Organic Chemistry Portal
Reactions >> Special Topics

Organocatalysis

Organocatalysis uses small organic molecules predominantly composed of C, H, O, N, S and P to accelerate chemical reactions. The advantages of organocatalysts include their lack of sensitivity to moisture and oxygen, their ready availability, low cost, and low toxicity, which confers a huge direct benefit in the production of pharmaceutical intermediates when compared with (transition) metal catalysts.

In the example of the Knoevenagel Condensation, it is believed that piperidine forms a reactive iminium ion intermediate with the carbonyl compound:

Another organocatalyst is DMAP, which acts as an acyl transfer agent:

Steglich Esterification

Thiazolium salts are versatile umpolung reagents (acyl anion equivalents), for example finding application in the Stetter Reaction:

All of these organocatalysts are able to form temporary covalent bonds. Other catalysts can form H-bonds, or engage in pi-stacking and ion pair interactions (phase transfer catalysts). Catalysts may be specially designed for a specific task - for example, facilitating enantioselective conversions.

An early example of an enantioselective Stetter Reaction is shown below: :


D. Enders, K. Breuer, J. Runsink, Helv. Chim. Acta, 1996, 79, 1899-1902.


model explaining the facial selectivity

Enantioselective Michael Addition using phase transfer catalysis:


T. Ooi, D. Ohara, K. Fukumoto, K. Maruoka, Org. Lett., 2005, 7, 3195-3197.

The first enantioselective organocatalytic reactions had already been described at the beginning of the 20th century, and some astonishing, selective reactions such as the proline-catalyzed synthesis of optically active steroid partial structures by Hajos, Parrish, Eder, Sauer and Wiechert had been reported in 1971 (Z. G. Hajos, D. R. Parrish, J. Org. Chem. 1974, 39, 1615; U. Eder, G. Sauer, R. Wiechert, Angew. Chem. Int. Ed. 1971, 10, 496, DOI). However, the transition metal-based catalysts developed more recently have drawn the lion’s share of attention.


Hajos-Parrish-Eder-Sauer-Wiechert reaction (example)

The first publications from the groups of MacMillan, List, Denmark, and Jacobson paved the way in the year 1990. These reports introduced highly enantioselective transformations that rivaled the metal-catalyzed reactions in both yields and selectivity. Once this foundation was laid, mounting interest in organocatalysis was reflected in a rapid increase in publications on this topic from a growing number of research groups.

Proline-derived compounds have proven themselves to be real workhorse organocatalysts. They have been used in a variety of carbonyl compound transformations, where the catalysis is believed to involve the iminium form. These catalysts are cheap and readily accessible:


A. J. A. Cobb, D. M. Shaw, D. A. Longbottom, J. B. Gold, S. V. Ley, Org. Biomol. Chem., 2005, 3, 84-96.


Y. Hayashi, T. Sumiya, J. Takahashi, H. Gotoh, T. Urushima, M. Shoji, Angew. Chem. Int. Ed., 2006, 45, 958-961.


Kumaragurubaran, K. Juhl, W. Zhuang, A. Gogevig, K. A. Jorgensen, J. Am. Chem. Soc., 2002, 124, 6254-6255.

A general picture of recent developments: V. D. B. Bonifacio, Proline Derivatives in Organic Synthesis, Org. Chem. Highlights 2007, March 25.


Books on Organocatalysis


Asymmetric Organocatalysis

Albrecht Berkessel, Harald Gröger
Hardcover, 440 Pages
First Edition, 2005
ISBN: 3-527-30517-3 - Wiley-VCH


Recent Literature

Display all abstracts


A BINOL-derived boro-phosphate catalyzes an enantioselective reduction of α-trifluoromethylated imines to provide chiral α-trifluoromethylated amines in high yields and with excellent enantioselectivities in the presence of catecholborane as hydride source under mild conditions.
H. He, X. Tang, Y. Cao, J. C. Antilla, J. Org. Chem., 2021, 86, 4336-4345.


A combination of pyrenedione (PD) and KOtBu achieves a facile alcohol dehydrogenation under visible-light excitation in the presence of aerobic oxygen as the terminal oxidant. The resulting carbonyl compounds can be easily converted to vinyl nitriles in a single-pot reaction. This environmentally benign, organocatalytic α-olefination of nitriles operates at low temperature.
A. K. Bains, Y. Ankit, D. Adhikari, Org. Lett., 2021, 23, 2019-2023.


