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Within the area of organocatalysis, (thio)urea organocatalysis describes the use of ureas and thioureas to accelerate and stereochemically alter organic transformations. The effects arise through hydrogen-bonding interactions between the substrate and the (thio)urea. Unlike classical catalysts, these organocatalysts interact by non-covalent interactions, especially hydrogen bonding ("partial protonation"). The scope of these small-molecule H-bond donors termed (thio)urea organocatalysis covers both non-stereoselective and stereoselective applications.[1]


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

Catalyst-substrate interactionsEdit

Hydrogen-bonding between thiourea derivatives and carbonyl substrates involve two hydrogen bonds provided by coplanar amino substituents in the (thio)urea.[2][3][4]
[5] Squaramides engage in double H-bonding interactions and are often superior to thioureas.[6]

Ketone complex with Schreiner's N,N'-bis[3,5-bis(trifluoromethyl)phenyl thiourea. The double hydrogen-bonding, clamp-like binding motif is evident.[4][7]

Advantages of thiourea organocatalystsEdit

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%)[3]
  • high TOF (Turn-Over-Frequency) values (up to 5,700 h−1)[3]
  • 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 [3]
  • catalysis under almost neutral conditions (pka 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.[8]


H-bond accepting substrates include carbonyl compounds, imines, nitroalkenes. The Diels-Alder reaction is one process that can benefit from (thio)urea catalysts.


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

Further readingEdit

  • Christian M. Kleiner, Peter R. Schreiner (2006). "Hydrophobic amplification of noncovalent organocatalysis". Chem. Commun.: 4315–4017.
  • Z. Zhang and P. R. Schreiner (2007). "Thiourea-Catalyzed Transfer Hydrogenation of Aldimines". Synlett. 2007 (9): 1455–1457. doi:10.1055/s-2007-980349.
  • Wanka, Lukas; Chiara Cabrele; Maksims Vanejews; Peter R. Schreiner (2007). "γ-Aminoadamantanecarboxylic Acids Through Direct C–H Bond Amidations". European Journal of Organic Chemistry. 2007 (9): 1474–1490. doi:10.1002/ejoc.200600975. ISSN 1434-193X.


  1. ^ Kotke, Mike; Schreiner, Peter R. (October 2009). "(Thio)urea Organocatalysts". In Petri M. Pihko (ed.). Hydrogen Bonding in Organic Synthesis. pp. 141 to 251. ISBN 978-3-527-31895-7.
  2. ^ Alexander Wittkopp, Peter R. Schreiner, "Diels-Alder Reactions in Water and in Hydrogen-Bonding Environments", book chapter in "The Chemistry of Dienes and Polyenes" Zvi Rappoport (Ed.), Volume 2, John Wiley & Sons Inc.; Chichester, 2000, 1029-1088. ISBN 0-471-72054-2.
    Alexander Wittkopp, "Organocatalysis of Diels-Alder Reactions by Neutral Hydrogen Bond Donors in Organic and Aqueous Solvents", dissertation written in German, Universität Göttingen, 2001. English abstract/download: [1]
    Peter R. Schreiner, review: "Metal-free organocatalysis through explicit hydrogen bonding interactions", Chem. Soc. Rev. 2003, 32, 289-296. abstract/download:[2]
    M. Kotke and P. R. Schreiner (2006). "Acid-free, organocatalytic acetalization". Tetrahedron. 62 (2–3): 434–439. doi:10.1016/j.tet.2005.09.079.M. P. Petri (2004). "Activation of Carbonyl Compounds by Double Hydrogen Bonding: An Emerging Tool in Asymmetric Catalysis". Angewandte Chemie International Edition. 43 (16): 2062–2064. doi:10.1002/anie.200301732. PMID 15083451.
    Yoshiji Takemoto, review: "Recognition and activation by ureas and thioureas: stereoselective reactions using ureas and thioureas as hydrogen-bonding donors", Org. Biomol. Chem. 2005, 3, 4299-4306. abstract/download: [3]Mark S. Taylor, Eric N. Jacobsen (2006). "Asymmetric Catalysis by Chiral Hydrogen-Bond Donors". Angewandte Chemie International Edition. 45 (10): 1520–1543. doi:10.1002/anie.200503132. PMID 16491487.J. C. Stephen (2006). "Organocatalysis Mediated by (Thio)urea Derivatives". Chemistry: A European Journal. 12 (21): 5418–5427. doi:10.1002/chem.200501076. PMID 16514689.
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