View source for Chemistry:Urea

{{Short description|Organic compound}}
{{chembox
| Verifiedfields = correct
| Watchedfields = correct
| verifiedrevid = 443307328
| ImageFileL1 = Urea Structural Formula V2.svg
| ImageFileR1 = Urea 3D ball.png
| ImageFileL2 = Urea 3D spacefill.png
| ImageFileR2 = Sample of Urea.jpg
| PIN = Urea<ref name=iupac2013>{{cite book | title = Nomenclature of Organic Chemistry : IUPAC Recommendations and Preferred Names 2013 (Blue Book) | publisher = [[Organization:Royal Society of Chemistry|The Royal Society of Chemistry]] | date = 2014 | location = Cambridge | pages = 416, 860–861 | doi = 10.1039/9781849733069-FP001 | isbn = 978-0-85404-182-4 | quote = The compound H<sub>2</sub>N-CO-NH<sub>2</sub> has the retained named ‘urea’, which is the preferred IUPAC name, (…). The systematic name is ‘carbonyl diamide’.}}</ref>
| SystematicName = Carbonyl diamide<ref name=iupac2013 />
| pronounce = urea {{IPAc-en|j|ʊəˈr|iː|ə}}, carbamide {{IPAc-en|ˈ|k|ɑːr|b|ə|m|aɪ|d}}
| OtherNames = {{ubl|Carbamide|Carbonyldiamide|Carbonyldiamine|Diaminomethanal|Diaminomethanone}}
| IUPACName =
|Section1 = {{Chembox Identifiers
| IUPHAR_ligand = 4539
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 16199
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB03904
| SMILES = C(=O)(N)N
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 8W8T17847W
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00023
| InChI = 1/CH4N2O/c2-1(3)4/h(H4,2,3,4)
| InChIKey = XSQUKJJJFZCRTK-UHFFFAOYAF
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 985
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/CH4N2O/c2-1(3)4/h(H4,2,3,4)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = XSQUKJJJFZCRTK-UHFFFAOYSA-N
| CASNo = 57-13-6
| CASNo_Ref = {{cascite|correct|CAS}}
| PubChem = 1176
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 1143
| RTECS = YR6250000
| Beilstein = 635724
| Gmelin = 1378
 }}
|Section2 = {{Chembox Properties
| Formula = {{chem2|CO(NH2)2}}
| MolarMass = 60.06 g/mol
| Appearance = White solid
| Density = 1.32 g/cm<sup>3</sup>
| Solubility = 545 g/L (at 25 °C)<ref name="Solubility">{{cite book|url=https://books.google.com/books?id=cfFzJFthLCIC&pg=PP1|title = Handbook of Aqueous Solubility Data|isbn = 9781439802465|last1 = Yalkowsky|first1 = Samuel H.|last2 = He|first2 = Yan|last3 = Jain|first3 = Parijat|date = 19 April 2016| publisher=CRC Press }}</ref>
| SolubleOther = 500 g/L glycerol<ref>{{cite web|url=http://msdssearch.dow.com/PublishedLiteratureDOWCOM/dh_0032/0901b8038003228b.pdf?filepath=glycerine/pdfs/noreg/115-00668.pdf|title=Solubility of Various Compounds in Glycerine|work=msdssearch.dow.com|access-date=2014-04-12|archive-url=https://web.archive.org/web/20140413155224/http://msdssearch.dow.com/PublishedLiteratureDOWCOM/dh_0032/0901b8038003228b.pdf?filepath=glycerine%2Fpdfs%2Fnoreg%2F115-00668.pdf|archive-date=2014-04-13|url-status=dead}}</ref>
&nbsp;&nbsp;50&nbsp;g/L ethanol<br>
&nbsp;&nbsp;~4&nbsp;g/L [[Chemistry:Acetonitrile|acetonitrile]]<ref>{{cite journal|last1=Loeser|first1=Eric|last2=DelaCruz|first2=Marilyn|last3=Madappalli|first3=Vinay | name-list-style = vanc |title=Solubility of Urea in Acetonitrile–Water Mixtures and Liquid–Liquid Phase Separation of Urea-Saturated Acetonitrile–Water Mixtures|journal=Journal of Chemical & Engineering Data|date=9 June 2011|volume=56|issue=6|pages=2909–2913|doi=10.1021/je200122b}}</ref>
| MeltingPtC = 133 to 135
| BoilingPt = decomposes
| MeltingPt_notes =
| pKa =
| pKb = 13.9<ref name=pK>Calculated from 14−pK<sub>a</sub>. The value of pK<sub>a</sub> is given as 0.10 by the ''CRC Handbook of Chemistry and Physics'', 49th edition (1968–1969). A value of 0.18 is given by {{cite web|url=http://research.chem.psu.edu/brpgroup/pKa_compilation.pdf|title=pKa Data|last1=Williams|first1=R.|date=2001-10-24|archive-url=https://web.archive.org/web/20030824213333/http://research.chem.psu.edu/brpgroup/pKa_compilation.pdf|archive-date=August 24, 2003}}</ref>
| MagSus = −33.4·10<sup>−6</sup> cm<sup>3</sup>/mol
}}
|Section3 = {{Chembox Structure
| Dipole = 4.56 [[Debye|D]]
 }}
|Section4 = {{Chembox Thermochemistry
| Thermochemistry_ref = CRC Handbook
| HeatCapacity =
| Entropy =
| DeltaHf = −333.19 kJ/mol
| DeltaGf = −197.15 kJ/mol
| DeltaHc =
 }}
|Section5 =
|Section6 = {{Chembox Pharmacology
| ATCCode_prefix = B05
| ATCCode_suffix = BC02
| ATC_Supplemental = {{ATC|D02|AE01}}
}}
|Section7 = {{Chembox Hazards
| ExternalSDS = [https://www.inchem.org/documents/icsc/icsc/eics0595.htm ICSC 0595]
| FlashPt = Non-flammable
| LD50 = 8500 mg/kg (oral, rat)
| GHSPictograms = {{GHS07}}
| NFPA-H = 1
| NFPA-F = 1
| NFPA-R = 0
}}
|Section8 = {{Chembox Related
| OtherFunction = [[Chemistry:Thiourea|Thiourea]]<br />[[Chemistry:Hydroxycarbamide|Hydroxycarbamide]]
| OtherFunction_label = ureas
| OtherCompounds = {{ubl|Carbamide peroxide|[[Chemistry:Urea phosphate|Urea phosphate]]|[[Chemistry:Acetone|Acetone]]|[[Chemistry:Carbonic acid|Carbonic acid]]|[[Chemistry:Carbonyl fluoride|Carbonyl fluoride]]}}
}}
}}

'''Urea''', also called '''carbamide''' (because it is a diamide of [[Chemistry:Carbonic acid|carbonic acid]]), is an [[Chemistry:Organic compound|organic compound]] with [[Chemistry:Chemical formula|chemical formula]] {{chem2|CO(NH2)2}}. This [[Chemistry:Amide|amide]] has two [[Chemistry:Amine|amino groups]] (–{{chem2|NH2}}) joined by a carbonyl [[Chemistry:Functional group|functional group]] (–C(=O)–). It is thus the simplest amide of [[Chemistry:Carbamic acid|carbamic acid]].

Urea serves an important role in the [[Biology:Metabolism|metabolism]] of [[Chemistry:Nitrogen|nitrogen]]-containing compounds by animals and is the main nitrogen-containing substance in the [[Biology:Urine|urine]] of [[Biology:Mammal|mammal]]s. ''Urea'' is Neo-Latin, {{etymology|fr|{{wiktfra|urée}}|}}, {{etymology|grc|''{{wiktgrc|οὖρον}}'' ({{grc-transl|οὖρον}})|urine}}, itself from Proto-Indo-European ''*h₂worsom''.

It is a colorless, odorless solid, highly soluble in water, and practically non-toxic ({{LD50}} is 15 g/kg for rats).<ref>{{cite web |title=Urea - Registration Dossier - ECHA |url=https://echa.europa.eu/registration-dossier/-/registered-dossier/16152/7/1 |website=echa.europa.eu}}</ref> Dissolved in water, it is neither [[Chemistry:Acid|acid]]ic nor [[Chemistry:Base|alkaline]]. The body uses it in many processes, most notably [[Biology:Metabolic waste#Nitrogen wastes|nitrogen excretion]]. The [[Biology:Liver|liver]] forms it by combining two [[Chemistry:Ammonia|ammonia]] molecules ({{chem2|NH3}}) with a [[Chemistry:Carbon dioxide|carbon dioxide]] ({{chem2|CO2}}) molecule in the [[Chemistry:Urea cycle|urea cycle]]. Urea is widely used in [[Chemistry:Fertilizer|fertilizer]]s as a source of nitrogen (N) and is an important [[Chemistry:Raw material|raw material]] for the [[Engineering:Chemical industry|chemical industry]].

