Organocatalysis

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Justus von Liebig's synthesis of oxamide from dicyan and water represents the first organocatalytic reaction, with acetaldehyde further identified as the first discovered pure "organocatalyst", which act similarly to the then-named "ferments", now known as enzymes. Liebig oxamid synthese erste organokat Reaktion.png
Justus von Liebig's synthesis of oxamide from dicyan and water represents the first organocatalytic reaction, with acetaldehyde further identified as the first discovered pure "organocatalyst", which act similarly to the then-named "ferments", now known as enzymes.

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 compounds. [3] [4] [5] [6] [7] [8] Because of their similarity in composition and description, they are often mistaken as a misnomer for enzymes due to their comparable effects on reaction rates and forms of catalysis involved.

Contents

Organocatalysts which display secondary amine functionality can be described as performing either enamine catalysis (by forming catalytic quantities of an active enamine nucleophile) or iminium catalysis (by forming catalytic quantities of an activated iminium electrophile). This mechanism is typical for covalent organocatalysis. Covalent binding of substrate normally requires high catalyst loading (for proline-catalysis typically 20–30 mol%). Noncovalent interactions such as hydrogen-bonding facilitates low catalyst loadings (down to 0.001 mol%).

Organocatalysis offers several advantages. There is no need for metal-based catalysis thus making a contribution to green chemistry. In this context, simple organic acids have been used as catalyst for the modification of cellulose in water on multi-ton scale. [9] When the organocatalyst is chiral an avenue is opened to asymmetric catalysis; for example, the use of proline in aldol reactions is an example of chirality and green chemistry. [10] Organic chemists David MacMillan and Benjamin List were both awarded the 2021 Nobel Prize in chemistry for their work on asymmetric organocatalysis. [11]

Introduction

Regular achiral organocatalysts are based on nitrogen such as piperidine used in the Knoevenagel condensation. [12] DMAP used in esterifications [13] and DABCO used in the Baylis-Hillman reaction. [14] Thiazolium salts are employed in the Stetter reaction. These catalysts and reactions have a long history but current interest in organocatalysis is focused on asymmetric catalysis with chiral catalysts, called asymmetric organocatalysis or enantioselective organocatalysis. A pioneering reaction developed in the 1970s is called the Hajos–Parrish–Eder–Sauer–Wiechert reaction. Between 1968 and 1997, there were only a few reports of the use of small organic molecules as catalysts for asymmetric reactions (the Hajos–Parrish reaction probably being the most famous), but these chemical studies were viewed more as unique chemical reactions than as integral parts of a larger, interconnected field. [15]

Organocatalytic1.gif

In this reaction, naturally occurring chiral proline is the chiral catalyst in an Aldol reaction. The starting material is an achiral triketone and it requires just 3% of proline to obtain the reaction product, a ketol in 93% enantiomeric excess. This is the first example of an amino acid-catalyzed asymmetric aldol reaction. [16] [17]

The asymmetric synthesis of the Wieland-Miescher ketone (1985) is also based on proline and another early application was one of the transformations in the total synthesis of Erythromycin by Robert B. Woodward (1981). [18] A mini-review digest article focuses on selected recent examples of total synthesis of natural and pharmaceutical products using organocatalytic reactions. [19]

Many chiral organocatalysts are an adaptation of chiral ligands (which together with a metal center also catalyze asymmetric reactions) and both concepts overlap to some degree.

A breakthrough in the field of organocatalysis came in 1997 when Yian Shi reported the first general, highly enantioselective organocatalytic reaction with the catalytic asymmetric epoxidation of trans- and trisubstituted olefins with chiral dioxiranes. [20] Since that time, several different types of reactions have been developed.

