Synthesis of Ureas

Wohler s classical synthesis of urea from ammonium cyanate may be carried out by evaporating solutions of sodium cyanate and ammonium sulphate ... 

A similar reaction in which ammonia and carbon dioxide are heated under pres sure IS the basis of the industrial synthesis of urea Here the reactants first combine yielding a salt called ammonium carbamate... 

The hydroxyl derivative of X-CN is cyanic acid HO-CN it cannot be prepared pure due to rapid decomposition but it is probably present to the extent of about 3% when its tautomer, isocyanic acid (HNCO) is prepared from sodium cyanate and HCI. HNCO rapidly trimerizes to cyanuric acid (Fig. 8.25) from which it can be regenerated by pyrolysis. It is a fairly strong acid (Ka 1.2 x 10 at 0°) freezing at —86.8° and boiling at 23.5°C. Thermolysis of urea is an alternative route to HNCO and (HNCO)3 the reverse reaction, involving the isomerization of ammonium cyanate, is the clas.sic synthesis of urea by F. Wohler (1828) ... 

Ammonia and primary and secondary amines can be added to isocyanates to give substituted ureas. Isothiocyanates give thioureas. This is an excellent method for the preparation of ureas and thioureas, and these compounds are often used as derivatives for primary and secondary amines. Isocyanic acid (HNCO) also gives the reaction usually its salts (e.g., NaNCO) are used. Wohler s famous synthesis of urea involved the addition of ammonia to a salt of this acid. "... 

Figure 4.13 Piot showing the cumuiative growth of organic reactions discovered that are above and beiow the goiden atom economicai threshoid with the year of their discovery since Wbhier s synthesis of urea in 1 828.

The term organic chemistry was first used by the Swedish chemist Berzelius in 1807 (Larsson, 1981). He coined the name to describe the chemistry of substances derived from living matter. Berzelius was a staunch believer in the vis vitalis theory, which held that such substances were endowed with a mystical vital force that precluded their synthesis in the laboratory from materials of mineral origin. Ironically, it was a student of Berzelius, Wohler, who heralded the demise of vitalism with his synthesis of urea from ammonium cyanate (Wohler, 1928). In a letter to Berzelius in 1828, Wohler wrote I must tell you that I can make urea without requiring kidneys, or even an animal, whether a human being or a dog . 

For conversion of amide to other acid derivatives, a novel synthesis of urea glycosides in aqueous media has been reported via the reaction of Steyermark s glucosyl carbamate with amines in good yields (Eq. 9.17).38 This method was successfully applied to develop a new route to the synthesis of urea-tethered neo-glycoconjugates and pseudooligosaccharides. 

Dressman BA, Singh U, Kaldor SW. Solid phase synthesis of urea libraries using a diversifiable thiophenoxy carbonyl linker. Tetrahedron Lett 1998 39 3631-3634. 

Scialdone MA, Shuey SW, Soper P, Hamuro Y, Bums DM. Phosgenated p-nitrophenyl(polystyrene)ketoxime or phoxime resin. A new resin for the solid-phase synthesis of ureas via thermolytic cleavage of oxime-carbamates. J Org Chem 1998 63 4802-4807. 

The synthesis of urea-formaldehyde resin takes place in two stages. In the first stage, urea is hydroxymethylolated by the addition of formaldehyde to the amino groups of urea (Figure 19.1). This reaction is in reality a series of reactions that lead to the formation of mono-, di-, and trimethy-lolureas. Tetramethylolurea does not appear to be produced, at least not in a detectable quantity. The addition of formaldehyde to urea takes place over the entire pH range, but the reaction rate is dependent on the pH. 

Stanley Miller at the University of Chicago more than 50 years ago. This experiment (in fact, of course, many were carried out prior to the successful one) is probably as well known as the Wohler synthesis of urea Miller s doctoral supervisor, Harold Urey (winner of the Nobel Prize in 1934), had suggested to Miller that he simulate a reducing primeval Earth atmosphere (as required by the Oparin-Haldane hypothesis) to electrical discharges and see what happens . Urey apparently expected that such an experiment would lead to a huge variety of organic compounds. 

Scheme 7.47 Synthesis of urea derivatives on a solid support.

Wohler s synthesis of urea by which a product of the living cell was first prepared artificially more than a century ago is the prototype of many addition reactions which take place with the reactive molecules of cyanic acid and its esters, as well as with the series of analogous thio-compounds. In these reactions NH3 is added to the C = N double bond ... 

The paper by Krebs and Henseleit (1932), Experiments on the Formation of Urea in Animal Bodies (Klinische Wochenschrift 11,759), contained the phrases... in the synthesis of urea in the living cell, ornithine acts like a catalyst. We therefore draw the conclusion. .. that the primary reaction for the synthesis of urea from ammonia is... 

Wohler. Synthesis of urea from ammonium cyanate. Microscopic examination of plant and animal cells by Dutrochet, Schlieden, and Schwann led to acceptance of the cellular origin of all tissues. ... 

After Dalton, the word synthesis was not usually used yet in chemical parlance. Berzelius (1779-1848), Dumas (1800-1884) and even Wohler (1800-1882) refer to the classical synthesis of urea -achieved in 1828 by Wohler himself-as an artificial production or formation of an organic compound. Only after the publications by Kolbe (1818-1884), Frankland (1825-1899) and Bertholet (1827-1907) was the word synthesis normally used and became familiar to chemists. 

Tsipis, C. A. Karipidis, P. A. Mechanism of a Chemical Classic Quantum Chemical Investigation of the Autocatalyzed Reaction of the Serendipitous Wohler Synthesis of Urea. J. Am. Chem. Soc. 2003, 125, 2307-2318. 

The idea of describing the chemical reactions that are germane to the origin of life has a long history - particularly if one starts from Wohler s experiments in 1828 on the synthesis of urea, as recently proposed by Bada and Lazcano (2003). Wohler s reaction was a fortunate accident, in the sense that the German chemist did not have in mind any ambitious Faustian dream. In what follows some basic notions... 

The material in this chapter traced the history of organic chemistry from Wohler s synthesis of urea through Kekule s structure of benzene. The millions of organic chemicals known to exist can be classified into a relatively small number of families, each defined by a common functional group. During the last century, chemists have discovered how to mimic nature to synthesize organic chemicals. A multitude of familiar products are natural or synthesized organic chemicals. 

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