In 1828, [[Biography:Friedrich Wöhler|Friedrich Wöhler]] [[Chemistry:Wöhler synthesis|discovered]] that urea can be produced from inorganic starting materials, which was an important conceptual milestone in chemistry. This showed for the first time that a substance previously known only as a byproduct of life could be synthesized in the laboratory without biological starting materials, thereby contradicting the widely held doctrine of [[Vitalism|vitalism]], which stated that only living organisms could produce the chemicals of life.

==Properties==

===Molecular and crystal structure===
The urea molecule is planar when in a solid crystal because of sp<sup>2</sup> [[Physics:Orbital hybridisation|hybridization]] of the N orbitals.<ref name="Godfrey 1997">{{cite journal | last1=Godfrey | first1=Peter D. | last2=Brown | first2=Ronald D. | last3=Hunter | first3=Andrew N. | title=The shape of urea | journal=Journal of Molecular Structure | volume=413–414 | date=1997 | doi=10.1016/S0022-2860(97)00176-2 | pages=405–414| bibcode=1997JMoSt.413..405G }}</ref><ref name="Ishida 2004">{{cite journal | last1=Ishida | first1=Tateki | last2=Rossky | first2=Peter J. | last3=Castner | first3=Edward W. | title=A Theoretical Investigation of the Shape and Hydration Properties of Aqueous Urea: Evidence for Nonplanar Urea Geometry | journal=The Journal of Physical Chemistry B | volume=108 | issue=45 | date=2004 | issn=1520-6106 | doi=10.1021/jp0473218 | pages=17583–17590}}</ref> It is non-planar with C<sub>2</sub> symmetry when in the gas phase<ref name="West 2015">{{cite journal | last1=West | first1=Aaron C. | last2=Schmidt | first2=Michael W. | last3=Gordon | first3=Mark S. | last4=Ruedenberg | first4=Klaus | title=A Comprehensive Analysis in Terms of Molecule-Intrinsic, Quasi-Atomic Orbitals. III. The Covalent Bonding Structure of Urea | journal=The Journal of Physical Chemistry A | volume=119 | issue=41 | date=2015-10-15 | issn=1089-5639 | doi=10.1021/acs.jpca.5b03400 | pages=10368–10375| bibcode=2015JPCA..11910368W | url=https://lib.dr.iastate.edu/cgi/viewcontent.cgi?article=1624&context=chem_pubs }}</ref> or in aqueous solution,<ref name="Ishida 2004" /> with C–N–H and H–N–H bond angles that are intermediate between the [[Physics:Trigonal planar molecular geometry|trigonal planar]] angle of 120° and the [[Physics:Tetrahedral molecular geometry|tetrahedral]] angle of 109.5°. In solid urea, the oxygen center is engaged in two N–H–O [[Chemistry:Hydrogen bond|hydrogen bond]]s. The resulting dense and energetically favourable hydrogen-bond network is probably established at the cost of efficient molecular packing: The structure is quite open, the ribbons forming tunnels with square cross-section. The carbon in urea is described as sp<sup>2</sup> hybridized, the C-N bonds have significant double bond character, and the carbonyl oxygen is relatively basic. Urea's high aqueous solubility reflects its ability to engage in extensive hydrogen bonding with water.

By virtue of its tendency to form porous frameworks, urea has the ability to trap many organic compounds. In these so-called clathrates, the organic "guest" molecules are held in channels formed by interpenetrating helices composed of [[Chemistry:Hydrogen bond|hydrogen-bonded]] urea molecules.<ref name="Worsch 2002">{{cite book | date=2002 | last1=Worsch | first1=Detlev | last2=Vögtle | first2=Fritz | title=Topics in Current Chemistry | chapter=Separation of enantiomers by clathrate formation | publisher=Springer-Verlag | isbn=3-540-17307-2 | doi=10.1007/bfb0003835 | pages=21–41}}</ref>

As the [[Helix|helices]] are interconnected, all helices in a crystal must have the same [[Chemistry:Stereoisomerism|molecular handedness]]. This is determined when the crystal is nucleated and can thus be forced by seeding. The resulting crystals have been used to separate [[Chemistry:Racemic mixture|racemic mixture]]s.<ref name="Worsch 2002" />

===Reactions===
Urea is basic and is protonated readily. It is also a Lewis base, forming metal complexes of the type {{chem2|[M(urea)6]^{''n''+}|}}.

Urea reacts with [[Chemistry:Malonic acid|malonic]] esters to make [[Chemistry:Barbituric acid|barbituric acid]]s.

====Decomposition====
Molten urea decomposes into [[Chemistry:Ammonium cyanate|ammonium cyanate]] at about 152&nbsp;°C, and into [[Chemistry:Ammonia|ammonia]] and [[Chemistry:Isocyanic acid|isocyanic acid]] above 160&nbsp;°C:<ref name="Schaber 2004">{{cite journal | last1=Schaber | first1=Peter M. | last2=Colson | first2=James | last3=Higgins | first3=Steven | last4=Thielen | first4=Daniel | last5=Anspach | first5=Bill | last6=Brauer | first6=Jonathan | title=Thermal decomposition (pyrolysis) of urea in an open reaction vessel | journal=Thermochimica Acta | volume=424 | year=2004 | issue=1–2 | issn=0040-6031 | doi=10.1016/j.tca.2004.05.018 | pages=131–142}}</ref>
:{{chem2|CO(NH2)2 → [NH4]+[OCN]- → NH3 + HNCO}}

Heating above 160&nbsp;°C yields [[Chemistry:Biuret|biuret]] {{chem2|NH2CONHCONH2}} and [[Chemistry:Triuret|triuret]] {{chem2|NH2CONHCONHCONH2}} via reaction with isocyanic acid:<ref name="Meessen 2012">{{Ullmann |last=Meessen |first=Jozef H. |title=Urea |year=2012 |doi=10.1002/14356007.a27_333.pub2}}</ref><ref name="Schaber 2004"/>
:{{chem2|CO(NH2)2 + HNCO → NH2CONHCONH2}}
:{{chem2|NH2CONHCONH2 + HNCO → NH2CONHCONHCONH2}}

At higher temperatures it converts to a range of [[Chemistry:Condensation reaction|condensation product]]s, including [[Chemistry:Cyanuric acid|cyanuric acid]] {{chem2|(CNOH)3}}, [[Chemistry:Guanidine|guanidine]] {{chem2|HNC(NH2)2}}, and [[Chemistry:Melamine|melamine]].<ref name="Meessen 2012" /><ref name="Schaber 2004"/>

In aqueous solution, urea slowly equilibrates with ammonium cyanate. This [[Chemistry:Hydrolysis|hydrolysis]] cogenerates [[Chemistry:Isocyanic acid|isocyanic acid]], which can [[Chemistry:Isocyanic acid#Reactions|carbamylate]] proteins, in particular the N-terminal amino group, the side chain amino of [[Chemistry:Lysine|lysine]], and to a lesser extent the side chains of [[Chemistry:Arginine|arginine]] and [[Chemistry:Cysteine|cysteine]].<ref name="SA_PDF">{{cite web |last1=Aldrich |first1=Sigma |title=Urea Solution Product Information |url=https://www.sigmaaldrich.com/deepweb/assets/sigmaaldrich/product/documents/392/609/u4883dat.pdf |access-date=7 February 2023}}</ref><ref name="Burgess Deutscher 2009">{{cite book | last1=Burgess | first1=Richard R. | last2=Deutscher | first2=Murray P. | title=Guide to protein purification | publisher=Academic Press/Elsevier | publication-place=San Diego, Calif | date=2009 | isbn=978-0-12-374536-1 | oclc=463300660 | page=819}}</ref> Each carbamylation event adds 43 [[Dalton (unit)|daltons]] to the mass of the protein, which can be observed in [[Biology:Protein mass spectrometry|protein mass spectrometery]].<ref name="Burgess Deutscher 2009"/> For this reason, pure urea solutions should be freshly prepared and used, as aged solutions may develop a significant concentration of cyanate (20&nbsp;mM in 8&nbsp;M urea).<ref name="Burgess Deutscher 2009"/> Dissolving urea in ultrapure water followed by removing ions (i.e. cyanate) with a mixed-bed [[Chemistry:Ion-exchange resin|ion-exchange resin]] and storing that solution at 4&nbsp;°C is a recommended preparation procedure.<ref name="Deutscher 1990">{{cite book | last=Deutscher | first=M.P. | title=Guide to Protein Purification | publisher=Academic Press | series=Methods in enzymology | year=1990 | isbn=978-0-12-182083-1 | url=https://books.google.com/books?id=zTiRJHpKIQoC&pg=PR11 | access-date=2023-02-24 | page=267}}</ref> However, cyanate will build back up to significant levels within a few days.<ref name="Burgess Deutscher 2009"/> Alternatively, adding 25–50 mM [[Chemistry:Ammonium chloride|ammonium chloride]] to a concentrated urea solution decreases formation of cyanate because of the common ion effect.<ref name="Burgess Deutscher 2009"/><ref>{{cite journal | vauthors = Sun S, Zhou JY, Yang W, Zhang H | title = Inhibition of protein carbamylation in urea solution using ammonium-containing buffers | journal = Analytical Biochemistry | volume = 446 | pages = 76–81 | date = February 2014 | pmid = 24161613 | pmc = 4072244 | doi = 10.1016/j.ab.2013.10.024 }}</ref>