Organocatalyst classes

Organocatalysts for asymmetric synthesis can be grouped in several classes:

Examples of asymmetric reactions involving organocatalysts are:

Proline

Proline catalysis has been reviewed. [22] [23]

Imidazolidinone organocatalysis

Imidazolidinone Catalysts ImidazolidinoneCatalysts.svg
Imidazolidinone Catalysts

Imidazolidinones are catalysts for many transformations such as asymmetric Diels-Alder reactions and Michael additions. Chiral catalysts induce asymmetric reactions, often with high enantioselectivities. This catalyst works by forming an iminium ion with carbonyl groups of α,β-unsaturated aldehydes (enals) and enones in a rapid chemical equilibrium. This iminium activation is similar to activation of carbonyl groups by a Lewis acid and both catalysts lower the substrate's LUMO: [24] [25]

IminiumActivation.svg

The transient iminium intermediate is chiral which is transferred to the reaction product via chiral induction. The catalysts have been used in Diels-Alder reactions, Michael additions, Friedel-Crafts alkylations, transfer hydrogenations and epoxidations.

One example is the asymmetric synthesis of the drug warfarin (in equilibrium with the hemiketal) in a Michael addition of 4-hydroxycoumarin and benzylideneacetone: [26]

AsymmetricWarfarinSynthesis.svg

A recent exploit is the vinyl alkylation of crotonaldehyde with an organotrifluoroborate salt: [27]

AsymmetricVinylAlkylationLee2007.svg

For other examples of its use: see organocatalytic transfer hydrogenation and asymmetric Diels-Alder reactions.

Thiourea organocatalysis

A large group of organocatalysts incorporate the urea or the thiourea moiety. These catalytically effective (thio)urea derivatives termed (thio)urea organocatalysts provide explicit double hydrogen-bonding interactions to coordinate and activate H-bond accepting substrates. [28]

Their current uses are restricted to asymmetric multicomponent reactions, including those involving Michael addition, asymmetric multicomponent reactions for the synthesis of spirocycles, asymmetric multicomponent reactions involving acyl Strecker reactions, asymmetric Petasis reactions, asymmetric Biginelli reactions, asymmetric Mannich reactions, asymmetric aza-Henry reactions, and asymmetric reductive coupling reactions. [29]

Related Research Articles

<span class="mw-page-title-main">Enamine</span> Class of chemical compounds

An enamine is an unsaturated compound derived by the condensation of an aldehyde or ketone with a secondary amine. Enamines are versatile intermediates.

<span class="mw-page-title-main">Enantioselective synthesis</span> Chemical reaction(s) which favor one chiral isomer over another

Enantioselective synthesis, also called asymmetric synthesis, is a form of chemical synthesis. It is defined by IUPAC as "a chemical reaction in which one or more new elements of chirality are formed in a substrate molecule and which produces the stereoisomeric products in unequal amounts."

<span class="mw-page-title-main">Michael addition reaction</span> Reaction in organic chemistry

In organic chemistry, the Michael reaction or Michael 1,4 addition is a reaction between a Michael donor and a Michael acceptor to produce a Michael adduct by creating a carbon-carbon bond at the acceptor's β-carbon. It belongs to the larger class of conjugate additions and is widely used for the mild formation of carbon-carbon bonds.

<span class="mw-page-title-main">Henry reaction</span> Chemical reaction

The Henry reaction is a classic carbon–carbon bond formation reaction in organic chemistry. Discovered in 1895 by the Belgian chemist Louis Henry (1834–1913), it is the combination of a nitroalkane and an aldehyde or ketone in the presence of a base to form β-nitro alcohols. This type of reaction is also referred to as a nitroaldol reaction. It is nearly analogous to the aldol reaction that had been discovered 23 years prior that couples two carbonyl compounds to form β-hydroxy carbonyl compounds known as "aldols". The Henry reaction is a useful technique in the area of organic chemistry due to the synthetic utility of its corresponding products, as they can be easily converted to other useful synthetic intermediates. These conversions include subsequent dehydration to yield nitroalkenes, oxidation of the secondary alcohol to yield α-nitro ketones, or reduction of the nitro group to yield β-amino alcohols.

