Urea

UREA (carbamide) NH₂.CO.NH₂, the diamide of carbonic acid, the main constituent of human and other mammal, amphibian, and fish urine. In small quantities it is contained in the blood (the main constituent of serum blood residual nitrogen), lymph, transudates, exudates, saliva, milk, sweat, tears, bile, amniotic and cerebrospinal fluids, brain, muscles, in the vitreous body, in the aqueous humor of the eye, and in other organs and fluids of the animal organism; the content of U. can rise strongly under pathological conditions, upon retention of its excretion; in uremia U. appears in sputum. In significant quantities U. is contained in the blood, liver, muscles, and bile of sharks. U. has also been found in plants (fungi, mold fungi, higher plants). U. was discovered in 1773 by Rouelle, and in 1828 was synthesized by Wöhler (see). It crystallizes in the form of four-sided prisms with blunt pyramids at the ends, melts at 132°. It is easily soluble in water and in hot alcohol, insoluble in ether, neutral on litmus. It gives salts with acids (with 1 equivalent); among them the poorly soluble are: nitric U., NH₈.CO.NH₂.HN0₈, -microscopic thin rhomboidal or irregularly shaped hexagonal plates, mostly collected in heaps, - and oxalic U., (NH_a.CO.NH₂)₂H₂C_a0₄, - microscopic crystals having the form of short oblique prisms, pyramids, and thick rhomboidal plates. U. gives complex compounds with salts, for example with NaCl, -CQ(NH₈)₈NaCl-f-H₈0; with Hg(NO₃)_a - a poorly soluble compound 2CO(NH₂)₂.Hg(N0₃)₂+nHgO, where n may be 1, 2 or 3. U. is quantitatively precipitated from acetic acid solutions by a 10% alcoholic solution of xanthhydrol /C_bH_4ч 0<

>CH.OH in the form of a crystalline, very stable with respect to hot alkalis dioxanthyl-U.: /C_bH^k>0

If dry urea is carefully heated in a test tube on a small flame, U. first melts and then decomposes with the separation of ammonia and formation of biuret, 2CO(NH₂)₂ - NH₃ = NH₂.CO.NH.CO.NH₂, and of cyanuric acid, co/^NH\co 3NH₂.CO.NH₂-3NH₃= I

I NH\_CQ/NH If the residue after cooling the test tube is dissolved in NaOH and mixed with 1-2 drops of a dilute solution of CuS0₄, a pink or red coloration appears (biuret reaction). Upon heating with acids or alkalis or with water (under pressure), U., like all amides, undergoes hydrolysis, with the formation of ammonia and carbonic acid: CO(NH₂)₂ + 2H₂0->(NH₄)₂C0₃-> -*NH₃+C0₂. This same transformation also takes place under the influence of urease, the enzyme produced by certain bacteria, as well as that found in soybeans. Chlorous or hypochlorous alkali decomposes U. with the formation of C0₂, N₂ and water (see Borodin method). Under the influence of nitrous acid a similar decomposition takes place: CO(NH₂)₂+N_a0₃=CO_a+2N₂+2H₂0; for complete decomposition of U. by the Van Slyke method (see) about 8 hours are required. In formal titration U. remains neutral. - U. can be obtained by ordinary methods of synthesis of acid amides (see Amides). The technical method is the addition of water to cyanamide: CN.NH_a+ + H_aO=CO(NH₂)₂ or the combination of C0_a and NH₃ under pressure. From urine U. is isolated in the form of a nitrate salt, which is obtained by adding HN0₃ to an alcoholic extract of evaporated urine. The formation of U. in the animal organism takes place both by a synthetic and by a hydrolytic path. Part of U. (about 10%; Drechsel) is formed upon hydrolysis of arginine under the influence of arginase, the enzyme found by Kossel in the liver and splitting arginine into U. and ornithine /NH₂

