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., NH₂.CO.NH₂.HNO₃, - microscopic thin rhomboidal or irregularly shaped hexagonal plates, mostly collected in heaps, - and oxalic U., (NH₂.CO.NH₂)₂H₂C₂O₄, - microscopic crystals having the form of short oblique prisms, pyramids, and thick rhomboidal plates. U. gives complex compounds with salts, for example with NaCl, -CO(NH₂)₂NaCl+H₂O; with Hg(NO₃)₂ - a poorly soluble compound 2CO(NH₂)₂.Hg(NO₃)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 C₁₃H₁₀O₂

>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)₃ . CH(NH₂) COOH + H₂O = = NH₂ . CO . NH₂ + NH₂(CH₂)₃ CH(NH₂) COOH. It is possible, although not yet proven for the organism, that urea is formed from creatine. Regarding the synthesis of urea in the organism from NH₃, which is formed during the deamination of proteins and their breakdown products—amino acids, aminopurines—there are several possibilities. Intermediate products can be ammonium carbonate and ammonium carbamate, which subsequently, losing water, turns into urea: (NH₄)₂CO₃ - 2H₂O = NH₂ . CO . NH₂; NH₂ . COONH₄ - H₂O = NH₂ . CO . NH₂ (anhydride theory). Ammonium carbamate has indeed been detected in blood and urine (Drechsel). Experiments on animals have shown that ammonium carbonate and ammonium salts, capable of turning into carbonate salt, are converted into urea in the organism. In the works of R. Fosse, the theory of oxidative synthesis by Hofmeister was confirmed, according to which the -CO.NH₂ group in urea 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 temperature; this process, in Fosse's opinion, likely takes place during the formation of urea in plants. Urea is also formed during oxidation in an ammoniacal solution of many other compounds of the fatty series (carbohydrates, glycerin, etc.). The possibility of urea formation via direct oxidation of proteins, which was denied by many authors, has recently been reaffirmed by the works of Fosse.

The main site of urea formation in the animal organism is the liver; in small amounts, urea is formed in the muscles. That the liver is the main, although not the only, site of urea formation was shown by experiments of Nencki, I. P. Pavlov, Hahn, and others with the exclusion of the liver from the general circulation (Eck fistula), as well as observations on humans with cirrhosis, acute yellow atrophy of the liver, and phosphorus poisoning, in which, although not always, a decrease in urea excretion is observed. The introduction of urea or NH₃ causes nitrogen retention in the organism (Grafe, Abderhalden).

About 30 g of urea is excreted with human urine per day, which corresponds to 85-93% of the total amount of nitrogen in the urine. The amount of urea depends on the protein content in the diet, since urea is the main and final product of protein breakdown in the organism. In accordance with this, the excretion of urea with urine increases with an increase in protein breakdown in the organism (during febrile conditions, diabetes, intense muscular work, etc.). Furthermore, daily urea excretion increases with body weight. In children, more urea is excreted per 1 kg of body weight than in adults. With a lack of oxygen, for example, during severe and prolonged dyspnea, after profuse hemorrhages, urea excretion increases. It decreases with damage to the renal glomeruli, with an accumulation of urea occurring in the organism (an increase in the content of urea in the blood and saliva during nephritis and nephrosclerosis). The content of urea in saliva runs parallel to its content in the blood, on the basis of which it has been proposed to determine its content in saliva to judge the degree of urea retention in the blood (see also Urine, Metabolism, nitrogenous).

For the detection and, if possible, quantitative determination of urea in organs or serous fluids, blood, bile, and milk, the following procedure is used: the liquid to be investigated or the rapidly pulverized organ is mixed with 3-4 times the volume of alcohol and left, while stirring, for a day at room temperature. It is filtered, the residue is washed with alcohol, the filtrate is concentrated together with the wash liquid 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, which is then added to the alcohol-water liquid; the latter is evaporated on a water bath to remove alcohol, acidified with H₂SO₄, and peptones, creatinine, and bases are precipitated with phosphotungstic acid. 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 stream of CO₂, filtered again, the filtrate is concentrated by evaporation on a water bath to a small volume, and precipitated with Hg(NO₃)₂ under a slightly acidic reaction, which is maintained by the addition of Ba(OH)₂; then the liquid is neutralized with Ba(OH)₂, the precipitate of the mercury compound of urea is filtered off, washed with water, and decomposed with H₂S. After filtering off the HgS precipitate, the liquid is evaporated to remove H₂S, and the nitric acid urea is decomposed with an excess of BaCO₃; the mixture is evaporated to dryness and extracted with absolute alcohol. In the resulting solution, the amount of urea is determined by one of the methods described in the article Urine.

Derivatives of urea. When heating urea with acids or their acid chlorides or esters, the hydrogen of the amide group of urea is replaced by an acid residue, and ureides are formed (e.g., acetyl-urea CH₃.CO.NH.CO.NH₂). Ureides of acids substituted in the α-position with a halogen have pharmaceutical application as hypnotics, e.g., bromural. Ureides of dibasic acids are very common in the organism of animals and plants, especially derivatives of purine (e.g., uric acid, xanthine, and methylated xanthines) and pyrimidine. In the formation of ureides with a dibasic acid, either one COOH group can participate (such compounds are called uro-acids, e.g., NH₂.CO.NH.CO.COOH - oxaluric acid) or both COOH groups, with the formation of cycles, e.g., oxalylurea (parabanic acid) _/NH-CO CO _{ackslashNH-CO}, barbituric acid (see), mesoxalylurea (alloxan) _/NH-CO CO _{ackslashNH-CO} CO, etc. Ureides derived from glycolic acid are hydantoic acid NH₂.CO.NH.CH₂.COOH and hydantoin _/NH-CH2 CO _{ackslashNH-CO}. Hydantoins are anhydrides of uramino acids formed by boiling urea with amino acids in the presence of water or baryta water. The ureide of glyoxylic acid is allantoin _{/NH-CH-NH.CO.NH2} CO _{ackslashNH-CO}, the main final product of purine metabolism in all mammals except humans and anthropoid apes. Human urine apparently contains methyl-urea (Fosse) and a compound of urea with glucuronic acid. When concentrated solutions of urea act on proteins, compounds are formed that behave like alkaline albuminates. Urea is capable of converting coagulated proteins into solution. Urea sometimes reacts in the tautomeric form of iso-urea _/OH C=NH _ackslashNH2. Derivatives of iso-urea are obtained by the addition of alcohols to cyanamide in the presence of HCl: NH₂.C=N + HO.CH₃ = NH₂.C(OCH₃)=NH methyl-iso-urea. When phosgene acts on ammonia, thiourea is formed (CSCl₂ + 2NH₃ = CS(NH₂)₂ + 2HCl), which reacts mostly in the form of isothiourea. A derivative of thiourea is thiosinamine. L. Broude.