<span class="mw-page-title-main">CBS catalyst</span> Asymmetric catalyst derived from proline

The CBS catalyst or Corey–Bakshi–Shibata catalyst is an asymmetric catalyst derived from proline. It finds many uses in organic reactions such as the CBS reduction, Diels-Alder reactions and (3+2) cycloadditions. Proline, a naturally occurring chiral compound, is readily and cheaply available. It transfers its stereocenter to the catalyst which in turn is able to drive an organic reaction selectively to one of two possible enantiomers. This selectivity is due to steric strain in the transition state that develops for one enantiomer but not for the other.

The Strecker amino acid synthesis, also known simply as the Strecker synthesis, is a method for the synthesis of amino acids by the reaction of an aldehyde with cyanide in the presence of ammonia. The condensation reaction yields an α-aminonitrile, which is subsequently hydrolyzed to give the desired amino acid. The method is used for the commercial production of racemic methionine from methional.

In chemistry, transfer hydrogenation is a chemical reaction involving the addition of hydrogen to a compound from a source other than molecular H2. It is applied in laboratory and industrial organic synthesis to saturate organic compounds and reduce ketones to alcohols, and imines to amines. It avoids the need for high-pressure molecular H2 used in conventional hydrogenation. Transfer hydrogenation usually occurs at mild temperature and pressure conditions using organic or organometallic catalysts, many of which are chiral, allowing efficient asymmetric synthesis. It uses hydrogen donor compounds such as formic acid, isopropanol or dihydroanthracene, dehydrogenating them to CO2, acetone, or anthracene respectively. Often, the donor molecules also function as solvents for the reaction. A large scale application of transfer hydrogenation is coal liquefaction using "donor solvents" such as tetralin.

The Hajos–Parrish–Eder–Sauer–Wiechert and Barbas-List reactions in organic chemistry are a family of proline-catalysed asymmetric aldol reactions.

Asymmetric hydrogenation is a chemical reaction that adds two atoms of hydrogen to a target (substrate) molecule with three-dimensional spatial selectivity. Critically, this selectivity does not come from the target molecule itself, but from other reagents or catalysts present in the reaction. This allows spatial information to transfer from one molecule to the target, forming the product as a single enantiomer. The chiral information is most commonly contained in a catalyst and, in this case, the information in a single molecule of catalyst may be transferred to many substrate molecules, amplifying the amount of chiral information present. Similar processes occur in nature, where a chiral molecule like an enzyme can catalyse the introduction of a chiral centre to give a product as a single enantiomer, such as amino acids, that a cell needs to function. By imitating this process, chemists can generate many novel synthetic molecules that interact with biological systems in specific ways, leading to new pharmaceutical agents and agrochemicals. The importance of asymmetric hydrogenation in both academia and industry contributed to two of its pioneers — William Standish Knowles and Ryōji Noyori — being collectively awarded one half of the 2001 Nobel Prize in Chemistry.

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. The scope of these small-molecule H-bond donors termed (thio)urea organocatalysis covers both non-stereoselective and stereoselective applications.

In organic chemistry, the Baylis–Hillman, Morita–Baylis–Hillman, or MBH reaction is a carbon-carbon bond-forming reaction between an activated alkene and a carbon electrophile in the presence of a nucleophilic catalyst, such as a tertiary amine or phosphine. The product is densely functionalized, joining the alkene at the α-position to a reduced form of the electrophile.

<span class="mw-page-title-main">Hydrogen-bond catalysis</span>

Hydrogen-bond catalysis is a type of organocatalysis that relies on use of hydrogen bonding interactions to accelerate and control organic reactions. In biological systems, hydrogen bonding plays a key role in many enzymatic reactions, both in orienting the substrate molecules and lowering barriers to reaction. However, chemists have only recently attempted to harness the power of using hydrogen bonds to perform catalysis, and the field is relatively undeveloped compared to research in Lewis acid catalysis.

<span class="mw-page-title-main">Asymmetric counteranion directed catalysis</span> Catalysis in enantioselective synthesis

Asymmetric counteranion directed catalysis (ACDC) or chiral anion catalysis in enantioselective synthesis is the "induction of enantioselectivity in a reaction proceeding through a cationic intermediate by means of ion pairing with a chiral, enantiomerically pure anion provided by the catalyst". Although chiral Brønsted acid catalyzed reactions may well fall into this category of catalysis under the definition given here, the extent of proton transfer and the demarcation between hydrogen bonding and full proton transfer is often ambiguous. Hence, some authors may exclude ion pair formation by proton transfer as a type of chiral counteranion catalysis. The discussion below will focus on chiral ion pairs generated through means other than proton transfer.