===Analysis===
Urea is readily quantified by a number of different methods, such as the diacetyl monoxime colorimetric method, and the [[Chemistry:Berthelot's reagent|Berthelot reaction]] (after initial conversion of urea to ammonia via urease). These methods are amenable to high throughput instrumentation, such as automated flow injection analyzers<ref>{{cite journal | vauthors = Baumgartner M, Flöck M, Winter P, Luf W, Baumgartner W | title = Evaluation of flow injection analysis for determination of urea in sheep's and cow's milk | journal = Acta Veterinaria Hungarica | volume = 50 | issue = 3 | pages = 263–71 | year = 2005 | pmid = 12237967 | doi = 10.1556/AVet.50.2002.3.2 | s2cid = 42485569 | url = http://real.mtak.hu/49298/1/avet.50.2002.3.2.pdf }}</ref> and 96-well micro-plate spectrophotometers.<ref>{{cite journal| vauthors = Greenan NS, Mulvaney RL, Sims GK |year=1995|title= A microscale method for colorimetric determination of urea in soil extracts|journal= Communications in Soil Science and Plant Analysis|volume= 26|issue=15–16|pages=2519–2529|doi=10.1080/00103629509369465|bibcode=1995CSSPA..26.2519G |url=https://zenodo.org/record/1234433}}</ref>

==Related compounds==
{{main|Chemistry:Ureas}}

[[Chemistry:Ureas|Ureas]] describes a ''class'' of [[Chemistry:Chemical compound|chemical compound]]s that share the same functional group, a carbonyl group attached to two organic amine residues: {{chem2|R^{1}R^{2}N\sC(\dO)\sNR^{3}R^{4}|}}, where {{chem2|R^{1}, R^{2}, R^{3} and R^{4}|}} groups are [[Chemistry:Hydrogen|hydrogen]] (–H), organyl or other groups. Examples include carbamide peroxide, [[Chemistry:Allantoin|allantoin]], and [[Chemistry:Hydantoin|hydantoin]]. Ureas are closely related to [[Chemistry:Biuret|biuret]]s and related in structure to [[Chemistry:Amide|amide]]s, [[Chemistry:Carbamate|carbamate]]s, [[Chemistry:Carbodiimide|carbodiimide]]s, and thiocarbamides.

==Uses==

===Agriculture===
[[File:Urea process plant UFFL 01.jpg|left|thumb|A plant in Bangladesh that produces urea fertilizer.]]
More than 90% of world industrial production of urea is destined for use as a nitrogen-release [[Chemistry:Fertilizer|fertilizer]].<ref name="Meessen 2012" /> Urea has the highest nitrogen content of all solid nitrogenous fertilizers in common use. Therefore, it has a low transportation cost per unit of [[Biology:Plant nutrition#Nitrogen|nitrogen nutrient]]. The most common impurity of synthetic urea is [[Chemistry:Biuret|biuret]], which impairs plant growth. Urea breaks down in the soil to give [[Chemistry:Ammonium|ammonium ions]] ({{chem2|NH4+}}). The ammonium is taken up by the plant through its roots. In some soils, the ammonium is oxidized by bacteria to give [[Chemistry:Nitrate|nitrate]] ({{chem2|NO3-}}), which is also a nitrogen-rich plant nutrient. The loss of nitrogenous compounds to the atmosphere and runoff is wasteful and environmentally damaging so urea is sometimes modified to enhance the efficiency of its agricultural use. Techniques to make controlled-release fertilizers that slow the release of nitrogen include the encapsulation of urea in an inert sealant, and conversion of urea into derivatives such as [[Chemistry:Urea-formaldehyde|urea-formaldehyde]] compounds, which degrade into ammonia at a pace matching plants' nutritional requirements.

===Resins===
Urea is a raw material for the manufacture of urea-formaldehyde resins, used mainly in wood-based panels such as particleboard, fiberboard and [[Chemistry:Plywood|plywood]].

=== Explosives ===
Urea can be used to make [[Chemistry:Urea nitrate|urea nitrate]], a high explosive that is used industrially and as part of some improvised explosive devices.

===Automobile systems===
Urea is used in Selective Non-Catalytic Reduction (SNCR) and [[Chemistry:Selective catalytic reduction|Selective Catalytic Reduction (SCR)]] reactions to reduce the [[Chemistry:Nitrogen oxide|{{chem2|NO {''x''}|}}]] [[Chemistry:Pollutant|pollutant]]s in [[Physics:Exhaust gas|exhaust gas]]es from [[Physics:Combustion|combustion]] from [[Chemistry:Diesel fuel|diesel]], dual fuel, and lean-burn [[Chemistry:Natural gas|natural gas]] engines. The [[Engineering:BlueTec|BlueTec]] system, for example, injects a water-based urea solution into the exhaust system. Ammonia ({{chem2|NH3}}) produced by the [[Chemistry:Hydrolysis|hydrolysis]] of urea reacts with nitrogen oxides ({{chem2|NO_{''x''}|}}) and is converted into nitrogen gas ({{chem2|N2}}) and water within the catalytic converter. The conversion of noxious {{chem2|NO_{''x''}|}} to innocuous {{chem2|N2}} is described by the following simplified global equation:<ref>Duo et al., (1992). Can. J. Chem. Eng, '''70''', 1014–1020.</ref>
:{{chem2|4 NO + 4 NH3 + O2 → 4 N2 + 6 H2O}}
When urea is used, a pre-reaction (hydrolysis) occurs to first convert it to ammonia:
:{{chem2|CO(NH2)2 + H2O → 2 NH3 + CO2}}
Being a solid highly [[Chemistry:Solubility|soluble]] in water (545 g/L at 25&nbsp;°C),<ref name="Solubility" /> urea is much easier and safer to handle and store than the more [[Biology:Irritation|irritant]], caustic and hazardous [[Chemistry:Ammonia|ammonia]] ({{chem2|NH3}}), so it is the reactant of choice. Trucks and cars using these catalytic converters need to carry a supply of [[Chemistry:Diesel exhaust fluid|diesel exhaust fluid]], also sold as AdBlue, a solution of urea in water.

===Laboratory uses===
Urea in concentrations up to 10&nbsp;[[Physics:Molar concentration#Units|M]] is a powerful [[Biology:Protein|protein]] [[Biology:Denaturation (biochemistry)|denaturant]] as it disrupts the noncovalent bonds in the proteins. This property can be exploited to increase the solubility of some proteins. A mixture of urea and [[Chemistry:Choline chloride|choline chloride]] is used as a [[Chemistry:Deep eutectic solvent|deep eutectic solvent]] (DES), a substance similar to [[Physics:Ionic liquid|ionic liquid]]. When used in a deep eutectic solvent, urea gradually denatures the proteins that are solubilized.<ref>{{cite journal | first1 = Erwann | last1 = Durand | first2 = Jérôme | last2 = Lecomte | first3 = Bruno | last3 =Baréa | first4 = Georges | last4 = Piombo | first5 = Éric | last5 = Dubreucq | first6 = Pierre | last6 = Villeneuve | title = Evaluation of deep eutectic solvents as new media for ''Candida antarctica'' B lipase catalyzed reactions | journal = Process Biochemistry | publisher = [[Company:Elsevier|Elsevier]] | volume = 47 | issue = 12 | date = 2012-12-01 | pages = 2081–2089 | doi = 10.1016/j.procbio.2012.07.027 | issn = 1359-5113 | df = dmy-all}}.</ref>

Urea can in principle serve as a hydrogen source for subsequent power generation in [[Physics:Fuel cell|fuel cell]]s. Urea present in urine/wastewater can be used directly (though bacteria normally quickly degrade urea). Producing hydrogen by electrolysis of urea solution occurs at a lower voltage ({{val|0.37|u=V}}) and thus consumes less energy than the electrolysis of water ({{val|1.2|u=V}}).<ref>{{cite press release | last1 = Carow | first1 = Colleen | date = 2008-11-14 | url = http://www.ohio.edu/outlook/08-09/November/194.cfm | title = Researchers develop urea fuel cell | archive-url = https://web.archive.org/web/20170629211207/https://www.ohio.edu/outlook/08-09/November/194.cfm |archive-date = 2017-06-29 | access-date = 2022-01-06 | url-status = dead | work = [[Organization:Ohio University|Ohio University]] | df = dmy-all }}</ref>

