acetamide (2 mols.) (A. W. v. Hofmann, Ber., 1881, 14, p. 2725), or of methylamine on acetylurethane (G. Young, Jour. Chem. Soc., 1898, 73, p. 364). When heated with water it is decomposed into carbon dioxide, ammonia, methylamine and acetic acid. Bromural or a- bromisovaleryl urea, NH 2 -CO-NH-CO-CHBr-CH(CH 3 ) 2 , has been introduced as an hypnotic ; its action is mild, and interfered with by the presence of pain, cough or delirium.

The ureides of oxy-acids and dibasic acids form closed chain compounds (see ALLANTOIN; ALLOXAN; HYDANTOIN; PURIN). Parabanic acid (oxaVyl urea), CO[NH-CO] 2 , is formed by oxidizing uric acid ; or by condensing oxalic acid and urea in the presence of phosphorus oxychloride. It crystallizes in needles and is readily hydrolysed by alkalis. It behaves as a monobasic acid and forms unstable salts. When heated with urea, it forms oxalyl diureide, H 2 N-COCONH-CONH-CO-NH 2 . Dimethylparabanic acid ( cholesterophane), CO[NCH 3 -CC>] 2 , is formed by oxidizing caffeine or by metnylating parabanic acid. It crystallizes in plates, which melt at 145-5 C., and is soluble in cold water. Hydrochloric acid at 200 C. decomposes into oxalic acid, carbon dioxide and methylamine, whilst an alcoholic solution of a caustic alkali gives dimethyl urea and oxalic acid. Barbituric acid (malonyl urea), CH 2 [CO-NH]CO-2H 2 O, formed by condensing malonic acid with urea (E. Grimaux, Bull. Soc. Chem., 1879, 31, 146), crystallizes in prisms, which decompose on heating. It yields a nitroso derivative, is nitrated by nitric acid to dilituric acid and brominated by bromine. It is a dibasic acid. Veronal (q.v.) is diethyl malonyl urea. For isobarbituric acid see T. B. Johnson and E. V. McCollum, Jour. Biol. Chem., 1906, i, p. 437. Tartronyl urea (dialuric acid), CO[NH-CO]CH-OH, formed by the reduction of alloxan (J. v. Liebig and F. Wohler, Ann., 1838, 26, p. 276), or of alloxantin (A. 'Baeyer, Ann., 1863, 127, p. 12), crystallizes in needles or prisms and possesses a very acid reaction. It becomes red on exposure, and in the moist condition absorbs oxygen from the air, giving alloxantin. Allophanic acid, NH 2 -CQ-NH-CO 2 H, is not known in the free state, as when liberated from its salts, it is decomposed into urea and carboji dioxide. Its esters are formed by passing the vapours of cyanic acid into alcohols (W. Traube, Ber., 1889, 22, p. 1572):

CONH->NH 2 -CO 2 R-^NH 2 CO-NH-C0 2 R; by the action ol chlorcarbomc esters on urea (H. Schiff, Ann., 1896, 291, p. 367); and by the action of urethanes on urea chloride (L. Gattermann, Ber., 1888, 21 , p. 293 R). They are readily decomposed by alkalis, yielding cyanuric acid and ammonia. Biuret ( allophanamide), NH 2 -CO-NH-CO-NH 2 , is formed by heating urea; by the action of ammonia on allophanic ester; and by heating urea to 140 C. and passing chlorine into the melt at 140-150 C. (J. Thiele, Ann., 1898, 303, p. 95 Anm.). It crystallizes in needles which melt at 190 C. (with decomposition), and is readily soluble in hot water. When heated strongly it is decomposed into ammonia and cyanuric acid. Baryta water hydrolyses it to carbon dioxide, ammonia and urea. With silver nitrate and caustic soda it yields a silver salt, Ag 2 C 2 H 3 N 3 O 2 . With nitric acid in the presence of sulphuric acid it yields a nitro derivative.