<span class="mw-page-title-main">Synergistic catalysis</span>

Synergistic catalysis is a specialized approach to catalysis whereby at least two different catalysts act on two different substrates simultaneously to allow reaction between the two activated materials. While a catalyst works to lower the energy of reaction overall, a reaction using synergistic catalysts work together to increase the energy level of HOMO of one of the molecules and lower the LUMO of another. While this concept has come to be important in developing synthetic pathways, this strategy is commonly found in biological systems as well.

Proline organocatalysis is the use of proline as an organocatalyst in organic chemistry. This theme is often considered the starting point for the area of organocatalysis, even though early discoveries went unappreciated. Modifications, such as MacMillan’s catalyst and Jorgensen's catalysts, proceed with excellent stereocontrol.

In homogeneous catalysis, C2-symmetric ligands refer to ligands that lack mirror symmetry but have C2 symmetry. Such ligands are usually bidentate and are valuable in catalysis. The C2 symmetry of ligands limits the number of possible reaction pathways and thereby increases enantioselectivity, relative to asymmetrical analogues. C2-symmetric ligands are a subset of chiral ligands. Chiral ligands, including C2-symmetric ligands, combine with metals or other groups to form chiral catalysts. These catalysts engage in enantioselective chemical synthesis, in which chirality in the catalyst yields chirality in the reaction product.

<span class="mw-page-title-main">Dhevalapally B. Ramachary</span> Indian chemist

Dhevalapally B. RamacharyFTAS, FRSC, FASc, FNASc, also known as D. B. Ramachary, is an Indian chemist and professor at the School of Chemistry, University of Hyderabad. He has made numerous contributions in various fields of chemical science.

<span class="mw-page-title-main">Nitro-Mannich reaction</span>

The nitro-Mannich reaction is the nucleophilic addition of a nitroalkane to an imine, resulting in the formation of a beta-nitroamine. With the reaction involving the addition of an acidic carbon nucleophile to a carbon-heteroatom double bond, the nitro-Mannich reaction is related to some of the most fundamental carbon-carbon bond forming reactions in organic chemistry, including the aldol reaction, Henry reaction and Mannich reaction.

<span class="mw-page-title-main">Benjamin List</span> German chemist (born 1968)

Benjamin List is a German chemist who is one of the directors of the Max Planck Institute for Coal Research and professor of organic chemistry at the University of Cologne. He co-developed organocatalysis, a method of accelerating chemical reactions and making them more efficient. He shared the 2021 Nobel Prize in Chemistry with David MacMillan "for the development of asymmetric organocatalysis".

The ketimine Mannich reaction is an asymmetric synthetic technique using differences in starting material to push a Mannich reaction to create an enantiomeric product with steric and electronic effects, through the creation of a ketimine group. Typically, this is done with a reaction with proline or another nitrogen-containing heterocycle, which control chirality with that of the catalyst. This has been theorized to be caused by the restriction of undesired (E)-isomer by preventing the ketone from accessing non-reactive tautomers. Generally, a Mannich reaction is the combination of an amine, a ketone with a β-acidic proton and aldehyde to create a condensed product in a β-addition to the ketone. This occurs through an attack on the ketone with a suitable catalytic-amine unto its electron-starved carbon, from which an imine is created. This then undergoes electrophilic addition with a compound containing an acidic proton. It is theoretically possible for either of the carbonyl-containing molecules to create diastereomers, but with the addition of catalysts which restrict addition as of the enamine creation, it is possible to extract a single product with limited purification steps and in some cases as reported by List et al.; practical one-pot syntheses are possible. The process of selecting a carbonyl-group gives the reaction a direct versus indirect distinction, wherein the latter case represents pre-formed products restricting the reaction's pathway and the other does not. Ketimines selects a reaction group, and circumvent a requirement for indirect pathways.

