Thiourea organocatalysis explained

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 reactions.^[1]

Catalyst-substrate interactions

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]} Squaramide catalysts engage in double H-bonding interactions and are often superior to thioureas.^[6]

Thioureas are often found to be stronger hydrogen-bond donors (i.e., more acidic) than ureas^[7] because their amino groups are more positively charged. Quantum chemical analyses revealed that this counterintuitive phenomenon, which is not explainable by the relative electronegativities of O and S, results from the effective steric size of the chalcogen atoms.^[8]

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“
• 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
• 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.^[9]

Substrates

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

History

Early 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-bis3,5-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 ring
• the 3,5-bis(trifluoromethyl)phenyl-group is the preferred substituent

Catalysts

A broad variety of monofunctional and bifunctional (concept of bifunctionality) chiral double hydrogen-bonding (thio)urea organocatalysts have been developed.

See also

• Organocatalysis
• Hydrogen-bond catalysis
• Squaramide catalysis

Further reading

• Christian M. Kleiner, Peter R. Schreiner. Hydrophobic amplification of noncovalent organocatalysis. Chem. Commun.. 2006. 4315–4017.
• Z. Zhang and P. R. Schreiner . Thiourea-Catalyzed Transfer Hydrogenation of Aldimines . 2007 . . 2007. 9 . 1455–1457 . 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. 1434-193X. 10.1002/ejoc.200600975.

Notes and References

1. Book: Kotke. Mike. Schreiner. Peter R.. Hydrogen Bonding in Organic Synthesis. http://eu.wiley.com/WileyCDA/WileyTitle/productCd-352731895X.html. October 2009. 978-3-527-31895-7. 141 to 251. (Thio)urea Organocatalysts. Petri M. Pihko.
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. .
   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: http://webdoc.sub.gwdg.de/diss/2001/wittkopp/index.html
   Peter R. Schreiner, review: "Metal-free organocatalysis through explicit hydrogen bonding interactions", Chem. Soc. Rev. 2003, 32, 289-296. abstract/download:http://www.rsc.org/Publishing/Journals/CS/article.asp?doi=b107298f
   M. Kotke and P. R. Schreiner . 2006 . Acid-free, organocatalytic acetalization . . 62 . 2–3 . 434–439 . 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 . . 43 . 16 . 2062–2064 . 10.1002/anie.200301732 . 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: http://rsc.org/Publishing/Journals/OB/article.asp?doi=b511216hMark S. Taylor, Eric N. Jacobsen . 2006 . Asymmetric Catalysis by Chiral Hydrogen-Bond Donors . Angewandte Chemie International Edition . 45 . 10 . 1520–1543 . 10.1002/anie.200503132 . 16491487. J. C. Stephen . 2006 . Organocatalysis Mediated by (Thio)urea Derivatives . . 12 . 21 . 5418–5427 . 10.1002/chem.200501076 . 16514689.
3. Kotke. Mike. Peter Schreiner . 2007. Generally Applicable Organocatalytic Tetrahydropyranylation of Hydroxy Functionalities with Very Low Catalyst Loading. Synthesis. 2007. 5. 779–790. 0039-7881. 10.1055/s-2007-965917.
4. Schreiner. Peter R.. Alexander Wittkopp . 2002. H-Bonding Additives Act Like Lewis Acid Catalysts. Organic Letters. 4. 2. 217–220. 1523-7060. 11796054. 10.1021/ol017117s.
5. Book: Kotke, Mike. Hydrogen-Bonding (Thio)urea Organocatalysts in Organic Synthesis : State of the art and Practical Methods for Acetalization, Tetrahydropyranylation, and Cooperative Epoxide Alcoholysis. 2010-11-12. Ph.D.. 2009. University Giessen/Germany.
6. Chauhan, P. . Mahajan, S. . Kaya, U. . Hack, D. . Enders, D. . Bifunctional Amine-Squaramides: Powerful Hydrogen-Bonding Organocatalysts for Asymmetric Domino/Cascade Reactions. Adv. Synth. Catal.. 2015. 357. 2–3. 253–281. 10.1002/adsc.201401003.
7. Jakab . Gergely . Tancon . Carlo . Zhang . Zhiguo . Lippert . Katharina M. . Schreiner . Peter R. . (Thio)urea Organocatalyst Equilibrium Acidities in DMSO . Organic Letters . 2012 . 14 . 7 . 1724–1727 . 10.1021/ol300307c.
8. Nieuwland . Celine . Fonseca Guerra . Célia . How the Chalcogen Atom Size Dictates the Hydrogen‐Bond Donor Capability of Carboxamides, Thioamides, and Selenoamides . Chemistry – A European Journal . 2022 . 28 . 31 . e202200755 . 10.1002/chem.202200755. 1887/3512406 . free .
9. A. Wittkopp and P. R. Schreiner . Metal-Free, Noncovalent Catalysis of Diels-Alder Reactions by Neutral Hydrogen Bond Donors in Organic Solvents and in Water . 2003 . . 9 . 2 . 407–414 . 10.1002/chem.200390042 . 12532289.