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Thiourea organocatalysis
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<h2 id="catalyst-substrate-interactions">Catalyst-substrate interactions</h2> <p>Hydrogen-bonding between <a href="/facts/Thiourea/69a3dfSc">thiourea</a> derivatives and carbonyl substrates involve two hydrogen bonds provided by coplanar amino substituents in the (thio)urea.<a class="footnote-ref" id="fnref:2" href="#fn:2"><sup>2</sup></a><a class="footnote-ref" id="fnref:3" href="#fn:3"><sup>3</sup></a><a class="footnote-ref" id="fnref:4" href="#fn:4"><sup>4</sup></a><a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a> Squaramide catalysts engage in double H-bonding interactions and are often superior to thioureas.<a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a> </p><p><a href="/facts/Thiourea/69a3dfSc">Thioureas</a> are often found to be stronger <a href="/facts/Hydrogen_bond/85V86IIg">hydrogen-bond</a> donors (<i>i.e.,</i> more acidic) than <a href="/facts/Ureas/vjgWQdjU">ureas</a><a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> because their amino groups are more positively charged. <a href="/facts/Quantum_chemistry/H9AXV0lx">Quantum chemical analyses</a> revealed that this counterintuitive phenomenon, which is not explainable by the relative <a href="/facts/Electronegativity/H7Vq7Uah">electronegativities</a> of O and S, results from the effective steric size of the <a href="/facts/Chalcogen/nXLGmnqL">chalcogen</a> atoms.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> </p> <h2 id="advantages-of-thiourea-organocatalysts">Advantages of thiourea organocatalysts</h2> <p>（Thio) ureas are <a href="/facts/Green_chemistry/7csVY28w">green and sustainable</a> catalysts. When effective, they can offer these advantages: </p> <ul><li>absence of product inhibition due to weak <a href="/facts/Enthalpy/bBou8lCE">enthalpic</a> binding, but specific binding-“recognition“</li> <li>simple and inexpensive synthesis from primary amine functionalized (chiral-pool) starting materials and isothiocyanates</li> <li>easy to modulate and to handle (bench-stable), no inert gas atmosphere required</li> <li>catalysis under almost neutral conditions (pka thiourea 21.0) and mild conditions, acid-sensitive substrates are tolerated</li> <li>metal-free, nontoxic (compare traditional metal-containing Lewis-acid catalysts)</li> <li>water-tolerant, even catalytically effective in water or aqueous media.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a></li></ul> <h2 id="substrates">Substrates</h2> <p>H-bond accepting substrates include <a href="/facts/Carbonyl/KJ71bo3X">carbonyl</a> compounds, <a href="/facts/Imine/yK72z07j">imines</a>, <a href="/facts/Nitroalkene/kXeo800I">nitroalkenes</a>. The <a href="/facts/Diels-Alder_reaction/zc6dVpKl">Diels-Alder reaction</a> is one process that can benefit from (thio)urea catalysts. </p> <h2 id="history">History</h2> <p>Early contributions were made by Kelly, Etter, Jorgensen, Hine, Curran, Göbel, and De Mendoza (see review articles cited below) on <a href="/facts/Hydrogen_bonding/85V86IIg">hydrogen bonding</a> interactions of small, metal-free compounds with electron-rich binding sites. <a href="/facts/Peter_R._Schreiner/cGdkTwDu">Peter R. Schreiner</a> and co-workers identified and introduced electron-poor thiourea derivatives as hydrogen-bonding organocatalysts. Schreiner's thiourea, <i>N,N'</i>-bis3,5-bis(trifluormethyl)phenyl thiourea, combines all structural features for double H-bonding mediated organocatalysis: </p> <ul><li>electron-poor</li> <li>rigid structure</li> <li>non-coordinating, <a href="/facts/Electron_withdrawing_group/GDzV1DXL">electron withdrawing substituents</a> in 3,4, and/or 5 position of a <a href="/facts/Phenyl/Ql9Yx5uu">phenyl</a> ring</li> <li>the 3,5-bis(trifluoromethyl)phenyl-group is the preferred <a href="/facts/Substituent/6y9IE6G0">substituent</a></li></ul> <h2 id="catalysts">Catalysts</h2> <p>A broad variety of monofunctional and bifunctional (concept of bifunctionality) chiral double hydrogen-bonding (thio)urea organocatalysts have been developed. </p> <h2 id="see-also">See also</h2> <ul><li><a href="/facts/Organocatalysis/oR5c1RDJ">Organocatalysis</a></li> <li><a href="/facts/Hydrogen-bond_catalysis/mHyVpU4k">Hydrogen-bond catalysis</a></li> <li><a href="/facts/Squaramide_catalysis/tHwBl9pl">Squaramide catalysis</a></li></ul> <h2 id="further-reading">Further reading</h2> <ul><li>Christian M. Kleiner, Peter R. Schreiner (2006). "Hydrophobic amplification of noncovalent organocatalysis". <i>Chem. Commun.