In cycloadditions of carbon dioxide into epoxides to afford cyclic carbonates, a strained ion pair tris(alkylamino)cyclopropenium halide catalyst, in which the halide is repelled, is a very electrophilic H-bond donor, allowing it to activate the oxygen of the epoxide, while the more nucleophilic halide is better able to attack the methylene carbon of the epoxide.
J. Xu, A. Xian, Z. Li, J. Liu, Z. Zhang, R. Yan, L. Gao, B. Liu, L. Zhao, K. Guo, J. Org. Chem., 2021, 86, 3422-3432.


Organoiodine(I/III) chemistry enables a metal-free, catalytic enantioselective intermolecular oxyamination of aryl- and alkyl-substituted alkenes with N-(fluorosulfonyl)carbamate as a bifunctional N,O-nucleophile with high enantioselectivity and electronically controlled regioselectivity. The oxyaminated products can be easily deprotected in one step to reveal free amino alcohols in high yields.
C. Wata, T. Hashimoto, J. Am. Chem. Soc., 2021, 143, 1745-1751.


The use of a bifunctional organocatalyst and Cs2CO3 enables a direct carboxylation of terminal alkynes with CO2 at atmospheric pressure under mild temperatures to provide a range of propiolic acid derivatives in high yields with broad substrate scope. This work has demonstrated that this organocatalytic method offers a competitive alternative to metal catalysis.
J.-B. Shi, Q. Bu, B.-Y. Liu, B. Dai, N. Liu, J. Org. Chem., 2021, 86, 1850-1860.


Zwitterionic organocatalysts with an amide anion/iminium cation charge pair catalyze the isomerization of maleic acid diesters to give fumaric acid diesters. Whereas the cooperative effect of the charges lower the activation barrier for a Michael addition of the catalyst to the substrate, the key interaction results from a nonclassical hydrogen bond.
Y.-P. Lam, Z. Lam, Y.-Y. Yeung, J. Org. Chem., 2021, 86, 1183-1190.


A cooperative primary amine and ketone dual catalytic approach enables the asymmetric α-hydroxylation of β-ketocarbonyls with H2O2 in excellent yield and enantioselectivity. Notably, late-stage hydroxylation for peptidyl amide or chiral esters can also be achieved with high stereoselectivity.
M. Cai, K. Xu, Y. Li, Z. Nie, L. Zhang, S. Luo, J. Am. Chem. Soc., 2021, 143, 1078-1087.


tert-Butyldimethylsilyl (TBDMS) ethers of primary, secondary, and tertiary alcohols and phenolic TBDMS ethers are desilylated to their corresponding alcohols and phenols, respectively, in DMSO, at 80°C, in very good yield in the presence of P(MeNCH2CH2)3N as catalyst. Desilylations of tert-butyldiphenylsilyl (TBDPS) ethers were much less effective.
Z. Yu, J. G. Verkade, J. Org. Chem., 2000, 65, 2065-2068.


A photoredox-catalyzed decarboxylative cyclization reaction between commercially available α-oxocarboxylic acids and a hypervalent iodine(III) reagent provides 2,5-disubstituted 1,3,4-oxadiazoles in very good yields.
J. Li, X.-C. Lu, Y. Xu, J.-X. Wen, G.-Q. Hou, L. Liu, Org. Lett., 2020, 22, 9621-9626.


An efficient reaction of 1,3-bis(het)arylmonothio-1,3-diketones with sodium azide provides 3,5-bis(het)arylisoxazoles in high yields at room temperature in the presence of IBX as catalyst. The reaction is applicable to a broad range of substrates. The reaction of β-ketodithioesters with sodium azide furnishes β-ketonitriles in good yields.
M. A. P, G. L. Balaji, P. Iniyavan, H. Ila, J. Org. Chem., 2020, 85, 15422-15436.


An efficient carbene-catalyzed formal [4 + 2] annulation of β-silyl enones with a HOBT ester followed by ring opening with nucleophiles provides γ-keto-β-silyl esters and amides, most with extremely high enantioselectivities. γ-Keto-β-silyl esters can be easily converted into enantioenriched β,σ-dihydroxyl esters.
Y. Zhang, X. Huang, J. Guo, C. Wei, M. Gong, Z. Fu, Org. Lett., 2020, 22, 9545-9550.