References

  1. ↑ Justus von Liebig, Justus (1860). "Ueber die Bildung des Oxamids aus Cyan". Annalen der Chemie und Pharmacie. 113 (2): 246–247. doi:10.1002/jlac.18601130213.
  2. ↑ W. Langenbeck (1929). "Über organische Katalysatoren. III. Die Bildung von Oxamid aus Dicyan bei Gegenwart von Aldehyden". Liebigs Ann. 469: 16–25. doi:10.1002/jlac.19294690103.
  3. ↑ Berkessel, A.; Groeger, H. (2005). Asymmetric Organocatalysis. Weinheim: Wiley-VCH. ISBN   978-3-527-30517-9.
  4. ↑ Special Issue: List, Benjamin (2007). "Organocatalysis". Chem. Rev. 107 (12): 5413–5883. doi: 10.1021/cr078412e .
  5. ↑ Peter I. Dalko; Lionel Moisan (2004). "In the Golden Age of Organocatalysis". Angew. Chem. Int. Ed. 43 (39): 5138–5175. doi:10.1002/anie.200400650. PMID   15455437.
  6. ↑ Matthew J. Gaunt; Carin C.C. Johansson; Andy McNally; Ngoc T. Vo (2007). "Enantioselective organocatalysis". Drug Discovery Today. 12 (1/2): 8–27. doi:10.1016/j.drudis.2006.11.004. PMID   17198969.
  7. ↑ Dieter Enders; Christoph Grondal; Matthias R. M. Hüttl (2007). "Asymmetric Organocatalytic Domino Reactions". Angew. Chem. Int. Ed. 46 (10): 1570–1581. doi:10.1002/anie.200603129. PMID   17225236.
  8. ↑ Peter I. Dalko; Lionel Moisan (2001). "Enantioselective Organocatalysis". Angew. Chem. Int. Ed. 40 (20): 3726–3748. doi:10.1002/1521-3773(20011015)40:20<3726::AID-ANIE3726>3.0.CO;2-D. PMID   11668532.
  9. ↑ International Patent WO 2006068611 A1 20060629 " Direct Homogeneous and Heterogeneous Organic Acid and Amino Acid-Catalyzed Modification of Amines and Alcohols" Inventors: Armando Córdova, Stockholm, Sweden; Jonas Hafrén, Stockholm, Sweden.
  10. ↑ Example 4 in U.S. Patent 3,975,440 August 17, 1976, Filed Dec. 9, 1970 Zoltan G. Hajos and David R. Parrish.
  11. ↑ "2021 Nobel Prize in chemistry". Nobel Prize. Nobel Prize. Retrieved 6 October 2021.
  12. ↑ List, B. (2010). "Emil Knoevenagel and the Roots of Aminocatalysis". Angewandte Chemie International Edition in English. 49 (10): 1730–1734. doi:10.1002/anie.200906900. PMID   20175175.
  13. ↑ Neises, Bernhard; Steglich, Wolfgang (July 1978). "Simple Method for the Esterification of Carboxylic Acids". Angewandte Chemie International Edition in English. 17 (7): 522–524. doi:10.1002/anie.197805221.
  14. ↑ Basavaiah, Deevi; Rao, Anumolu Jaganmohan; Satyanarayana, Tummanapalli (March 2003). "Recent Advances in the Baylis−Hillman Reaction and Applications". Chemical Reviews. 103 (3): 811–892. doi:10.1021/cr010043d. PMID   12630854.
  15. ↑ MacMillan, David W. C. (2008). "The advent and development of organocatalysis". Nature. 455 (7211). Springer Science and Business Media LLC: 304–308. Bibcode:2008Natur.455..304M. doi:10.1038/nature07367. ISSN   0028-0836. PMID   18800128. S2CID   205215034.
  16. ↑ Z. G. Hajos, D. R. Parrish, German Patent DE 2102623 1971
  17. ↑ Zoltan G. Hajos; David R. Parrish (1974). "Asymmetric synthesis of bicyclic intermediates of natural product chemistry". J. Org. Chem. 39 (12): 1615–1621. doi:10.1021/jo00925a003.
