Organocatalysis

For Metal-Free Asymmetric Synthesis of Chiral Molecules

What Is Organocatalysis?

Organocatalysis is the use of specific organic molecules that can accelerate chemical reactions via catalytic activation. In contrast to the other two major classes of catalysts, organometallics, and enzymes, organocatalysis does not require the use of metals nor large complex molecules to achieve catalytic activation. Due to their efficiency and selectivity, organocatalysts are of interest in efforts toward sustainable chemistry. Indeed, organocatalysis supports a number of the main tenets of green chemistry, providing for less hazardous syntheses, more energy efficiency, and atom economy.

Asymmetric organocatalysis is useful to achieve desired enantiomeric and/or diastereomeric forms of compounds, particularly important in pharmaceutical syntheses. Reactions using organocatalysts typically proceed via four distinct mechanisms based on whether the catalyst acts as a Lewis acid, Lewis base, Bronsted acid, or Bronsted base. Thus, the scope of organocatalysis is quite broad, influencing many different classes of reactions.

What Are Advantages and Disadvantages of Organocatalysis?

There are numerous advantages to using organocatalysts in chiral syntheses. Organocatalysts tend to be relatively simple, robust molecules that are inexpensive and readily available. Organocatalysts can be tailored to be efficient at creating specific enantiomers. Since they are metal-free they are typically less toxic and create less hazardous waste for clean-up. The reaction conditions required for organocatalysis tend to be less extreme with regard to temperature/pressure and organocatalysts are less air and moisture sensitive than, for example, organometallic catalysts. Thus, organocatalysis holds much promise for achieving sustainable chemistry. Organocatalysts are quite useful for performing syntheses that are hard or impossible to do by other means. Though enzymatic catalysts are highly active, efficient and selective, they tend to have limited scope and favor the formation of one enantiomer, which may not be acceptable.

As far as disadvantages, organocatalysts are not as efficient or active when compared to enzymatic catalysis, for example. This means that catalyst loadings must much be higher, reactions tend to be slower and there are issues associated with work-up to separate the products from catalyst. Thus, scaling organocatalysis-based reactions for industrial application can be challenging. Furthermore, organocatalysts are not as efficient as organometallic catalysts when chemistry requires activating inert bonds such as in C-H functionalization. It is important to note that, accelerated by enhanced research in green chemistry, significant efforts are on-going in the use of earth-abundant metals such as iron to replace more toxic or expensive transition metals, thus somewhat mitigating one of the advantages of organocatalysis.

Examples of Organic Catalysts

In 2000, Professor David MacMillan coined the term “organocatalysis” to describe the use of sub-stoichiometric organic molecules to activate reactions. In 2005, Professor Benjamin List suggested that organocatalysts can be classified based on their mechanism, i.e., acting as Lewis acids or bases and Bronsted acids or bases. Some of the earlier work in the development of chiral metal free catalysts focused on the use of amine and ketone compounds. However, there has been substantial expansion of research and development of organocatalysts over the past 20 years. These include iminium ions, piperidines, enamines, 4-dimethylaminopyridine (DMAP), 2-amino-2'-hydroxy-1,1'-binaphthyl (NOBIN), prolines,imidazolidinones, thiazolium salts, ammonium enolates, and urea-, thiourea-, phosphene-, carbene-, phosphoric acid- based organocatalysts. Organocatalysts have been used for some of the most common reaction classes, including Diels-Alder, Freidel-Crafts, Mannich aminoalkylations, Michael addition reactions, aldol reactions, etc. There are thousands of organocatalysts that have been synthesized and used for a wide range of reaction classes.

Technology Supports In-Depth Understanding of Organocatalysis

The application of organocatalysis is growing exponentially because of its inherent advantages. Part of the reason for this growth is a direct result of in-depth understanding of the kinetics, mechanism and pathways of these catalytic processes. As more emphasis is placed on industrial applications of organocatalysis, there is an increasing need for information related to scale-up and optimizing reaction conditions.