L-proline catalyzes a reaction between α,β-unsaturated aldehydes and maleimides to provide biologically and pharmaceutically important phthalimides. The reaction involves an efficient benzannulation that proceeds via a formal [4 + 2] cycloaddition of azadiene intermediates generated in situ from enals and N-substituted maleimides.
M. S. Akhthar, Y. R. Lee, J. Org. Chem., 2020, 85, 15129-15138.


A catalytic amount of inexpensive salicylic acid promotes a straightforward and scalable synthesis of diphenyl arylphosphonates from anilines and triphenyl phosphite at 20°C within 1-2 h. The reaction proceeds via radical-radical coupling and tolerates a wide range of functional groups.
M. Estruch-Blasco, D. Felipe-Blanco, I. Bosque, J. C. González-Gómez, J. Org. Chem., 2020, 85, 14473-14485.


Very low loadings of a N,N-diethylacetamide derived phosphorane efficiently catalyze the cyanosilylation of a broad range of ketones. Aldehydes, aldimines, and ketimines are also viable substrates.
W.-B. Wu, X.-P. Zang, J. Zhou, J. Org. Chem., 2020, 85, 14342-14350.


A series of 20 chiral epoxides were obtained with excellent yields and enantioselectivities within short reaction times using hybrid amide-based Cinchona alkaloids as catalysts at very low loading. Moreover, the catalyst solution can be reused 10times, without further catalyst addition to the reaction mixture.
M. Majdecki, A. Tyszka-Gumkowska, J. Jurczak, Org. Lett., 2020, 22, 8687-8691.


Supramolecular nanoassemblies of an AIEE-ICT-active pyrazine derivative (TETPY) with strong absorption in the visible region catalyze the synthesis of a variety of a broad range of benzimidazoles, benzothiazoles and quinazolines in excellent yields under "metal-free" conditions in a mixed aqueous media.
S. Dadwal, M. Kumar, V. Bhalla, J. Org. Chem., 2020, 85, 13906-13919.


Pyrimidopteridine N-oxides as organic photoredox-active catalysts mediate a metal-free photoinduced decarboxylative Giese-type addition of carboxylic acids to a variety of electron-deficient alkenes.
. El-Hage, C. Schöll, J. Pospech, J. Org. Chem., 2020, 85, 13853-13867.


A degradable 1,3,5-triazo-2,4,6-triphosphorine (TAP) motif enables a dehydrative formation of amide bonds between diverse combinations of aromatic carboxylic acids and amines. The underlying reaction mechanism was investigated, and potential catalyst intermediates were characterized.
. S. Movahed, D. N. Sawant, D. B. Bagal, S. Saito, Synthesis, 2020, 52, 3253-3262.


The combination of  flavin and iodine catalyzes an aerobic oxidative C-N bond-forming process for the facile synthesis of imidazo[1,2-a]pyridines. This dual catalytic system can also be applied to the one-pot, three-step synthesis of 3-thioimidazo[1,2-a]pyridines from aminopyridines, ketones, and thiols.
H. Okai, K. Tanimoto, R. Ohkado, H. Iida, Org. Lett., 2020, 22, 8002-8006.


Chiral phosphoric acids catalyze an enantioselective addition of bi(cyclopentyl)diol-derived boronates to aldehydes to provide homoallylic, propargylic, and crotylic alcohols with high enantiomeric excess and diastereomeric ratios. A wide substrate scope was exhibited, and the novel boronates provided high enantiocontrol.
J. Yuan, P. Jain, J. C. Antilla, J. Org. Chem., 2020, 85, 12988-13003.


DBU catalyzes a rearrangement of diarylated secondary propargylic alcohols to give α,β-unsaturated carbonyl compounds in excellent yields. The typical 1,3-transposition of oxy functionality, characteristic of Meyer-Schuster rearrangements, is not observed. This method offers a broad substrate scope, functional-group tolerance, operational simplicity, and complete atom economy.
R. De, A. Savarimuthu, T. Ballav, P. Singh, J. Nanda, A. Hasija, D. Chopra, M. K. Bera, Synlett, 2020, 31, 1587-1592.


Please cite and link this page as follows:

Organocatalysis ( URL: https://www.organic-chemistry.org/topics/organocatalysis.shtm )