_# HN = C--------NH . (CH₂)_S . CH(NH₂) COOH + H₂O = = NH₂ . CO . NH₂ + NH₂(CH₂)₃ CH(NH₂) COOH. The formation of urea from creatine is possible, although not yet proven for the organism. Regarding the realization in the organism of the synthesis of U. from NH₃, which is formed during the deamination of proteins and the products of their breakdown—amino acids, aminopurines, there are several possibilities. Intermediate products may be carbonic and carbaminoic ammonium, which further, losing water, passes into U.: (NH₄)₂C0₃ - 2H₂0=NH₂ . CO . NH₂; NH₂ . COONH₄ - H₂0=NH₂ . CO . NH₂ (anhydride theory). Carbaminoic ammonium is indeed found in blood and urine (Drechsel). Experiments on animals showed that carbonic ammonium and ammonium salts capable of turning into carbonic salt pass into U. in the organism. In the works of Fosse (R. Fosse) the oxidative synthesis theory of Hofmeister (Hofmeister) received confirmation, according to which the group-CO.NH₂ in U. is a product of the oxidation of proteins, amino acids, etc. Urea is formed especially easily during the oxidation of formaldehyde in the presence of NH₃ at ordinary t°; this process, in the opinion of Fosse, probably takes place during the formation of U. in plants. Urea is also formed during oxidation in ammoniacal solution and many other compounds of the fatty series (carbohydrates, glycerin, etc.). The possibility of the formation of U. by direct oxidation of proteins, which was denied by many authors, is again affirmed in recent works by Fosse. The main place of formation of U. in the animal organism is the liver; in small quantities urea is formed in the muscles. That the liver is the main, although not the only, place of formation of urea was shown by the experiments of Nencki, I. P. Pavlov, Halm, and others, with the liver excluded from the general circulation (Eck's fistula), as well as observations on man in cirrhosis, acute yellow atrophy of the liver, and poisoning with P, in which, although not always, a decrease in the excretion of U. is observed. The introduction of U. or NH₃ causes a retention of N in the organism (Grafe, Abderhalden).-About 30 g of U. is excreted per day with human urine, which corresponds to 85-93% of the total amount of urine N. The amount of U. depends on the content of proteins in the food, since U. is the main and final product of protein breakdown in the organism. In accordance with this, the excretion of U. with urine increases with an intensification of protein breakdown in the organism (in febrile states, diabetes, intense muscular work, etc.). Furthermore, the daily excretion of U. increases with the living weight of the body. In children, more U. is excreted per 1 kg of body weight than in adults. In the absence of oxygen, e.g. during strong and prolonged shortness of breath, after profuse hemorrhages, the excretion of U. increases. It decreases with damage to the renal glomeruli, and at the same time there is an accumulation of U. in the organism (an increase in the content of U. in the blood and saliva in nephritis and nephrosclerosis). The content of urea in the saliva runs parallel to its content in the blood, on the basis of which it was proposed to judge the degree of retention of U. in the blood by determining its content in the saliva (see also Urine, Metabolism, Nitrogen). For the discovery and, if possible, quantitative determination of U. in organs or serous fluids, blood, bile, milk, the following procedure is used: the liquid to be investigated or a quickly crushed organ is mixed with a 3-4-fold volume of alcohol and left, with stirring, for a day at room t°. The filtrate is filtered, the residue is washed with alcohol, the filtrate together with the wash liquid is concentrated in a vacuum at 50°, acidified with acetic acid, and extracted in a separatory funnel with chloroform to remove phosphatides, fats, and cholesterol. The chloroform extract is washed with water, to which the water is then added to the alcohol-water liquid; the latter is evaporated on a water bath to remove alcohol, acidified with H₂SO₄, and precipitated with phosphotungstic acid peptones, creatinine, and bases. The precipitate is filtered off and washed with water acidified with H₂SO₄. The combined filtrates are precipitated with Ba(OH)₂, the excess of which is removed by a current of CO₂, filtered again, the filtrate is concentrated by evaporation on a water bath to a small volume, and Hg(NO₃)₂ is precipitated at a weakly acidic reaction, which is maintained by adding Ba(OH)₂; then the liquid is neutralized with Ba(OH)₂, the precipitate of the mercury compound of U. is filtered off, washed with water, and decomposed with H₂S. After filtering off the precipitate of HgS, the liquid is evaporated to remove H₂S and the nitrate of U. is decomposed with an excess of BaCO₃; the mixture is evaporated to dryness and extracted with absolute alcohol. The amount of U. is determined in the resulting solution by one of the methods described in the article Urine. Urea Derivatives. Upon heating Urea with acids or their acid chlorides or complex esters, the hydrogen of the amide group of Urea is replaced by an acid residue, ureides are formed (e.g. acetyl-urea CH₃.CO.NH. .CO.NH₂). Ureides of acids, halogens substituted in the alpha-position, have a pharmacological application as hypnotics, e.g. barbital. Ureides of dibasic acids are very widespread in the organisms of animals and plants, especially the derivatives of purine (e.g. ureic acid, xanthine, and methylated xanthines), pyrimidine. In the formation of ureides with a dibasic acid, either one COOH-group (such compounds are called uric acids, e.g. NH₂ . CO . NH . CO . COOH - oxaluric acid) or both COOH-groups can participate, in which case cycles are formed, e.g. oxalylurea /NH-CO (parabanic acid) ^co

I barbituric \NH-CO acid (see), mesoxalylurea (alloxan) _/nh-co

^>co and others. Ureides of glycolic acid are hydantoinic acid NH₂ . CO . NH . CH₂. COOH _/NH-CH₂ and hydantoin. Hydantoins are amides of uramino acids formed by boiling urea with amino acids in the presence of water or barium water. Ureide of glyoxylic acid is alloxan /NH-CH-NH.CO.NHa. Hydantoins are the main end product of purine metabolism in all mammals except man and man-like apes. In human urine is apparently contained methyl-Urea (Foeppl) and a compound of urea with glucuronic acid. - Upon the action of concentrated solutions of Urea on proteins, compounds are formed that behave as alkaline albuminates. Urea is capable of converting coagulated proteins into solution. Urea sometimes reacts in the tautomeric form of iso-Urea _/on ciznh. ⁴NH₂ Iso-Urea derivatives are obtained by adding alcohols to cyanamide in the presence of HCl: NH₃ . C ; N + HO . CH₃ = NH₂ . C ⁴0-CH₃ methyl-iso-Urea. Upon the action of thiophosgene on ammonia, thiourea is formed (CSCl₂ + 2NH₃ = CS(NH₂)₂ + -+-2HCl), which reacts mainly in the form of isothiourea. Thiourea derivative is thiocyanamide.

l. Brode.