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 or 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 several 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, which are 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, Brønsted acid, or Brønsted base. Thus, the scope of organocatalysis is quite broad, influencing many different classes of reactions.
This white paper presents examples from recent peer-reviewed research that show how the in-depth information and precise control provided by METTLER TOLEDO technologies aid in supporting green and sustainable chemistry across four thematic topics:
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 regarding 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.
Regarding disadvantages, organocatalysts are not as efficient or active as enzymatic catalysis. This means that catalyst loadings must be much higher, reactions tend to be slower, and there are issues associated with work-up to separate the products from the catalyst. Thus, scaling organocatalysis-based reactions for industrial applications can be challenging. Furthermore, organocatalysts are less efficient than 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 ongoing 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.
In 2000, Professor David MacMillan coined the term “organocatalysis” to describe the use of sub-stoichiometric organic molecules to activate reactions¹. In 2005, Professor Benjamin List suggested that organocatalysts can be classified based on their mechanism, i.e., acting as Lewis acids or bases and Brønsted 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.
1. Imbler, S., Santora, M., & Engelbrecht, C. (2021, October 6). Nobel Prize in Chemistry Awarded to Scientists for Tool That Builds Better Catalysts. The New York Times. https://www.nytimes.com/2021/10/06/science/nobel-prize-chemistry.html
The application of organocatalysis is growing exponentially because of its inherent advantages. Part of the reason for this growth is a direct result of an in-depth understanding of the kinetics, mechanisms, 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 the 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 -90 °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 analysis by chromatography is required, EasySampler™ is an automated sampling technology for inline sample 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. For online HPLC analysis, DirectInject-LC™ can be used for near real-time reaction and crystallization understanding. Fully automated rapid reaction sampling and injection transforms HPLC into a powerful new technology for online reaction monitoring.
EasyMax and OptiMax automated synthesis reactors are chemistry workstations ideal for the research, development, and parameter optimization of organocatalytic reactions. The synthesis workstations offer exact control of virtually all reaction variables, including those performed at elevated or sub-ambient temperatures.
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.
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.
DirectInject-LC represents a major breakthrough in chemical reaction analysis, providing in-situ, real-time liquid chromatography analysis capability. DirectInject-LC facilitates rapid, in-situ analysis of samples through fully automated sampling and injection, enabling continuous monitoring of reaction progress.
Schnitzer, T., & Wennemers, H. (2020). Deactivation of Secondary Amine Catalysts via Aldol Reaction–Amine Catalysis under Solvent-Free Conditions. The Journal of Organic Chemistry, 85(12), 7633–7640. https://doi.org/10.1021/acs.joc.0c00665
The authors comment that chiral amines are excellent catalysts for reactions of electrophiles with ketones or aldehydes, but that undesired side products can deactivate the catalyst at very low catalyst levels. 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. Still, for both catalyst loadings, the rate slowed down over time. Further, they observed that the lowest nitroolefin concentration provided a 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 deactivated the catalyst by forming an intermediate off-cycle compound and that the deactivation is greatest at high substrate concentrations and low catalyst loadings. Furthermore, they achieved excellent yields at low catalyst loading by using a highly chemoselective peptide catalyst. They commented that with respect to product yield, using these amine catalysts, chemoselectivity, reactivity, and stereoselectivity is important. This is particularly important when considering solvent-free reactions desirable for sustainable chemistry.
Zhang, Z., & List, B. (2013). Kinetics of the Chiral Disulfonimide‐Catalyzed Mukaiyama Aldol reaction. Asian Journal of Organic Chemistry, 2(11), 957–960. https://doi.org/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 Brønsted 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 several 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 chiral sulfonamide-catalyzed Mukaiyama aldol reaction via Reaction Progress Kinetic Analysis (RPKA) based on data from ReactIR experiments.
Based 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).
Zhang, Z., Bae, H. Y., Guin, J., Rabalakos, C., Van Gemmeren, M., Leutzsch, M., Klussmann, M., & List, B. (2016). Asymmetric counteranion-directed Lewis acid organocatalysis for the scalable cyanosilylation of aldehydes. Nature Communications, 7(1). https://doi.org/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 cyanohydrin product. The authors report that an inactive period of the catalyst is observed that can be reversibly induced by water. In-situ FTIR was used to further understand this development 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 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 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.