Thiourea, or sulphocarbamide, CS(NH 2 ) 2 , is formed by prolonged fusion of ammonium thiocyanate (E. Reynolds, Ann., 1869, 150, p. 224), by passing sulphuretted hydrogen into an ethereal solution of cyanamide (E. Baumann, Ber., 1873, 6, p. 1375), or by heating isopersulpho-cyanic acid (F. D. Chattaway, Jour. Chem. Soc., 1897, 71, p. 612). It crystallizes in thick prisms which melt at 180 C. and is readily soluble in water. When heated for some time with water to 140 C. in a sealed tube, it is transformed into ammonium thiocyanate, a similar result being obtained by heating the base alone for some hours to 160-170 C. On heating alone for some hours to 170-180 C. it is converted into guanidine thiocyanate. It is hydrolysed by alkalis, giving carbon dioxide, ammonia and sulphuretted hydrogen. It is readily desulphurized by silver oxide, mercuric oxide or lead oxide. Potassium permanganate oxidizes it to urea (R. Maly, Monats., 1890, n, p. 278). It acts as a weak base and forms salts with one equivalent of an acid.

The alkyl derivatives of thiourea are obtained by the action of ammonia and of primary and secondary amines on the mustard oils (A. W. Hofmann, Ber., 1867, I, p. 27):

CSNR+NH 8 = NH 2 -CS-NHR;CSNR+NH 2 R = R.NH-CS-NHR, or by heating the amide salts of the alkyl dithio-carbaminic acids, viz., NR-CS-S(NH 3 R). The monoalkyl derivatives are desulphurized by lead hydroxide in the presence of sodium carbonate, the o/S dialkyl and trialkyl derivatives being unaffected (A. E. Dixon, Jour. Chem. Soc., 1893, 63, p. 325). The dialkyl thipureas when digested with mercuric oxide and amines give guanidines. CS(NHR) 2 +NH 2 R+HgO->HgS + RN:C(NHR) 2 .

Thiourea and many of its unsymmetrical derivatives have marked physiological action; thiourea causes a slowing of the pulse and respiration, cardiac failure, and death in convulsions; phenyl-, ethyl- and acetyl-thiourea are actively toxic. The most important derivative pharmacologically is allyl-thiourea, also known as thiosinamine or rhodallin, NH 2 -CS-NH-CH 2 -CH:CH 2 .

Thiosemicarbazide, NH 2 -CS-NH-NH 2 , prepared from hydrazine sulphate, potassium carbonate and thiocyanate (N. Freund, Ber., 1895, 28, p. 946; 1896, 29, p. 2501), crystallizes in long needles,* which melt at 181-183 C. The addition of sodium nitrite to an aqueous solution of its hydrochloride converts it into amido-triaz- sulphol J . The hydrochloride with potassium cyanate gives hydrazothio-carbonamide, NH 2 -CO-NH-NH-CS-NH 2 .

Medicine. Urea has been given in medicine in doses of 10 to 60 grs. either in mixture or hypodermically. It has been used with success as an antiperiodic and antipyretic in ague, and also as a diuretic in gout and kidney affections. Thiosinamine is given internally in doses of J to I gr. in capsule. Larger doses usually upset the digestion. It has been used for the cure of lupus and of keloid, in which case it is administered hypodermically. In keloid 20 minims of a 10% solution is injected directly into the part. It causes a local reaction with absorption of the scar tissue. For this reason it is used to remove corneal opacities, deafness due to thickening of the membrane, stricture of the oesophagus and hypertrophy of the pylorus, it has also been successful in the treatment of adhesive parametritis. Fibrolysin is a modified form of thiosinamine made by mixing it with sodium salicylate Fibrolysin is freely soluble and may be given in hypodermic or intra-muscular injection. Like thiosinamine it has a specific action on scar tissue and has been used in urethral strictures. Both these preparations should only be used in cases where it is possible to exclude any tuberculous foci, or by their action in breaking down protective fibrous tissues they may cause a quiescent lesion to become active. In large doses toxic symptoms are produced, death following on coma.

Note - this article incorporates content from Encyclopaedia Britannica, Eleventh Edition, (1910-1911)

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