Within the area of

organocatalysis In organic chemistry, organocatalysis is a form of catalysis in which the rate of a chemical reaction is increased by an organic catalyst. This "organocatalyst" consists of carbon, hydrogen, sulfur and other nonmetal elements found in organic com ...

, (thio)urea organocatalysis describes the use of

urea Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid. Urea serves an important ...

s and

thiourea Thiourea () is an organosulfur compound with the formula and the structure . It is structurally similar to urea (), except that the oxygen atom is replaced by a sulfur atom (as implied by the ''thio-'' prefix); however, the properties of urea a ...

s to accelerate and stereochemically alter organic transformations. The effects arise through

hydrogen-bonding In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a l ...

interactions between the substrate and the (thio)urea. Unlike classical catalysts, these organocatalysts interact by non-covalent interactions, especially

hydrogen bonding In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a l ...

("partial

protonation In chemistry, protonation (or hydronation) is the adding of a proton (or hydron, or hydrogen cation), (H+) to an atom, molecule, or ion, forming a conjugate acid. (The complementary process, when a proton is removed from a Brønsted–Lowry acid ...

"). The scope of these small-molecule H-bond donors termed (thio)urea

covers both non-stereoselective and stereoselective applications.

History

Pioneering contributions were made by Kelly, Etter, Jorgensen, Hine, Curran, Göbel, and De Mendoza (see review articles cited below) on

interactions of small, metal-free compounds with electron-rich binding sites. Peter R. Schreiner and co-workers identified and introduced electron-poor thiourea derivatives as hydrogen-bonding organocatalysts. Schreiner's thiourea, ''N,N''-bis 3,5-bis(trifluormethyl)phenyl thiourea, combines all structural features for double H-bonding mediated organocatalysis: * electron-poor * rigid structure * non-coordinating, electron withdrawing substituents in 3,4, and/or 5 position of a

phenyl In organic chemistry, the phenyl group, or phenyl ring, is a cyclic group of atoms with the formula C6 H5, and is often represented by the symbol Ph. Phenyl group is closely related to benzene and can be viewed as a benzene ring, minus a hydrogen ...

ring * the 3,5-bis(trifluoromethyl)phenyl-group is the preferred substituent

Catalyst-substrate interactions

Hydrogen-bonding between

derivatives and carbonyl substrates involve two hydrogen bonds provided by coplanar amino substituents in the (thio)urea.
Squaramides engage in double H-bonding interactions and are often superior to thioureas. thioureaT1coor

Advantages of thiourea organocatalysts

Thio) ureas are green and sustainable catalysts. When effective, they can offer these advantages: * absence of product inhibition due to weak enthalpic binding, but specific binding-“recognition“ * low catalyst-loading (down to 0.001 mol%) * high TOF (Turn-Over-Frequency) values (up to 5,700 h⁻¹) * simple and inexpensive synthesis from primary amine functionalized (chiral-pool) starting materials and isothiocyanates * easy to modulate and to handle (bench-stable), no inert gas atmosphere required * immobilization on a solid phase (polymer-bound organocatalysts), catalyst recovery and reusability * catalysis under almost neutral conditions (pk_a thiourea 21.0) and mild conditions, acid-sensitive substrates are tolerated * metal-free, nontoxic (compare traditional metal-containing Lewis-acid catalysts) * water-tolerant, even catalytically effective in water or aqueous media.

Substrates

H-bond accepting substrates include

carbonyl In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups. A compound containi ...

compounds,

imine In organic chemistry, an imine ( or ) is a functional group or organic compound containing a carbon–nitrogen double bond (). The nitrogen atom can be attached to a hydrogen or an organic group (R). The carbon atom has two additional single bon ...

nitroalkene A nitroalkene, or nitro olefin, is a functional group combining the functionality of its constituent parts, an alkene and nitro group, while displaying its own chemical properties through alkene activation, making the functional group useful in sp ...

s. The Diels-Alder reaction is one process that can benefit from (thio)urea catalysts.

Catalysts

A broad variety of monofunctional and bifunctional (concept of bifunctionality) chiral double hydrogen-bonding (thio)urea organocatalysts have been developed to accelerate various synthetically useful organic transformations

References