Urea in concentrations up to 8&nbsp;M can be used to make fixed brain tissue transparent to visible light while still preserving fluorescent signals from labeled cells. This allows for much deeper imaging of neuronal processes than previously obtainable using conventional one photon or two photon confocal microscopes.<ref>{{cite journal | vauthors = Hama H, Kurokawa H, Kawano H, Ando R, Shimogori T, Noda H, Fukami K, Sakaue-Sawano A, Miyawaki A | title = Scale: a chemical approach for fluorescence imaging and reconstruction of transparent mouse brain | journal = Nature Neuroscience | volume = 14 | issue = 11 | pages = 1481–8 | date = August 2011 | pmid = 21878933 | doi = 10.1038/nn.2928 | s2cid = 28281721 }}</ref>

===Medical use===
[[Chemistry:Urea-containing cream|Urea-containing cream]]s are used as topical dermatological products to promote [[Medicine:Fluid replacement|rehydration]] of the [[Biology:Skin|skin]]. Urea 40% is indicated for [[Medicine:Psoriasis|psoriasis]], xerosis, [[Medicine:Onychomycosis|onychomycosis]], [[Medicine:Ichthyosis|ichthyosis]], eczema, keratosis, keratoderma, corns, and calluses. If covered by an occlusive dressing, 40% urea preparations may also be used for nonsurgical [[Medicine:Debridement|debridement]] of nails. Urea 40% "dissolves the intercellular matrix"<ref>{{cite web|url=http://www.odanlab.com/urisec/winter/|title=UriSec 40 How it Works|date=January 2009|publisher=Odan Laboratories|access-date=February 15, 2011|archive-date=2 February 2011|archive-url=https://web.archive.org/web/20110202150107/http://www.odanlab.com/urisec/winter/|url-status=dead}}</ref><ref name="Urea40">{{cite web |url=https://odanlab.com/product/urisec-40/ |title=UriSec 40% Cream |publisher=Odan Laboratories |access-date=August 20, 2021}}</ref> of the nail plate. Only diseased or dystrophic nails are removed, as there is no effect on healthy portions of the nail.<ref>{{Cite book |last=Habif |first=Thomas P. |url=https://books.google.com/books?id=kDWlWR5UbqQC&dq=Urea+removed+dystrophic+nails&pg=PA961 |title=Clinical Dermatology E-Book |date=2009-11-25 |publisher=Elsevier Health Sciences |isbn=978-0-323-08037-8 |language=en}}</ref> This drug (as carbamide peroxide) is also used as an earwax removal aid.<ref name="WebMD-eardrops">{{cite web |title=Carbamide Peroxide Drops GENERIC NAME(S): CARBAMIDE PEROXIDE |url=https://www.webmd.com/drugs/2/drug-3616/carbamide-peroxide-otic-ear/details |publisher=WebMD |access-date=August 19, 2021}}</ref>

Urea has also been studied as a [[Chemistry:Diuretic|diuretic]]. It was first used by Dr. W. Friedrich in 1892.<ref>{{cite journal | vauthors = Crawford JH, McIntosh JF | title = The use of urea as a diuretic in advanced heart failure | journal = Archives of Internal Medicine | volume = 36 | issue = 4 | pages = 530–541 | location = New York | date = 1925 | doi = 10.1001/archinte.1925.00120160088004 }}
</ref> In a 2010 study of ICU patients, urea was used to treat euvolemic [[Medicine:Hyponatremia|hyponatremia]] and was found safe, inexpensive, and simple.<ref>{{cite journal | vauthors = Decaux G, Andres C, Gankam Kengne F, Soupart A | title = Treatment of euvolemic hyponatremia in the intensive care unit by urea | journal = Critical Care | volume = 14 | issue = 5 | pages = R184 | date = 14 October 2010 | pmid = 20946646 | pmc = 3219290 | doi = 10.1186/cc9292 | doi-access = free }}</ref>

Like [[Medicine:Saline|saline]], urea has been injected into the [[Biology:Uterus|uterus]] to induce [[Medicine:Abortion|abortion]], although this method is no longer in widespread use.<ref>{{cite journal | vauthors = Diggory PL | title = Induction of therapeutic abortion by intra-amniotic injection of urea | journal = British Medical Journal | volume = 1 | issue = 5739 | pages = 28–9 | date = January 1971 | pmid = 5539139 | pmc = 1794772 | doi = 10.1136/bmj.1.5739.28 }}</ref>

The [[Chemistry:Blood urea nitrogen|blood urea nitrogen]] (BUN) test is a measure of the amount of nitrogen in the blood that comes from urea. It is used as a marker of [[Medicine:Renal function|renal function]], though it is inferior to other markers such as [[Chemistry:Creatinine|creatinine]] because blood urea levels are influenced by other factors such as diet, dehydration,<ref>{{cite journal | vauthors = Traynor J, Mactier R, Geddes CC, Fox JG | title = How to measure renal function in clinical practice | journal = BMJ | volume = 333 | issue = 7571 | pages = 733–7 | date = October 2006 | pmid = 17023465 | pmc = 1592388 | doi = 10.1136/bmj.38975.390370.7c }}</ref> and liver function.

Urea has also been studied as an excipient in Drug-coated Balloon (DCB) coating formulation to enhance local drug delivery to stenotic blood vessels.<ref>{{Cite journal|last1=Werk Michael|last2=Albrecht Thomas|last3=Meyer Dirk-Roelfs|last4=Ahmed Mohammed Nabil|last5=Behne Andrea|last6=Dietz Ulrich|last7=Eschenbach Götz|last8=Hartmann Holger|last9=Lange Christian|date=2012-12-01|title=Paclitaxel-Coated Balloons Reduce Restenosis After Femoro-Popliteal Angioplasty|journal=Circulation: Cardiovascular Interventions|volume=5|issue=6|pages=831–840|doi=10.1161/CIRCINTERVENTIONS.112.971630|pmid=23192918|doi-access=free}}</ref><ref>{{Cite journal|last=Wöhrle|first=Jochen|date=2012-10-01|title=Drug-Coated Balloons for Coronary and Peripheral Interventional Procedures|journal=Current Cardiology Reports|volume=14|issue=5|pages=635–641|doi=10.1007/s11886-012-0290-x|pmid=22825918|s2cid=8879713}}</ref> Urea, when used as an [[Chemistry:Excipient|excipient]] in small doses (~3&nbsp;μg/mm<sup>2</sup>) to coat DCB surface was found to form crystals that increase drug transfer without adverse toxic effects on vascular endothelial cells.<ref>{{Cite journal|last1=Kolachalama|first1=Vijaya B.|last2=Shazly|first2=Tarek|last3=Vipul C. Chitalia|last4=Lyle|first4=Chimera|last5=Azar|first5=Dara A.|last6=Chang|first6=Gary H.|date=2019-05-02|title=Intrinsic coating morphology modulates acute drug transfer in drug-coated balloon therapy|journal=Scientific Reports|volume=9|issue=1|pages=6839|doi=10.1038/s41598-019-43095-9|pmid=31048704|pmc=6497887|bibcode=2019NatSR...9.6839C}}</ref>

Urea labeled with [[Physics:Carbon-14|carbon-14]] or [[Physics:Carbon-13|carbon-13]] is used in the urea breath test, which is used to detect the presence of the bacterium ''Helicobacter pylori'' (''H. pylori'') in the [[Biology:Stomach|stomach]] and [[Biology:Duodenum|duodenum]] of humans, associated with peptic ulcers. The test detects the characteristic enzyme [[Biology:Urease|urease]], produced by ''H. pylori'', by a reaction that produces ammonia from urea. This increases the pH (reduces the acidity) of the stomach environment around the bacteria. Similar bacteria species to ''H. pylori'' can be identified by the same test in animals such as [[Biology:Ape|ape]]s, [[Biology:Dog|dog]]s, and [[Biology:Cat|cat]]s (including [[Biology:Big cat|big cat]]s).