</i>: 4315–4017.</li> <li>Z. Zhang and P. R. Schreiner (2007). "Thiourea-Catalyzed Transfer Hydrogenation of Aldimines". <i><a href="/facts/Synlett/HH77erof">Synlett</a></i>. 2007 (9): 1455–1457. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1055%2Fs-2007-980349">10.1055/s-2007-980349</a>.</li> <li>Wanka, Lukas; Chiara Cabrele; Maksims Vanejews; Peter R. Schreiner (2007). "γ-Aminoadamantanecarboxylic Acids Through Direct C–H Bond Amidations". <i>European Journal of Organic Chemistry</i>. 2007 (9): 1474–1490. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1002%2Fejoc.200600975">10.1002/ejoc.200600975</a>. <a href="/facts/ISSN_(identifier)/DPAflDvU">ISSN</a> <a href="https://search.worldcat.org/issn/1434-193X">1434-193X</a>.</li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Kotke, Mike; Schreiner, Peter R. (October 2009). "(Thio)urea Organocatalysts". In Petri M. Pihko (ed.). Hydrogen Bonding in Organic Synthesis. Wiley. pp. 141 to 251. ISBN 978-3-527-31895-7. <a href="978-3-527-31895-7" target="_blank">978-3-527-31895-7</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>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. <a href="/wiki/ISBN_(identifier)" target="_blank">/wiki/ISBN_(identifier)</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Kotke, Mike; Peter Schreiner (2007). "Generally Applicable Organocatalytic Tetrahydropyranylation of Hydroxy Functionalities with Very Low Catalyst Loading". Synthesis. 2007 (5): 779–790. doi:10.1055/s-2007-965917. ISSN 0039-7881. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Schreiner, Peter R.; Alexander Wittkopp (2002). "H-Bonding Additives Act Like Lewis Acid Catalysts". Organic Letters. 4 (2): 217–220. doi:10.1021/ol017117s. ISSN 1523-7060. PMID 11796054. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>Kotke, Mike (2009). Hydrogen-Bonding (Thio)urea Organocatalysts in Organic Synthesis : State of the art and Practical Methods for Acetalization, Tetrahydropyranylation, and Cooperative Epoxide Alcoholysis (Ph.D.). University Giessen/Germany. Retrieved 2010-11-12. <a href="http://geb.uni-giessen.de/geb/volltexte/2010/7835/" target="_blank">http://geb.uni-giessen.de/geb/volltexte/2010/7835/</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Chauhan, P.; Mahajan, S.; Kaya, U.; Hack, D.; Enders, D. (2015). "Bifunctional Amine-Squaramides: Powerful Hydrogen-Bonding Organocatalysts for Asymmetric Domino/Cascade Reactions". Adv. Synth. Catal. 357 (2–3): 253–281. doi:10.1002/adsc.201401003. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>Jakab, Gergely; Tancon, Carlo; Zhang, Zhiguo; Lippert, Katharina M.; Schreiner, Peter R. (2012). "(Thio)urea Organocatalyst Equilibrium Acidities in DMSO". Organic Letters. 14 (7): 1724–1727. doi:10.1021/ol300307c. PMID 22435999. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>Nieuwland, Celine; Fonseca Guerra, Célia (2022). "How the Chalcogen Atom Size Dictates the Hydrogen-Bond Donor Capability of Carboxamides, Thioamides, and Selenoamides". Chemistry – A European Journal. 28 (31): e202200755. doi:10.1002/chem.202200755. hdl:1887/3512406. PMC 9324920. PMID 35322485. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9324920" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9324920</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>A. Wittkopp and P. R. Schreiner (2003). "Metal-Free, Noncovalent Catalysis of Diels-Alder Reactions by Neutral Hydrogen Bond Donors in Organic Solvents and in Water". Chemistry: A European Journal. 9 (2): 407–414. doi:10.1002/chem.200390042. PMID 12532289. <a href="/wiki/Chemistry:_A_European_Journal" target="_blank">/wiki/Chemistry:_A_European_Journal</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li> </ol>