Catalyzed Reactions

Catalyzed reactions are typically used to accelerate the rate by which a specific chemistry proceeds. Essentially, the action of the catalyst is to provide an alternative, lower energy pathway for the reaction.  For this to occur, the catalytic substance interacts with a reactant and forms an intermediate compound. This intermediate is transient in that after it forms, it breaks apart leaving the original catalyst species unchanged. A catalyst is not affected by the reaction as far as the chemical structure or mass at reaction completion.

There are two general types of catalyzed reactions:

• Heterogeneous Catalyzed Reaction is when the catalyst and the reactant exist in two different phases, such as a solid catalyst with a reactant in solution.
• Homogeneous Catalyzed Reaction is when the catalyst and the reactant are in the same phase, such as when the catalyst and the reactants are dissolved in the same solution.  

• Catalysts create an alternative path to increase the speed and outcome of a reaction, so a thorough understanding of the reaction kinetics is important. Not only does that provide information about the rate of the reaction, but also provides insight into the mechanism of the reaction.
• Catalyst interaction with a reactant is also of interest. Catalyzed reactions produce transient intermediates that are the key to the catalytic process, the reaction rate, and the end-products.  Identifying intermediates produced by catalytic reactions is an ongoing area of research, and tools that give insight to the presence and structure of the intermediate are useful.
• Measuring the effect of reaction variables and conditions on a catalytic process is important for reaction optimization. Temperature, pressure, reactant, and catalyst concentrations, as well as other chemical and physical parameters have profound effect on the products, yield and by-products produced in a catalytic reaction. 
• Investigating the activity and measuring products and by-products produced by different catalysts for a given reaction is important in order to choose the best combination of catalyst and reaction conditions. 
  
• Measuring and understanding the energetics of a catalyzed reaction are important to ensure a safe reaction and successful scale-up.     

• Investigate homogeneous and heterogeneous catalyzed reactions under actual reaction conditions, including at elevated pressure and temperature.
• Detect and aid in the identification of key catalyzed reaction intermediates.
• Rapidly acquire data for determining reaction kinetics, understanding reaction mechanism, and pathway.
• Instantly track and measure products and by-products produced by catalytic reactions.
• Test and develop ideal reaction conditions for optimizing end-product yield and minimize side products.
• Rapidly determine best catalyst and conditions for specific reaction.
• Eliminate the time delays that come from traditional sample extraction and offline analyses.
• Eliminate the introduction of air, moisture, or disturbing reaction resulting from sample extraction.
• Minimize operator exposure to toxic chemicals, potentially energetic reactions, or hazardous reaction conditions.

Adapted with permission from Tuba, R., Mika, L., Bodor, A. Pustai, Z., Toth, I. and Horvath, I., “Mechanism of the Pyridine-Modified Cobalt-Catalyzed Hydroxymethoxycarbonylation of 1,3-Butadiene”, Organometallics, 22, 2003, 1582-1584. Copyright (2018) American Chemical Society.

Using high pressure ReactIR, researchers investigated the hydromethoxycarbonylation of 1,3-butadiene to methyl-3-pentenoate.  In the presence of pyridine, Co₂(CO)₈ was known to catalyze this reaction. At the time of the research, no intermediates had been identified and one of the goals of the project was to identify intermediates.  

Initially, methanol was used as a solvent and the 1,3-butadiene was added to an equilibrium mixture of Co₂(CO)₈ and [Co(MeOH)₆][Co-(CO)₄]₂ under 75 bar of carbon monoxide at 100^oC.  Based on the ReactIR profile, the researchers identified an intermediate, η³-C₄H₇Co(CO)₃,and after heating the reaction for several hours, the methyl-3-pentenoate product formed along with a mixture of Co₂(CO)₈ and [Co(MeOH)₆][Co-(CO)₄]₂.

ReactIR revealed and aided in the identification of the cobalt intermediates and provided additional insight into the catalytic mechanism.