===Miscellaneous uses===
* An ingredient in [[Chemistry:Diesel exhaust fluid|diesel exhaust fluid]] (DEF), which is 32.5% urea and 67.5% de-ionized water. DEF is sprayed into the exhaust stream of diesel vehicles to break down dangerous {{chem2|NO_{''x''}|}} [[Earth:Emission standard|emissions]] into harmless [[Chemistry:Nitrogen|nitrogen]] and [[Chemistry:Water|water]].
* A component of animal feed, providing a relatively cheap source of nitrogen to promote growth
* A non-corroding alternative to rock salt for road [[Chemistry:Deicing|de-icing]].<ref>{{cite book|title=Heavy Duty Truck Systems|date=2015|publisher=Cengage Learning|isbn=9781305073623|page=1117|url=https://books.google.com/books?id=bxrDCgAAQBAJ&pg=PA1117}}</ref> It is often the main ingredient of pet friendly salt substitutes although it is less effective than traditional rock salt or calcium chloride.<ref>{{cite book|title=Chlorides—Advances in Research and Application: 2013 Edition|date=2013|publisher=ScholarlyEditions|isbn=9781481674331|page=77|url=https://books.google.com/books?id=hydgJr0zayAC&pg=PA77}}</ref>
* A main ingredient in hair removers such as Nair and Veet
* A browning agent in factory-produced pretzels
* An ingredient in some [[Medicine:Cream (pharmaceutical)|skin cream]],<ref>{{cite web|url=http://www.dooyoo.co.uk/skin-care/lacura-multi-intensive-serum/1264192/ |title=Lacura Multi Intensive Serum – Review – Excellent value for money – Lacura Multi Intensive Serum "Aqua complete" |publisher=Dooyoo.co.uk |date=2009-06-19 |access-date=2010-12-28}}</ref> moisturizers, hair conditioners, and [[Medicine:Shampoo|shampoo]]s
* A cloud seeding agent, along with other salts<ref>{{cite journal |last1=Knollenberg |first1=Robert G. |title=Urea as an Ice Nucleant for Supercooled Clouds |journal=American Meteorological Society |date=March 1966 |volume=23 |issue=2 |page=197 |doi=10.1175/1520-0469(1966)023<0197:UAAINF>2.0.CO;2 |bibcode=1966JAtS...23..197K |doi-access=free }}</ref>
* A flame-proofing agent, commonly used in dry chemical [[Engineering:Fire extinguisher|fire extinguisher]] charges such as the urea-[[Chemistry:Potassium bicarbonate|potassium bicarbonate]] mixture
* An ingredient in many [[Medicine:Tooth whitening|tooth whitening]] products
* An ingredient in dish soap
* Along with [[Chemistry:Diammonium phosphate|diammonium phosphate]], as a yeast nutrient, for fermentation of [[Chemistry:Sugar|sugar]]s into [[Chemistry:Ethanol|ethanol]]
* A nutrient used by [[Earth:Plankton|plankton]] in ocean nourishment experiments for [[Earth:Climate engineering|geoengineering]] purposes
* As an additive to extend the working temperature and open time of hide glue
* As a solubility-enhancing and moisture-retaining additive to dye baths for textile dyeing or printing<ref>{{cite web |last1=Burch |first1=Paula E. |title=Dyeing FAQ: What is urea for, in dyeing? Is it necessary? |url=http://www.pburch.net/dyeing/FAQ/urea.shtml |website=All About Hand Dyeing |date= 13 November 1999|access-date=24 August 2020}}</ref>
* As an optical parametric oscillator in nonlinear optics<ref>{{cite web|url=https://patents.google.com/patent/US4639923A/en |title=Optical parametric oscillator using urea crystal
 |publisher=Google Patents}}</ref><ref>{{cite journal|title=Urea optical parametric oscillator |journal=Applied Physics Letters |volume=44 |issue=1 |pages=25–27 |publisher=AIP Publishing|doi=10.1063/1.94590 |year=1984 |last1=Donaldson |first1=William R. |last2=Tang |first2=C. L. |bibcode=1984ApPhL..44...25D }}</ref>

==Physiology==
Amino acids from ingested food (or produced from catabolism of muscle protein) that are used for the synthesis of proteins and other biological substances can be oxidized by the body as an alternative source of energy, yielding urea and [[Chemistry:Carbon dioxide|carbon dioxide]].<ref>{{cite journal | vauthors = Sakami W, Harrington H | title = Amino acid metabolism | journal = Annual Review of Biochemistry | volume = 32 | issue = 1 | pages = 355–98 | year = 1963 | pmid = 14144484 | doi = 10.1146/annurev.bi.32.070163.002035 }}</ref> The oxidation pathway starts with the removal of the amino group by a [[Biology:Transaminase|transaminase]]; the amino group is then fed into the [[Chemistry:Urea cycle|urea cycle]]. The first step in the conversion of amino acids into [[Biology:Metabolic waste#Nitrogen wastes|metabolic waste]] in the liver is removal of the alpha-amino nitrogen, which produces [[Chemistry:Ammonia|ammonia]]. Because ammonia is toxic, it is excreted immediately by fish, converted into [[Chemistry:Uric acid|uric acid]] by birds, and converted into urea by mammals.<ref>{{cite web | title = Urea | publisher = [[Organization:Imperial College London|Imperial College London]] | url = http://www.ch.ic.ac.uk/rzepa/mim/environmental/html/urea_text.htm | access-date = 2015-03-23 }}</ref>

Ammonia ({{chem2|NH3}}) is a common byproduct of the metabolism of nitrogenous compounds. Ammonia is smaller, more volatile, and more mobile than urea. If allowed to accumulate, ammonia would raise the [[Chemistry:PH|pH]] in cells to toxic levels. Therefore, many organisms convert ammonia to urea, even though this synthesis has a net energy cost. Being practically neutral and highly soluble in water, urea is a safe vehicle for the body to transport and excrete excess nitrogen.

Urea is synthesized in the body of many organisms as part of the [[Chemistry:Urea cycle|urea cycle]], either from the oxidation of [[Chemistry:Amino acid|amino acid]]s or from [[Chemistry:Ammonia|ammonia]]. In this cycle, amino groups donated by ammonia and {{sc|L}}-aspartate are converted to urea, while {{sc|L}}-[[Chemistry:Ornithine|ornithine]], [[Chemistry:Citrulline|citrulline]], {{sc|L}}-argininosuccinate, and {{sc|L}}-[[Chemistry:Arginine|arginine]] act as intermediates. Urea production occurs in the [[Biology:Liver|liver]] and is regulated by ''N''-acetylglutamate. Urea is then dissolved into the blood (in the [[Medicine:Reference ranges for blood tests|reference range]] of 2.5 to 6.7&nbsp;mmol/L) and further transported and excreted by the kidney as a component of [[Biology:Urine|urine]]. In addition, a small amount of urea is excreted (along with [[Chemistry:Sodium chloride|sodium chloride]] and water) in sweat.

In water, the amine groups undergo slow displacement by water molecules, producing ammonia, ammonium ions, and bicarbonate ions. For this reason, old, stale urine has a stronger odor than fresh urine.

===Humans===
The cycling of and excretion of urea by the kidneys is a vital part of mammalian metabolism. Besides its role as carrier of waste nitrogen, urea also plays a role in the countercurrent exchange system of the nephrons, that allows for reabsorption of water and critical ions from the excreted [[Biology:Urine|urine]]. Urea is reabsorbed in the inner medullary collecting ducts of the nephrons,<ref name=boron837>{{cite book |author=Walter F. Boron |title=Medical Physiology: A Cellular And Molecular Approach |publisher=Elsevier/Saunders |isbn=1-4160-2328-3 |year=2005 }} Page 837</ref> thus raising the osmolarity in the medullary interstitium surrounding the thin descending limb of the loop of Henle, which makes the water reabsorb.

By action of the [[Biology:Urea transporter 2|urea transporter 2]], some of this reabsorbed urea eventually flows back into the thin descending limb of the tubule,<ref>{{cite book | pmid = 23737200| year = 2011| vauthors = Klein J, Blount MA, Sands JM | title = Comprehensive Physiology| volume = 1| issue = 2| pages = 699–729 | doi = 10.1002/cphy.c100030| chapter = Urea Transport in the Kidney| isbn = 9780470650714}}</ref> through the collecting ducts, and into the excreted urine. The body uses this mechanism, which is controlled by the antidiuretic hormone, to create hyperosmotic urine — i.e., urine with a higher concentration of dissolved substances than the [[Biology:Blood plasma|blood plasma]]. This mechanism is important to prevent the loss of water, maintain [[Physics:Blood pressure|blood pressure]], and maintain a suitable concentration of [[Chemistry:Sodium|sodium]] ions in the blood plasma.

The equivalent nitrogen content (in [[Gram|gram]]s) of urea (in [[Mole (unit)|mmol]]) can be estimated by the conversion factor 0.028&nbsp;g/mmol.<ref>Section 1.9.2 (page 76) in: {{cite book |author=Jacki Bishop |author2=Thomas, Briony |title=Manual of Dietetic Practice |publisher=Wiley-Blackwell |year=2007 |isbn=978-1-4051-3525-2}}</ref> Furthermore, 1&nbsp;gram of nitrogen is roughly equivalent to 6.25&nbsp;grams of [[Biology:Protein|protein]], and 1&nbsp;gram of protein is roughly equivalent to 5&nbsp;grams of [[Biology:Muscle|muscle]] tissue. In situations such as muscle wasting, 1&nbsp;mmol of excessive urea in the urine (as measured by urine volume in litres multiplied by urea concentration in mmol/L) roughly corresponds to a muscle loss of 0.67&nbsp;gram.