Acquiring high-quality data for these measurements requires precise and accurate control of fundamental reaction parameters/variables, including temperature, pressure, reactant dosing rate and stirring rate. EasyMax and OptiMax automated chemical reactors are used in academic and industrial labs for this purpose. EasyMax's capability has recently been expanded to enable precise control of temperatures as low as -78 °C, thereby extending the design space for catalytic processes, in general. Additionally, EasyMax can be equipped with calorimetric capability (EasyMax HFCal) for measuring reaction thermodynamic properties and for safety considerations.

The assurance provided by superior reactor control facilitates confidence in the measurement accuracy of reaction species that include reagents, reactants, catalyst species, transient intermediates and by-product impurities. Data-rich experiments from in-situ, real-time tracking of these reaction species speed the development of kinetic parameters and support for proposed reaction mechanisms including catalytic cycles. As demonstrated in chemical literature, in-situ, real-time FTIR and Raman spectroscopy are well-proven methods for in-depth understanding of catalytic reactions. ReactIR and ReactRaman are specifically designed for chemical reaction analysis, and feature a range of insertion probes and flow cells that handle the broad temperature and pressure range often required for catalytic reaction investigations. When offline analysis by chromatography is required, EasySampler is an automated sampling technology for inline acquisition, quenching and dilution of reaction samples. This technology allows samples to be retrieved under reaction conditions, eliminating the issues associated with manual sampling of chemistry performed at challenging temperatures, pressures and/or air sensitive reactions.

Control For Investigation of Organocatalytic Reactions

EasyMax and OptiMax automated synthesis reactors are chemistry workstations ideal for the research, development, and parameter optimization of organocatalytic reactions. The synthesis workstations offer highly precise control of virtually all reaction variables, including those performed at elevated or subambient temperatures.

Control all critical parameters including reagent dosing rate, temperature, mixing, pressure, etc.
Proven technology for performing kinetics and mechanistic investigations.
Provide superior support for DoE studies and data rich experiments, such as Reaction Progress Kinetics Analysis.
Ideal for optimization and scale-up of organo-, organometallic-, and enzyme-based catalytic reactions
Fully integrates in-situ, real-time spectroscopy including ReactIR (FTIR), ReactRaman (Raman), as well as EasySampler for automated, in-situ reactor sampling when offline analysis is required.
iC software enables automated execution and control of all experiments and peripheral equipment, as well as full data capture and record keeping

Spectroscopy for Organocatalytic Reactions

Industry-Standard Technology For Organocatalysis

ReactIR and ReactRaman systems enable scientists to measure reaction trends and profiles in real-time, providing highly specific information about kinetics, mechanism, pathways, and the influence of reaction variables on performance. Using molecular spectroscopy, these analyzers track reactants, reagents, intermediates, catalytic species, products, and by-products as they vary during the course of the reaction. Raman and FTIR are complementary methods and depending on the chemistry investigated, each has its own strengths.

Concentration vs time profiling provides kinetic parameters and insight into reaction mechanisms including catalytic cycles
In-situ analysis eliminates analysis delays and irreproducibility associated with sampling for offline analysis
Measure batch or continuous flow syntheses
Insertion probes and flow cells available to accommodate the diverse reactions conditions associated catalytic reactions
Well-proven in the peer-reviewed literature for structural and kinetic insights in catalytic and non-catalytic reactions

Learn more about FTIR and Raman Spectroscopy.

Representative Sampling For Organocatalysis

Representative, 24/7 Sampling of Organocatalytic Reactions

Inline Automated Sampling

EasySampler provides pre-programmed or instantaneous, automated sampling of chemical reactions over an entire reaction sequence. EasySampler automatically captures reaction samples, quenches samples immediately at reaction conditions, and finally dilutes the sample to a user-specified concentration.

