Urea1

[57-13-6]  · CH4N2O  · Urea  · (MW 60.07)

(nitrogen nucleophile; carbonyl cation equivalent; formation of inclusion complexes is used to purify long, slender compounds)

Physical Data: mp 132.7-132.9 °C; d 1.335 g cm-3.

Solubility: sol H2O (108 g/100 mL at 20 °C), EtOH (5.4 g/100 mL at 20 °C), MeOH (22 g/100 mL at 20 °C).

Form Supplied in: colorless solid.

Purification: reagent graded commercial products are sufficiently pure for most purposes. For further purification, see Perrin and Armarego.2

Nitrogen Nucleophile.

The three heteroatoms of urea, i.e. two nitrogens and an oxygen, are moderately nucleophilic. A number of highly regioselective alkylation reactions of urea have been developed. In most cases, the nitrogen atom is alkylated to afford the corresponding ureides or amino compounds. On heating a mixture of a carboxylic acid and urea (1) at around 160 °C, the corresponding amide is obtained (eq 1).3,4 In the presence of Triphenyl Phosphite and Pyridine, aromatic carboxylic acids react with urea at lower temperatures to give the corresponding arylcarbonylureas in good yields (eq 2).5

Urea serves as a nitrogen nucleophile toward tertiary carbocationic species to give N-t-alkylureas;6,7 for example, the t-butyl cation, generated by treatment of t-BuOH with H2SO4, is trapped with urea to give t-BuNHCONH2, a useful precursor of t-Butylamine (eqs 3 and 4).6

Urea reacts with orthoesters and related compounds to form alkylideneurea derivatives. The reaction with N,N-Dimethylformamide Diethyl Acetal gives N-carbamoyl-N,N-dimethylamidine (eq 5).8 Active methylene compounds may further participate in the condensation reaction of Triethyl Orthoformate and urea to form ureidomethylene derivatives (eq 6).9 Treatment of urea with Chlorine in the presence of Calcium Carbonate provides monochlorourea, which may be utilized as a source of Hypochlorous Acid (eq 7).10,11

Under mild conditions, urea undergoes nucleophilic addition to carbon-carbon triple bonds (eq 8)12 and double bonds (eq 9)13 activated by the coordination of PdII species. Under 1 atm of Carbon Monoxide, intramolecular aminocarbonylation proceeds at 0 °C to room temperature to provide protected b-amino acids (eq 9).13

Two of the three heteronucleophilic centers of urea react with difunctionalized carbonyl compounds (e.g. dicarbonyl compounds, a-halo- or a-hydroxy carbonyl compounds, and a,b-unsaturated carbonyl compounds) to furnish a wide range of nitrogen heterocycles. The dicarbonyl compounds include Glyoxal, a-diketones (eqs 10 and 11),14-16 a-keto esters (eq 12),17 oxalic and malonic esters (eq 13),18,19 b-diketones (eq 14),20 and b-keto esters (eq 15).21 A three component connection reaction of urea, aldehydes, and b-keto esters provides dihydropyrimidines (Biginelli reaction) (eq 16).22

The reaction of urea and carbonyl compounds with a-substituents, such as a-hydroxy ketones23 and a-halo ketones,11 may afford either imidazol-2-one derivatives (eq 17) or oxazole derivatives (eq 18).24 The latter is a rare example of the N,O-dialkylation of urea.

a,b-Unsaturated ketones and acids react with urea to give dihydropyrimidine derivatives (eq 19)25 and dihydrouracils (eq 20),26 respectively. a,b-Unsaturated aldehydes and ketones with b-substituents, such as alkoxy,27 amino,28 halogeno,29 trichloromethyl,30 etc.,31 provide substituted pyrimidines (eq 21).

Carbonyl Cation Equivalent.

In the reaction with heteronucleophiles, urea acts as a carbonyl cation or dication equivalent, like phosgene and carbonates, though requiring more drastic conditions. N-Substituted or N,N-disubstituted ureas can be prepared by transamination of the urea nitrogen atoms with primary amines (eqs 22 and 23).32 Reaction of urea with vic-diamines (eq 24)33 and 2-aminophenols (eq 25)34 gives imidazolidin-2-ones and oxazolidin-2-ones, respectively. The reaction with aliphatic 2-amino alcohols, on the other hand, gives imidazolidin-2-ones via substitution by the hydroxyl group for a nitrogen of urea (eq 26).35,36 The cis-1,5-dimethyl-4-phenylimidazolidin-2-ones, obtained by fusing (-)- or (+)-ephedrine hydrochloride and urea, are useful chiral auxiliaries for asymmetric syntheses.36

Catalyst.

The conversion of Tetracyanoethylene into dicyanoketene acetals is catalyzed by urea (eq 27).37

Inclusion Compounds (Differentiation of Linear Compounds from Branched Ones).1,38

Urea forms inclusion complexes, taking normal alkanes having six or more carbon atoms as guests.39 In the complexes, hydrogen bonded urea molecules are oriented in a helical lattice, constructing a cylinder-shaped channel. The guest molecule is not bonded to the host but merely trapped in the cylinder. The diameter of the channel is usually about 5.25 Å. Aliphatic hydrocarbons with a single methyl branch, such as 3-methylhexadecane, that form the complex require a channel diameter of about 5.5 Å. This seems the upper limit of thickness. Not only hydrocarbons but many kinds of functionalized alkanes can be included if they are long and slender enough. Compounds that form inclusion complexes include 1-bromohexane, 1- and 2-octanol, 2-heptanone, 1-cyclopentylnonane, and 2-, 3-, and 4- methyltridecane. On the other hand, the following compounds do not form the complex: 3-ethyldodecane, 2-bromooctane, 1-cyclohexyloctane, and 2,4-dimethyldodecane.40 Thus linear compounds, as in the former group, can be separated from a mixture with small or branched ones such as in the latter. syn-9,10-Dihydroxystearic acid has been separated from its anti counterpart.41 The syn-diol (mp 95 °C), which is estimated to require a channel diameter of 5.4 Å, readily forms a urea complex. On the other hand, the anti-diol (mp 131 °C), which requires a channel diameter of 6 Å, does not form a complex.38

Related Reagents.

Hydrogen Peroxide-Urea.


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Yoshinao Tamaru & Keigo Fugami

Nagasaki University, Japan



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