===Other species===
In [[Biology:Marine biology|aquatic]] organisms the most common form of nitrogen waste is ammonia, whereas land-dwelling organisms convert the toxic ammonia to either urea or [[Chemistry:Uric acid|uric acid]]. Urea is found in the urine of [[Biology:Mammal|mammal]]s and [[Biology:Amphibian|amphibian]]s, as well as some fish. Birds and saurian reptiles have a different form of nitrogen metabolism that requires less water, and leads to nitrogen excretion in the form of uric acid. [[Biology:Tadpole|Tadpole]]s excrete ammonia, but shift to urea production during metamorphosis. Despite the generalization above, the urea pathway has been documented not only in mammals and amphibians, but in many other organisms as well, including birds, [[Biology:Invertebrate|invertebrate]]s, insects, plants, [[Biology:Yeast|yeast]], [[Biology:Fungi|fungi]], and even [[Biology:Microorganism|microorganism]]s.<ref>{{Cite web|last=PubChem|title=urea cycle|url=https://pubchem.ncbi.nlm.nih.gov/pathway/PlantCyc:TEA_PWY-4984|access-date=2021-06-28|website=pubchem.ncbi.nlm.nih.gov|language=en}}</ref>

==Adverse effects==
Urea can be irritating to skin, eyes, and the respiratory tract. Repeated or prolonged contact with urea in fertilizer form on the skin may cause [[Medicine:Dermatitis|dermatitis]].<ref>{{Cite book |last1=Schliemann |first1=S. |url=https://books.google.com/books?id=0yyx-DzCymIC&dq=Urea+can+be+irritating+to+skin&pg=PA52 |title=Skin Protection: Practical Applications in the Occupational Setting |last2=Elsner |first2=Peter |date=2007-01-01 |publisher=Karger Medical and Scientific Publishers |isbn=978-3-8055-8218-6 |language=en}}</ref>

High concentrations in the blood can be damaging. Ingestion of low concentrations of urea, such as are found in typical human [[Biology:Urine|urine]], are not dangerous with additional water ingestion within a reasonable time-frame. Many animals (e.g. [[Unsolved:Camel urine|camel]]s, rodents or dogs) have a much more concentrated urine which may contain a higher urea amount than normal human urine.

Urea can cause [[Biology:Algal bloom|algal bloom]]s to produce toxins, and its presence in the runoff from fertilized land may play a role in the increase of toxic blooms.<ref>{{cite journal|url=https://www.nature.com/news/2008/081027/full/news.2008.1190.html|title=Urea pollution turns tides toxic|first=Amy|last=Coombs | name-list-style = vanc |date=27 October 2008|journal=Nature|access-date=5 August 2018|doi=10.1038/news.2008.1190}}</ref>

The substance decomposes on heating above melting point, producing toxic gases, and reacts violently with strong oxidants, nitrites, inorganic chlorides, chlorites and perchlorates, causing fire and explosion.<ref>[https://www.cdc.gov/niosh/ipcsneng/neng0595.html International Chemical Safety Cards: UREA]. cdc.gov</ref>

==History==
Urea was first discovered in urine in 1727 by the Dutch scientist Herman Boerhaave,<ref>
Boerhaave called urea "sal nativus urinæ" (the native, ''i.e.'', natural, salt of urine). See:
* The first mention of urea is as "the essential salt of the human body" in: Peter Shaw and Ephraim Chambers, ''A New Method of Chemistry'' …, vol 2, (London, England: J. Osborn and T. Longman, 1727), [https://archive.org/stream/newmethodofchemi00boer#page/192/mode/2up page 193: Process LXXXVII].
* Boerhaave, Herman ''Elementa Chemicae'' …, volume 2, (Leipzig ("Lipsiae"), (Germany): Caspar Fritsch, 1732), [https://books.google.com/books?id=OH45AAAAcAAJ&pg=PA276 page 276].
* For an English translation of the relevant passage, see: Peter Shaw, ''A New Method of Chemistry'' …, 2nd ed., (London, England: T. Longman, 1741), [https://archive.org/stream/newmetchemi02boer#page/198/mode/2up/ page 198: Process CXVIII: The native salt of urine]
* Lindeboom, Gerrit A. ''Boerhaave and Great Britain'' …, (Leiden, Netherlands: E.J. Brill, 1974), [https://books.google.com/books?id=yOIUAAAAIAAJ&pg=PA51 page 51].
* Backer, H. J. (1943) "Boerhaave's Ontdekking van het Ureum" (Boerhaave's discovery of urea), ''Nederlands Tijdschrift voor Geneeskunde'' (Dutch Journal of Medicine), '''87''' : 1274–1278 (in Dutch).
</ref> although this discovery is often attributed to the {{wipe|France}} chemist Hilaire Rouelle as well as [[Biography:William Cruickshank (chemist)|William Cruickshank]].<ref>{{Cite journal | last1 = Kurzer | first1 = Frederick | last2 = Sanderson | first2 = Phyllis M. | name-list-style = vanc | year = 1956 | title = Urea in the History of Organic Chemistry | journal = Journal of Chemical Education | volume = 33 | pages = 452–459 | doi = 10.1021/ed033p452 | issue = 9 | bibcode = 1956JChEd..33..452K }}
</ref>

Boerhaave used the following steps to isolate urea:<ref>{{cite web |title=Why Pee is Cool – entry #5 – "How Pee Unites You With Rocks" |date=October 11, 2011 |url=http://www.scienceminusdetails.com/2011/10/why-pee-is-cool-entry-5-how-pee-united.html |publisher=Science minus details |access-date=August 9, 2016}}</ref><ref>{{Cite journal|last1=Kurzer|first1=Frederick|last2=Sanderson|first2=Phyllis M.|year=1956|title=Urea in the History of Organic Chemistry|journal=Journal of Chemical Education|volume=33|issue=9|at=p. 454|bibcode=1956JChEd..33..452K|doi=10.1021/ed033p452|name-list-style=vanc}}</ref>
# Boiled off water, resulting in a substance similar to fresh cream
# Used filter paper to squeeze out remaining liquid
# Waited a year for solid to form under an oily liquid
# Removed the oily liquid
# Dissolved the solid in water
# Used [[Chemistry:Recrystallization|recrystallization]] to tease out the urea

In 1828, the {{wipe|Germany}} chemist [[Biography:Friedrich Wöhler|Friedrich Wöhler]] obtained urea artificially by treating [[Chemistry:Silver cyanate|silver cyanate]] with [[Chemistry:Ammonium chloride|ammonium chloride]].<ref>Wöhler, Friedrich (1828) [http://gallica.bnf.fr/ark:/12148/bpt6k15097k/f261.image "Ueber künstliche Bildung des Harnstoffs"] (On the artificial formation of urea), ''Annalen der Physik und Chemie'', '''88''' (2) : 253–256. Available in English at [http://www.chemteam.info/Chem-History/Wohler-article.html Chem Team].
</ref><ref>
{{cite book | title = Molecules That Changed The World | last1 = Nicolaou | first1 = Kyriacos Costa | name-list-style = vanc |  first2 = Tamsyn | last2 = Montagnon | year = 2008 | publisher = Wiley-VCH | isbn = 978-3-527-30983-2 | page = 11 }}
</ref><ref>
{{cite journal | vauthors = Gibb BC | title = Teetering towards chaos and complexity | journal = Nature Chemistry | volume = 1 | issue = 1 | pages = 17–8 | date = April 2009 | pmid = 21378787 | doi = 10.1038/nchem.148 | bibcode = 2009NatCh...1...17G }}
</ref>
:{{chem2|AgNCO + [NH4]Cl → CO(NH2)2 + AgCl}}
This was the first time an organic compound was artificially synthesized from inorganic starting materials, without the involvement of living organisms. The results of this experiment implicitly discredited [[Vitalism|vitalism]], the theory that the chemicals of living organisms are fundamentally different from those of inanimate matter. This insight was important for the development of [[Chemistry:Organic chemistry|organic chemistry]]. His discovery prompted Wöhler to write triumphantly to Jöns Jakob Berzelius:
:"''I must tell you that I can make urea without the use of kidneys, either man or dog. Ammonium cyanate is urea.''"
In fact, his second sentence was incorrect. [[Chemistry:Ammonium cyanate|Ammonium cyanate]] {{chem2|[NH4]+[OCN]-}} and urea {{chem2|CO(NH2)2}} are two different chemicals with the same [[Chemistry:Empirical formula|empirical formula]] {{chem2|CON2H4}}, which are in chemical equilibrium heavily favoring urea under standard conditions.<ref>{{Cite journal | author = Shorter, J. | year = 1978 | title = The conversion of ammonium cyanate into urea—a saga in reaction mechanisms | journal = [[Organization:Chemical Society Reviews|Chemical Society Reviews]] | volume = 7 | issue = 1 | pages = 1–14 | doi = 10.1039/CS9780700001 }}</ref> Regardless, with his discovery, Wöhler secured a place among the pioneers of organic chemistry.