  18. ↑ R. B. Woodward; E. Logusch; K. P. Nambiar; K. Sakan; D. E. Ward; B. W. Au-Yeung; P. Balaram; L. J. Browne; et al. (1981). "Asymmetric total synthesis of erythromcin. 1. Synthesis of an erythronolide A secoacid derivative via asymmetric induction". J. Am. Chem. Soc. 103 (11): 3210–3213. doi:10.1021/ja00401a049.
  19. ↑ B. -F. Sun (2015). "Total synthesis of natural and pharmaceutical products powered by organocatalytic reactions". Tetrahedron Lett. 56 (17): 2133–2140. doi: 10.1016/j.tetlet.2015.03.046 .
  20. ↑ Wang, Zhi-Xian; Tu, Yong; Frohn, Michael; Zhang, Jian-Rong; Shi, Yian (1997-11-01). "An Efficient Catalytic Asymmetric Epoxidation Method". Journal of the American Chemical Society. 119 (46): 11224–11235. doi:10.1021/ja972272g. ISSN   0002-7863.
  21. ↑ Bertelsen, Søren (2009). "Organocatalysis—after the gold rush". Chemical Society Reviews. 38 (8): 2178–89. doi:10.1039/b903816g. PMID   19623342.
  22. ↑ Gaunt, M. J.; Johansson, C. C. C.; McNally, A.; Vo, N. T. (2007). "Enantioselective organocatalysis". Drug Discovery Today. 12 (1–2): 8–27. doi:10.1016/j.drudis.2006.11.004. PMID   17198969.
  23. ↑ Kucherenko, A. S.; Siyutkin, D. E.; Maltsev, O. V.; Kochetkov, S. V.; Zlotin, S. G. (2013). "Asymmetric organocatalysis: From proline to highly efficient immobilized organocatalysts". Russian Chemical Bulletin. 61 (7): 1313. doi:10.1007/s11172-012-0177-4. S2CID   93168492.
  24. ↑ Gérald Lelais; David W. C. MacMillan (2006). "Modern Strategies in Organic Catalysis: The Advent and Development of Iminium Activation" (PDF). Aldrichimica Acta. 39 (3): 79.
  25. ↑ Erkkilä, Anniinä; Majander, Inkeri; Pihko, Petri M. (2007). "Iminium Catalysis". Chem. Rev. 107 (12): 5416–5470. doi:10.1021/cr068388p. PMID   18072802.
  26. ↑ Nis Halland; Tore Hansen; Karl Anker Jørgensen (2003). "Organocatalytic Asymmetric Michael Reaction of Cyclic 1,3-Dicarbonyl Compounds and α,β-Unsaturated Ketones – A Highly Atom-Economic Catalytic One-Step Formation of Optically Active Warfarin Anticoagulant". Angew. Chem. Int. Ed. 42 (40): 4955–4957. doi:10.1002/anie.200352136. PMID   14579449.
  27. ↑ Sandra Lee; David W. C. MacMillan (2007). "Organocatalytic Vinyl and Friedel-Crafts Alkylations with Trifluoroborate Salts" (PDF). J. Am. Chem. Soc. 129 (50): 15438–15439. doi:10.1021/ja0767480. PMID   18031044. S2CID   34848947.
  28. ↑ Madarász, Ádám; Dósa, Zsolt; Varga, Szilárd; Soós, Tibor; Csámpai, Antal; Pápai, Imre (July 2016). "Thiourea Derivatives as Brønsted Acid Organocatalysts" (PDF). ACS Catalysis. 6 (7): 4379–4387. doi:10.1021/acscatal.6b00618.
  29. ↑ Parvin, Tasneem; Yadava, Rahul; Choudhury, Lokman (2020). "Recent applications of thiourea-based organocatalysts in asymmetric multicomponent reactions (AMCRs)". Org. Biomol. Chem. 18: 5513–5532. doi:10.1039/D0OB00595A.
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