Provides accurate, reproducible, and representative samples at user-defined time points for analysis by offline HPLC to investigate reaction kinetics and generate impurity profiles
Sample heterogeneous mixtures, air- and moisture-sensitive reactions, and reactions under pressure and/or hazardous conditions
Set up experiments to run 24/7 to maximize organizational and personal productivity
Eliminate safety issues, tedium, and potential irreproducibility of manual sampling

Learn more about automated sampling systems.

Applications

Featured Article: Deactivation of Amine Organocatalysts

ReactIR Provides Insight Into Catalyst Deactivation Process

Schnitzer, T. and Wennemers, H. (2020). Deactivation of Secondary Amine Catalysts via Aldol Reaction–Amine Catalysis under Solvent-Free Conditions, J. Org. Chem. 85(12), 7633–7640.

The authors comment that chiral amines are excellent catalysts for reactions of electrophiles with ketones or aldehydes, but that at very low catalyst level undesired side products can deactivate the catalyst. To probe the deactivation process for amine catalysts, they used a tripeptide that effectively catalyzes conjugate addition reactions of aldehydes and nitroolefins at a catalyst loading of ≤1 mol %. In their experiments, they used in-situ FTIR (ReactIR) to track reaction rates as a function of time for the formation of the γ-nitroaldehyde product under conditions of varying reactant concentrations and catalyst loadings.

At a catalyst loading of 1% or 0.1%, the highest concentration of the nitroolefin starting material resulted in the highest reaction rate, but for both catalyst loadings, the rate slows down over time. Further, they observed that the lowest nitroolefin concentration actually provided the higher reaction rate and that after 16 hours, more product was formed by reactions with lower starting material concentration. They stated that a compound formed over time as the reaction proceeds must be deactivating the catalyst.

Through further investigation, they determined that an aldol reaction was deactivating the catalyst by the formation of an intermediate off-cycle compound, and that the deactivation is greatest at high substrate concentrations and low catalyst loadings. Furthermore, by using a highly chemoselective peptide catalyst they were able to achieve excellent yields at low catalyst loading. They commented that with respect to product yield using these amine catalysts, chemoselectivity, as well as reactivity and stereoselectivity, is important. This is particularly important when considering solvent-free reactions that are desirable for sustainable chemistry

Featured Article: Kinetics of Organocatalyzed Mukaiyama Aldol Reaction

Kinetic Parameters Determined By ReactIR Data Analyzed via RPKA

Zhang, Z. & List, B. (2013). Kinetics of the Chiral Disulfonimide‐Catalyzed Mukaiyama Aldol Reaction. Asian J. Org. Chem.,2, 957 – 960. DOI: 10.1002/ajoc.201300182.

The authors comment that the Mukaiyama aldol reaction is an effective, proven method for the development of chiral molecules. In previous work, the authors developed chiral sulfonimides, which are strong Bronsted acids and when silylated, are excellent organic Lewis acid catalysts that can catalyze Mukaiyama aldol reactions with high enantioselectivity. Further they state that they have investigated a number of Lewis acid catalyzed transformations and wished to develop more insight into the mechanism of these organocatalysts. In the research covered in this article, they performed a kinetic study of the the chiral disulfonimide-catalyzed Mukaiyama aldol reaction via Reaction Progress Kinetic Analysis (RPKA) based on data from ReactIR experiments.

Base on these experiments, they determined that the rate equation for the Mukaiyama aldol reaction catalyzed by disulfonimide 4 can be described as rate=k^x[1]^{0.55 x}[2]^x[4], and that the activation energy is 2.9 kcal mol^-1, consistent with the observation that the reaction proceeds rapidly even at low temperature. Further, based on the kinetics, they proposed a catalytic cycle in which the catalyst resting state may be a combination of silylated catalyst (5) and the catalyst-bound aldehyde (6).