===Historical preparation===
Urea was first noticed by Herman Boerhaave in the early 18th century from evaporates of urine. In 1773, Hilaire Rouelle obtained crystals containing urea from human urine by evaporating it and treating it with alcohol in successive filtrations.<ref>Rouelle (1773) [https://books.google.com/books?id=q1ATAAAAQAAJ&pg=PA451 "Observations sur l'urine humaine, & sur celle de vache & de cheval, comparées ensemble"] (Observations on human urine and on that of the cow and horse, compared to each other), ''Journal de Médecine, de Chirurgie et de Pharmacie'', '''40''' : 451–468. Rouelle describes the procedure he used to separate urea from urine on pages 454–455.</ref> This method was aided by [[Biography:Carl Wilhelm Scheele|Carl Wilhelm Scheele]]'s discovery that urine treated by concentrated [[Chemistry:Nitric acid|nitric acid]] precipitated crystals. Antoine François, comte de Fourcroy and [[Biography:Louis Nicolas Vauquelin|Louis Nicolas Vauquelin]] discovered in 1799 that the nitrated crystals were identical to Rouelle's substance and invented the term "urea."<ref>Fourcroy and Vauquelin (1799) [https://books.google.com/books?id=LsrBxKHCiAwC&pg=PA48 "Extrait d’un premier mémoire des cit. Fourcroy et Vaulquelin, pour servir à l’histoire naturelle, chimique et médicale de l’urine humaine, contenant quelques faits nouveaux sur son analyse et son altération spontanée"] (Extract of a first memoir by citizens Fourcroy and Vauquelin, for use in the natural, chemical, and medical history of human urine, containing some new facts of its analysis and its spontaneous alteration), ''Annales de Chimie'', '''31''' : 48–71. On page 69, urea is named "urée".</ref><ref>Fourcroy and Vauqeulin (1800) [https://books.google.com/books?id=0zhOAAAAcAAJ&pg=PA80 "Deuxième mémoire: Pour servir à l’histoire naturelle, chimique et médicale de l’urine humaine, dans lequel on s’occupe spécialement des propriétés de la matière particulière qui le caractérise,"] (Second memoir: For use in the natural, chemical and medical history of human urine, in which one deals specifically with the properties of the particular material that characterizes it), ''Annales de Chimie'', '''32''' : 80–112; 113–162. On page 91, urea is again named "urée".</ref> Berzelius made further improvements to its purification<ref>{{cite book| last = Rosenfeld | first = Louis | name-list-style = vanc |title=Four Centuries of Clinical Chemistry|url=https://books.google.com/books?id=KPX6Yvax9jkC&pg=PA41|date=1999|publisher=CRC Press|isbn=978-90-5699-645-1|pages=41–}}</ref> and finally William Prout, in 1817, succeeded in obtaining and determining the chemical composition of the pure substance.<ref>{{cite journal| last = Prout | first = William | name-list-style = vanc |year=1817|url=https://books.google.com/books?id=3-kaAQAAMAAJ&pg=PA526 |title=Observations on the nature of some of the proximate principles of the urine; with a few remarks upon the means of preventing those diseases, connected with a morbid state of that fluid|journal=Medico-Chirurgical Transactions|volume=8|pages=526–549|pmc=2128986| pmid = 20895332 | doi = 10.1177/095952871700800123 }}</ref> In the evolved procedure, urea was precipitated as urea nitrate by adding strong nitric acid to urine. To purify the resulting crystals, they were dissolved in boiling water with charcoal and filtered. After cooling, pure crystals of urea nitrate form. To reconstitute the urea from the nitrate, the crystals are dissolved in warm water, and [[Chemistry:Barium carbonate|barium carbonate]] added. The water is then evaporated and anhydrous alcohol added to extract the urea. This solution is drained off and evaporated, leaving pure urea.

==Laboratory preparation==
Ureas in the more general sense can be accessed in the laboratory by reaction of [[Chemistry:Phosgene|phosgene]] with primary or secondary [[Chemistry:Amine|amine]]s:
:{{chem2|COCl2 + 4 RNH2 → (RNH)2CO + 2 [RNH3]+Cl-}}
These reactions proceed through an [[Chemistry:Isocyanate|isocyanate]] intermediate. Non-symmetric ureas can be accessed by the reaction of primary or secondary amines with an isocyanate.

Urea can also be produced by heating [[Chemistry:Ammonium cyanate|ammonium cyanate]] to 60&nbsp;°C.
:{{chem2|[NH4]+[OCN]- → (NH2)2CO}}

==Industrial production==
In 2020, worldwide production capacity was approximately 180 million tonnes.<ref>{{cite web |title=Urea production statistics |url=https://www.ifastat.org/supply/Nitrogen%20Products/Urea |website=www.ifastat.org |publisher=International Fertilizer Association |access-date=19 April 2023}}</ref>

For use in industry, urea is produced from synthetic [[Chemistry:Ammonia|ammonia]] and [[Chemistry:Carbon dioxide|carbon dioxide]]. As large quantities of carbon dioxide are produced during the ammonia manufacturing process as a byproduct of burning hydrocarbons to generate heat (predominantly natural gas, and less often petroleum derivatives or coal), urea production plants are almost always located adjacent to the site where the ammonia is manufactured.

===Synthesis===
[[File:THC 2003.902.071 Urea Plant.tif|thumb|right | Urea plant using ammonium carbamate briquettes, Fixed Nitrogen Research Laboratory, ca. 1930]]
The basic process, patented in 1922, is called the '''Bosch–Meiser urea process''' after its discoverers [[Biography:Carl Bosch|Carl Bosch]] and Wilhelm Meiser.<ref>{{cite patent |country=US |number=1429483 |title=Process of Manufacturing Urea |gdate=1922-09-19 |fdate=1920-07-09 |invent1=Carl Bosch |invent2=Wilhelm Meiser |assign1=BASF |url=https://patentimages.storage.googleapis.com/36/5a/32/ccce45be728586/US1429483.pdf}}</ref> The process consists of two main equilibrium reactions, with incomplete conversion of the reactants. The first is '''carbamate formation''': the fast exothermic reaction of liquid ammonia with gaseous carbon dioxide ({{chem2|CO2}}) at high temperature and pressure to form [[Chemistry:Ammonium carbamate|ammonium carbamate]] ({{chem2|[NH4]+[NH2COO]-}}):<ref name="Meessen 2012"/>

:{{chem2|2 NH3 + CO2 ⇌ [NH4]+[NH2COO]-}}{{space|5}}(Δ''H'' = −117&nbsp;kJ/mol at 110&nbsp;atm and 160&nbsp;°C)<ref name="Meessen 2012"/><ref name="Brouwer 2009">{{cite web |last1=Brouwer |first1=Mark |title=Thermodynamics of the Urea Process |url=https://ureaknowhow.com/pdflib/391_2009%2006%20Brouwer%20UreaKnowHow.com%20Thermodynamics%20of%20the%20%20Urea%20Process.pdf |website=ureaknowhow.com |access-date=26 February 2023}}</ref>
The second is '''urea conversion''': the slower endothermic decomposition of ammonium carbamate into urea and water:
:{{chem2|[NH4]+[NH2COO]- ⇌ CO(NH2)2 + H2O}}{{space|5}}(Δ''H'' = +15.5&nbsp;kJ/mol at 160–180&nbsp;°C)<ref name="Meessen 2012"/><ref name="Brouwer 2009"/>
The overall conversion of {{chem2|NH3}} and {{chem2|CO2}} to urea is exothermic, with the reaction heat from the first reaction driving the second. The conditions that favor urea formation (high temperature) have an unfavorable effect on the carbamate formation equilibrium. The process conditions are a compromise: the ill-effect on the first reaction of the high temperature (around 190&nbsp;°C) needed for the second is compensated for by conducting the process under high pressure (140–175&nbsp;bar), which favors the first reaction. Although it is necessary to compress gaseous carbon dioxide to this pressure, the ammonia is available from the ammonia production plant in liquid form, which can be pumped into the system much more economically. To allow the slow urea formation reaction time to reach equilibrium, a large reaction space is needed, so the synthesis reactor in a large urea plant tends to be a massive pressure vessel.

===Reactant recycling===
Because the urea conversion is incomplete, the urea must be separated from the unconverted reactants, including the ammonium carbamate. Various commercial urea processes are characterized by the conditions under which urea forms and the way that unconverted reactants are further processed.