When pyridine was used as the solvent, the intermediate species [CoPy₆][Co(CO₄]₂ was the only metal species identified.  After the mixture was heated, the cobalt-pyridine intermediate disappeared and the presence of η³-C₄H₇Co(CO)₃ and the methyl-3-pentenoate product was observed in the ReactIR spectral profile.

With further mixing under temperature, the η³-C₄H₇Co(CO)₃ intermediate converted to[CoPy₆][Co(CO₄]₂ and additional pentanoate product formed. The researchers reported that the conversion of η³-C₄H₇Co(CO)₃ to methyl-3-pentenoate was four times faster when pyridine was used as a solvent, as compared to methanol. 

In this example, ReactIR was useful for detecting the cobalt-pyridine intermediate and provided information about the catalytic mechanism. ReactIR revealed that the conversion rate was much faster when pyridine was used as a solvent. This demonstrates the use of in situ FTIR in determining the best catalyst/solvent combination for optimizing a catalytic reaction.

Rueping, M., Bootwicha, T., Sugiono, E., “Continuous-flow catalytic asymmetric hydrogenations: Reaction optimization using FTIR in-line analysis, Beilstein J. Org. Chem. (2012), 8, 300-307.

In this research, scientists showed for the first time the capability for continuous flow chemistry to perform a catalytic asymmetric transfer hydrogenation reaction.  To monitor the formation of the product, a ReactIR system equipped with a specially designed ATR flow cell was utilized and coupled with the microreactor. Since one of the goals of the work was to find an optimum set of conditions for the reaction, the ReactIR was attached at the end of the reaction stream.  

Their initial efforts focused on the asymmetric hydrogenation of benzoxazine in the presence of Hantzsch dihydropyridine as a hydrogen source and a chiral Brønsted acid catalyst. IR bands at 1479 cm-1 and 1495 cm-1 for the benzoxazine reactant and the dihydrobenzoxazine product, respectively, were used for tracking purposes

The ability to track these bands in real-time with online FTIR provided the means by which optimization of the reaction was accomplished. 

Among the many advantages of using continuous micro flow technology for investigating reactions is the ability to rapidly change reaction variables, such as reactant and catalyst concentration, flow rate, and temperature, and to see the effect of these changes on the reaction outcome.

In the catalyzed asymmetric hydrogenation of benzoxazine to dihydrobenzoxazine, a ramping of reaction temperature from 5 ^oC to 60 ^oC was performed.  The authors reported achieving a 98 % product yield by performing the reaction at 60 ^oC at a flow rate of 0.1 ml and a residence time of 1 hour. 

Using the information from this initial work, the scientist went on to apply this catalytic microflow reaction protocol to a series of benzoxzines, quinolines, quinoxalines, and 3H-indoles.  Reaction conditions for each of these series were optimized.

The authors concluded by stating: “By applying the FTIR inline monitoring, reaction parameters can be screened rapidly in a single reaction setup, and the optimal reaction conditions can be obtained much faster as compared to the classical sequence of conducting the reaction followed by analysis.”

Small and Lightweight
The streamlined profile fits easily into physically constrained areas such as a fumehood.

Reaction Monitoring Under Any Chemical Conditions
Options are available for batch or flow chemistry, and a variety of conditions including elevated pressure/ temperature reactions and corrosive reagents.

No Liquid-Nitrogen Required
Infrared measurements can be made continually and unattended for as long as necessary to accommodate a synthesis. 

Powerful Software
iC IR software makes set up and obtaining reaction profiles straightforward and intuitive. iC Kinetics and Reaction Progress Kinetic Analysis software is available that uses the IR data to quickly and easily develop reaction rate information.

In this webinar, Huw M. L. Davies, Professor of Chemistry at Emory University, discusses Fourier Transform Infrared (FTIR) spectroscopy to understand the effect of catalyst, substrate, and carbenoid precursor on the rate and efficiencies of rhodium catalyzed reactions. Optimized systems with a substrate to catalyst loading of greater than 1,000,000 were developed.