Featured Article: Investigation of Catalyst Dormant Period

ReactIR Provides Insight Into Affect of Water In Pre-catalyst Cycle

Zhang, Z., Bae, H.Y., Guin, J., Rabalakos, C.,van Gemmeren, M., Leutzsch, M., Klussmann, M. and List, B. (2016). Asymmetric counteranion-directed Lewis acid organocatalysis for the scalable cyanosilylation of aldehydes. Nat. Commun., 7, 12478. DOI: 10.1038/ncomms12478

The authors report developing an asymmetric Lewis acid organocatalysis method for cyanosilylation of aldehydes using trimethylsilyl cyanide and a chiral disulfonimide pre-catalyst. As a result of the high activity, catalyst loadings of 0.05 % to 0.005 % were effective in producing the desired the cyanohydrin product. The authors report that an inactive period of the catalyst is observed that can be reversibly induced by water. To further understand this development, in-situ FTIR was used and provided significant insight into the pre-catalytic cycle.

To monitor the concentration of the aldehyde reactant, the 1703 cm^-1 carbonyl band was tracked vs. time. Interestingly, no reaction was observed for a period of time, after which the transformation proceeded quite rapidly. The authors thought that the reason for the dormant period might be related to water in the reaction mixture, and though an experimental protocol of adding controlled amounts of water to the reaction mixture, proved that water was indeed responsible for the lack of activity via hydrolysis of the catalytically active species. In earlier work in which a silyl ketene acetal was reacted with an aldehyde in the presence of a disulfonimide catalyst, no dormant period was observed. They thought that this might be due to the high reactivity of the silyl ketene acetal with the pre-catalyst, instantly regenerating the active Lewis acid organocatalyst. To test this hypothesis in the current work, they used a catalytic amount of silyl ketene acetal as an activator and found that the dormant period was avoided. Based on further experiments, they proposed a pre-catalytic cycle that reflects the dormant period.