====Conventional recycle processes====

In early "straight-through" urea plants, reactant recovery (the first step in "recycling") was done by letting down the system pressure to atmospheric to let the carbamate decompose back to ammonia and carbon dioxide. Originally, because it was not economic to recompress the ammonia and carbon dioxide for recycle, the ammonia at least would be used for the manufacture of other products such as [[Chemistry:Ammonium nitrate|ammonium nitrate]] or [[Chemistry:Ammonium sulfate|ammonium sulfate]], and the carbon dioxide was usually wasted. Later process schemes made recycling unused ammonia and carbon dioxide practical. This was accomplished by the "total recycle process", developed in the 1940s to 1960s and now called the "conventional recycle process". It proceeds by depressurizing the reaction solution in stages (first to 18–25 bar and then to 2–5 bar) and passing it at each stage through a steam-heated ''carbamate decomposer'', then recombining the resulting carbon dioxide and ammonia in a falling-film ''carbamate condenser'' and pumping the carbamate solution back into the urea reaction vessel.<ref name="Meessen 2012" />

==== Stripping recycle process ====

The "conventional recycle process" for recovering and reusing the reactants has largely been supplanted by a [[Chemistry:Stripping|stripping]] process, developed in the early 1960s by [[Company:Stamicarbon|Stamicarbon]] in The Netherlands, that operates at or near the full pressure of the reaction vessel. It reduces the complexity of the multi-stage recycle scheme, and it reduces the amount of water recycled in the carbamate solution, which has an adverse effect on the equilibrium in the urea conversion reaction and thus on overall plant efficiency. Effectively all new urea plants use the stripper, and many total recycle urea plants have converted to a stripping process.<ref name="Meessen 2012"/><ref name="Meessen 2014">{{cite journal |last=Meessen |first=Jozef |title=Urea synthesis |journal=Chemie Ingenieur Technik |publisher=Wiley |volume=86 | issue=12| date=2014 |issn=0009-286X |doi=10.1002/cite.201400064 |pages=2180–2189|doi-access=free }}</ref>

In the conventional recycle processes, carbamate decomposition is promoted by reducing the overall pressure, which reduces the partial pressure of both ammonia and carbon dioxide, allowing these gasses to be separated from the urea product solution. The stripping process achieves a similar effect without lowering the overall pressure, by suppressing the partial pressure of just one of the reactants in order to promote carbamate decomposition. Instead of feeding carbon dioxide gas directly to the urea synthesis reactor with the ammonia, as in the conventional process, the stripping process first routes the carbon dioxide through the stripper. The stripper is a carbamate decomposer that provides a large amount of gas-liquid contact. This flushes out free ammonia, reducing its partial pressure over the liquid surface and carrying it directly to a carbamate condenser (also under full system pressure). From there, reconstituted ammonium carbamate liquor is passed to the urea production reactor. That eliminates the medium-pressure stage of the conventional recycle process.<ref name="Meessen 2012"/><ref name="Meessen 2014"/>

=== Side reactions ===
The three main side reactions that produce impurities have in common that they decompose urea.

Urea hydrolyzes back to ammonium carbamate in the hottest stages of the synthesis plant, especially in the stripper, so residence times in these stages are designed to be short.<ref name="Meessen 2012"/>

[[Chemistry:Biuret|Biuret]] is formed when two molecules of urea combine with the loss of a molecule of ammonia.
:{{chem2|2 NH2CONH2 → NH2CONHCONH2 + NH3}}
Normally this reaction is suppressed in the synthesis reactor by maintaining an excess of ammonia, but after the stripper, it occurs until the temperature is reduced.<ref name="Meessen 2012"/> Biuret is undesirable in urea fertilizer because it is toxic to crop plants to varying degrees,<ref name="Mikkelsen 1990">{{cite journal | last=Mikkelsen | first=R. L | title=Biuret in urea fertilizer | journal=Fertilizer Research | volume=26 | issue=1–3 | year=1990 | issn=0167-1731 | doi=10.1007/bf01048769 | pages=311–318| s2cid=5970745 }}</ref> but it is sometimes desirable as a nitrogen source when used in animal feed.<ref>{{cite journal | last1=Fonnesbeck | first1=Paul V. | last2=Kearl | first2=Leonard C. | last3=Harris | first3=Lorin E. | title=Feed Grade Biuret as a Protein Replacement for Ruminants. A Review | journal=Journal of Animal Science | publisher=Oxford University Press (OUP) | volume=40 | issue=6 | date=1975 | issn=0021-8812 | doi=10.2527/jas1975.4061150x | pages=1150–1184 | url=https://academic.oup.com/jas/article-abstract/40/6/1150/4699012}}</ref>

[[Chemistry:Isocyanic acid|Isocyanic acid]] HNCO and [[Chemistry:Ammonia|ammonia]] {{chem2|NH3}} results from the thermal decomposition of [[Chemistry:Ammonium cyanate|ammonium cyanate]] {{chem2|[NH4]+[OCN]-}}, which is in [[Chemistry:Chemical equilibrium|chemical equilibrium]] with urea:
:{{chem2|CO(NH2)2 → [NH4]+[OCN]- → HNCO + NH3}}
This decomposition is at its worst when the urea solution is heated at low pressure, which happens when the solution is concentrated for prilling or granulation (see below). The reaction products mostly volatilize into the overhead vapours, and recombine when these condense to form urea again, which contaminates the process condensate.<ref name="Meessen 2012"/>

=== Corrosion ===

[[Chemistry:Ammonium carbamate|Ammonium carbamate]] solutions are highly corrosive to metallic construction materials – even to resistant forms of [[Chemistry:Stainless steel|stainless steel]] – especially in the hottest parts of the synthesis plant such as the stripper. Historically [[Chemistry:Corrosion|corrosion]] has been minimized (although not eliminated) by continuous injection of a small amount of [[Chemistry:Oxygen|oxygen]] (as air) into the plant to establish and maintain a [[Engineering:Passivation|passive]] oxide layer on exposed stainless steel surfaces. Highly corrosion resistant materials have been introduced to reduce the need for passivation oxygen, such as specialized duplex stainless steels in the 1990s, and [[Chemistry:Zirconium|zirconium]] or zirconium-clad titanium tubing in the 2000s.<ref name="Meessen 2012"/>

=== Finishing ===

Urea can be produced in solid forms ([[Chemistry:Prill|prill]]s, granules, pellets or crystals) or as solutions.

==== Solid forms ====

For its main use as a fertilizer urea is mostly marketed in solid form, either as prills or granules. Prills are solidified droplets, whose production predates satisfactory urea granulation processes. Prills can be produced more cheaply than granules, but the limited size of prills (up to about 2.1&nbsp;mm in diameter), their low crushing strength, and the caking or crushing of prills during bulk storage and handling make them inferior to granules. Granules are produced by acretion onto urea seed particles by spraying liquid urea in a succession of layers. [[Physics:Formaldehyde|Formaldehyde]] is added during the production of both prills and granules in order to increase crushing strength and suppress caking. Other shaping techniques such as pastillization (depositing uniform-sized liquid droplets onto a cooling conveyor belt) are also used.<ref name="Meessen 2012"/>

==== Liquid forms ====

Solutions of [[Chemistry:UAN|urea and ammonium nitrate]] in water (UAN) are commonly used as a liquid fertilizer. In admixture, the combined solubility of ammonium nitrate and urea is so much higher than that of either component alone that it gives a stable solution with a total nitrogen content (32%) approaching that of solid ammonium nitrate (33.5%), though not, of course, that of urea itself (46%). UAN allows use of ammonium nitrate without the explosion hazard.<ref name="Meessen 2012"/> In UAN accounts for 80% of the liquid fertilizers in the US.<ref name="Ren 2021">{{cite journal | last1=Ren | first1=Baizhao | last2=Guo | first2=Yanqing | last3=Liu | first3=Peng | last4=Zhao | first4=Bin | last5=Zhang | first5=Jiwang | title=Effects of Urea-Ammonium Nitrate Solution on Yield, N2O Emission, and Nitrogen Efficiency of Summer Maize Under Integration of Water and Fertilizer | journal=Frontiers in Plant Science | volume=12 | date=2021-08-03 | page=700331 | issn=1664-462X | doi=10.3389/fpls.2021.700331 | pmid=34413867 | pmc=8369924 | doi-access=free }}</ref>

== See also ==
* [[Chemistry:Wöhler synthesis|Wöhler urea synthesis]]
* [[Chemistry:Thiourea|Thiourea]]

== References ==
{{Reflist|30em}}

==External links==
* {{PPDB|1728}}

{{Blood substitutes and perfusion solutions}}
{{Functional Groups}}
{{E number infobox 920-929}}

[[Category:Nitrogen cycle]]
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{{Sourceattribution|Urea}}