This presentation includes:

• The study of donor/acceptor carbenoids which are the central intermediates behind the chemistry.
• How to apply carbenoid chemistry towards the synthesis of pharmaceutical targets.

• Catalyst Reaction Optimization
• Enzymatic Catalysis
• Monitoring Hydrogenation Reactions
• Measuring Polymerization Reactions
• Highly Reactive Chemistry
• Synthesis Reactions

Gain insight into kinetics, thermodynamics, catalytic cycles and mechanisms of reactions to ensure safe and effective processes. With the increase in the use of organometallic catalysis and organocatalysis in the development and manufacturing of pharmaceuticals and chemicals, tools for developing and optimizing these reactions across scale are critical.  Experimental data acquired by PAT used in conjunction with Dynochem and Reaction Lab advanced modeling tools provide an effective means to gain insight into catalytic reactions. In assessing kinetics during development of catalytic reactions, Reaction Lab simultaneously models the effect of variables, including temperature, pressure, catalyst loading, reactant, product and by-product concentrations to provide a best set of reaction conditions. The response of the reaction to specific varying parameters and conditions can be observed, and response surfaces generated that give insight into yield/impurity tradeoffs as well as robustness of the reaction. The entire catalytic reaction can be modeled or individual steps in the catalytic cycle can be assessed to provide improved models when necessary. Dynochem enables scale-up of catalytic reactions by modeling the effect of variables, including temperature, pressure, mixing rates and heat transfer to quickly identify appropriate process conditions that ensure both safe operation and meet yield/impurity targets. Particularly important in optimizing and scale-up of catalytic reactions that are inherently energetic or that are performed under potentially hazardous conditions, Dynochem helps in managing risk through the development of response surface models that reveal safe operating conditions.

Below is a selection of industry-related publications where heterogeneous and homogeneous catalyzed reactions were successfully investigated:

• Wu, X., Ding, G., Lu, W., Yang, L., Wang, J., Zhang, Y., Xie, X., & Zhang, Z. (2021). Nickel-Catalyzed Hydrosilylation of Terminal Alkenes with Primary Silanes via Electrophilic Silicon–Hydrogen Bond Activation. Organic Letters, 23(4), 1434–1439. https://doi.org/10.1021/acs.orglett.1c00111
• Mao, H., Wang, H., Meng, T., Wang, C., Hu, X., Xiao, Z., & Liu, J. (2021). An efficient environmentally friendly CuFe2O4/SiO2 catalyst for vanillyl mandelic acid oxidation in water under atmospheric pressure and a mechanism study. New Journal of Chemistry, 45(2), 982–992. https://doi.org/10.1039/d0nj04798h
• Baalbaki, H. A., Roshandel, H., Hein, J. E., & Mehrkhodavandi, P. (2021). Conversion of dilute CO2 to cyclic carbonates at sub-atmospheric pressures by a simple indium catalyst. Catalysis Science & Technology, 11(6), 2119–2129. https://doi.org/10.1039/d0cy02028a
• Ren, R., Huang, P., Zhao, W., Li, T., Liu, M., & Wu, Y. (2021). A New ternary organometallic Pd(ii)/Fe(iii)/Ru(iii) self-assembly monolayer: the essential ensemble synergistic for improving catalytic activity. RSC Advances, 11(3), 1250–1260. https://doi.org/10.1039/d0ra09347e
• An, Q., Wang, L., Bi, S., Zhao, W., Wei, D., Li, T., Liu, M., & Wu, Y. (2021). Sandwich structured aryl-diimine Pd (II)/Co (II) monolayer—Fabrication, catalytic performance, synergistic effect and mechanism investigation. Molecular Catalysis, 501, 111359. https://doi.org/10.1016/j.mcat.2020.111359
• Gray, M., Hines, M. T., Parsutkar, M. M., Wahlstrom, A. J., Brunelli, N. A., & RajanBabu, T. V. (2020). Mechanism of Cobalt-Catalyzed Heterodimerization of Acrylates and 1,3-Dienes. A Potential Role of Cationic Cobalt(I) Intermediates. ACS Catalysis, 10(7), 4337–4348. https://doi.org/10.1021/acscatal.9b05455
• Kariofillis, S. K., Shields, B. J., Tekle-Smith, M. A., Zacuto, M. J., & Doyle, A. G. (2020). Nickel/Photoredox-Catalyzed Methylation of (Hetero)aryl Chlorides Using Trimethyl Orthoformate as a Methyl Radical Source. Journal of the American Chemical Society, 142(16), 7683–7689. https://doi.org/10.1021/jacs.0c02805
• Verissimo Lobo, V. T., Pacheco Ortiz, R. W., Gonçalves, V. O. O., Cajaiba, J., & Kartnaller, V. (2020). Kinetic Modeling of Maleic Acid Isomerization to Fumaric Acid Catalyzed by Thiourea Determined by Attenuated Total Reflectance Fourier-Transform Infrared Spectroscopy. Organic Process Research & Development, 24(6), 988–996. https://doi.org/10.1021/acs.oprd.9b00487
• Deacy, A. C., Moreby, E., Phanopoulos, A., & Williams, C. K. (2020). Co(III)/Alkali-Metal(I) Heterodinuclear Catalysts for the Ring-Opening Copolymerization of CO2 and Propylene Oxide. Journal of the American Chemical Society, 142(45), 19150–19160. https://doi.org/10.1021/jacs.0c07980
• Maier, T. M., Gawron, M., Coburger, P., Bodensteiner, M., Wolf, R., van Leest, N. P., de Bruin, B., Demeshko, S., & Meyer, F. (2020). Low-Valence Anionic α-Diimine Iron Complexes: Synthesis, Characterization, and Catalytic Hydroboration Studies. Inorganic Chemistry, 59(21), 16035–16052. https://doi.org/10.1021/acs.inorgchem.0c02606
• Dreimann, J. M., Kohls, E., Warmeling, H. F. W., Stein, M., Guo, L. F., Garland, M., Dinh, T. N., & Vorholt, A. J. (2019). In Situ Infrared Spectroscopy as a Tool for Monitoring Molecular Catalyst for Hydroformylation in Continuous Processes. ACS Catalysis, 9(5), 4308–4319. https://doi.org/10.1021/acscatal.8b05066
• Andrea, K. A., & Kerton, F. M. (2019). Triarylborane-Catalyzed Formation of Cyclic Organic Carbonates and Polycarbonates. ACS Catalysis, 9(3), 1799–1809. https://doi.org/10.1021/acscatal.8b04282
• Dechert-Schmitt, A. M., Garnsey, M. R., Wisniewska, H. M., Murray, J. I., Lee, T., Kung, D. W., Sach, N., & Blackmond, D. G. (2019). Highly Modular Synthesis of 1,2-Diketones via Multicomponent Coupling Reactions of Isocyanides as CO Equivalents. ACS Catalysis, 9(5), 4508–4515. https://doi.org/10.1021/acscatal.9b00581
• Masson-Makdissi, J., Jang, Y. J., Prieto, L., Taylor, M. S., & Lautens, M. (2019). Rhodium-Catalyzed Tandem Isomerization–Allylation: From Diallyl Carbonates to α-Quaternary Aldehydes. ACS Catalysis, 9(12), 11808–11812. https://doi.org/10.1021/acscatal.9b04128
• Wei, B., Sharland, J. C., Lin, P., Wilkerson-Hill, S. M., Fullilove, F. A., McKinnon, S., Blackmond, D. G., & Davies, H. M. L. (2019). In Situ Kinetic Studies of Rh(II)-Catalyzed Asymmetric Cyclopropanation with Low Catalyst Loadings. ACS Catalysis, 10(2), 1161–1170. https://doi.org/10.1021/acscatal.9b04595