Publications

Organocatalytic Reactions in Publications

Puglisi, A. and Rossi, S. (2021). Stereoselective organocatalysis and flow chemistry. Phys. Sci. Rev., Volume 6 (4). https://doi.org/10.1515/psr-2018-0099
Strassfeld, D.A., Algera, R.F., Wickens, Z.K. and Jacobsen, E.N. (2021). A Case Study in Catalyst Generality: Simultaneous, Highly Enantioselective Brønsted- and Lewis-Acid Mechanisms in Hydrogen-Bond-Donor Catalyzed Oxetane Openings. J. Am. Chem. Soc. 143(25), 9585-9594. https://doi.org/10.1021/jacs.1c03992
Maligres, P.E., et al. (2021). Discovery and Development of an Unusual Organocatalyst for the Conversion of Thymidine to Furanoid Glycal. Org. Proc. Res. Dev. https://doi.org/10.1021/acs.oprd.1c00186
Hutchinson, G., Alamillo-Ferrer, C. and Burés, J. (2021). Mechanistically Guided Design of an Efficient and Enantioselective Aminocatalytic α‑Chlorination of Aldehydes. J. Am. Chem. Soc. 143, 6805−6809. https://doi.org/10.1021/jacs.1c02997
Schnitzer, T. and Wennemers, H. (2020). Deactivation of Secondary Amine Catalysts via Aldol Reaction–Amine Catalysis under Solvent-Free Conditions, J. Org. Chem. 85(12), 7633–7640. https://doi.org/10.1021/acs.joc.0c00665
Nicholls, R. et al. (2018). Guanidine-Catalyzed Reductive Amination of Carbon Dioxide with Silanes: Switching between Pathways and Suppressing Catalyst Deactivation. ACS Catalysis, 8 (4)., 3678-3687. https://doi.org/10.1021/acscatal.7b04108
Dai, J., et al. (2017). Sulfonated Polyaniline as Solid Organocatalyst for Dehydration of Fructose into 5-Hydroxymethylfurfural. Green Chem., 19, 1932-1939.
Zhang, Z., Bae, H.Y., Guin, J., Rabalakos, C.,van Gemmeren, M., Leutzsch, M., Klussmann, M. and List, B. (2016). Asymmetric counteranion-directed Lewis acid organocatalysis for the scalable cyanosilylation of aldehydes. Nat Commun., 7, 12478. DOI: 10.1038/ncomms12478
Zeng, X-P. et al. (2016). Activation of Chiral (Salen)AlCl Complex by Phosphorane for Highly Enantioselective Cyanosilylation of Ketones and Enones. J Am. Chem. Soc., 138(1), 416-425. doi: 10.1021/jacs.5b11476.
Atodiresei, I., Vila, C. and Rueping, M. (2015) Asymmetric Organocatalysis in Continuous Flow: Opportunities for Impacting Industrial Catalysis. ACS Catal., 5, 1972−1985 DOI: 10.1021/acscatal.5b00002
Varga, E., et al. (2015). Mechanistic investigations of a bifunctional squaramide organocatalysts in asymmetric Michael reaction and observation of stereoselective retro-Michael reaction. RSC Adv., 5, 95079–95086. DOI: 10.1039/c5ra19593d
Zhao, W., Gnanou, Y. and Hadjichristidis, N. (2015). Organocatalysis by Hydrogen-Bonding: A New Approach to Controlled/Living Polymerization of α-Amino acid N-carboxyanhydrides. Polym. Chem. 6, 6193–6201. http://dx.doi.org/10.1039/c5py00874c.
Kaoukabi, A. et al. (2015). The use of ionic liquids as an organocatalyst for controlled ring-opening polymerization of ϵ-caprolactone. Ind. Crops Prod., 72, 16-23. https://doi.org/10.1016/j.indcrop.2015.02.002
Zhang, Z. & List, B. (2013). Kinetics of the Chiral Disulfonimide‐Catalyzed Mukaiyama Aldol Reaction. Asian J. Org. Chem., 2, 957 – 960. DOI: 10.1002/ajoc.201300182.
Wu, G-P. and Darensbourg, D. (2012). Tandem Metal Coordination Copolymerization and Organocatalytic Ring-opening Polymerization via Water to Synthesize Diblock Copolymers of Styrene Oxide/CO2 and Lactide., J. Am. Chem. Soc., 134(42), 17739–17745. https://doi.org/10.1021/ja307976c
Rueping, M., Bootwicha, T. & Sugiono, E., (2012). Continuous-flow catalytic asymmetric hydrogenations: Reaction optimization using FTIR inline analysis. Beilstein J. Org. Chem., 8, 300–307. https://doi.org/10.3762/bjoc.8.32
Van Humbeck, J.F., Simonovich, S.P., Knowles, R.R. and MacMillan, D.W.C. (2010). Concerning the Mechanism of the FeCl3-Catalyzed αOxyamination of Aldehydes. Evidence for a Non-SOMO Activation Pathway. J Am Chem Soc.,132(29), 10012–10014. doi:10.1021/ja1043006.
Seebach, D. et al. (2007). Are Oxazolidinones Really Unproductive, Parasitic Species in Proline Catalysis? – Thoughts and Experiments Pointing to an Alternative View, Helv. Chim. Acta, 90, 425-471. ‘
Denmark,S.E. and Chung, W-j (2006). Lewis Base Catalyzed Addition of Trimethylsilyl Cyanide to Aldehydes. J. Org. Chem., 71(10), 4002–4005. https://doi.org/10.1021/jo060153q
France, S. et al. (2004). Catalytic, Asymmetric α-Chlorination of Acid Halides, J. Am. Chem. Soc., 126(13), 4245–4255. https://doi.org/10.1021/ja039046t
Taggi, A.E., Hafez, A.M., Wack, H., Young, B., Ferraris, D. & Lectka, T. (2002). The Development of the First Catalyzed Reaction of Ketenes and Imines: Catalytic, Asymmetric Synthesis of β-Lactams, J. Am. Chem. Soc., 124(23), 6626–6635. https://doi.org/10.1021/ja0258226
Denmark, S.E. & Stavenger, R.A. (2000). Asymmetric Catalysis of Aldol Reactions with Chiral Lewis Bases, Acc. Chem. Res. 33(6), 432–440. https://doi.org/10.1021/ar960027g

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