Hydrogenation Reactions

Hydrogenations are among the most important reaction class in the production of both bulk and fine chemicals. By adding hydrogen atoms to an organic compound, double or triple bond functionality is reduced, forming single bonds. In a single step, a hydrogenation reaction allows the formation of C-C simple bonds from alkenes and alkynes, C-O bonds from ketones, and aldehyde or esters, and C-N (amines) from imines or nitriles, etc. 

Metal catalysts are often used in hydrogenation reactions to reduce the high energy barrier to the transformation. For example, in the case of transforming alkenes and alkynes into alkanes, nickel, palladium or platinum catalysts are required. Hydrogenations can either be homogenous or heterogenous, using metals adsorbed on various substrates. In the former case, for example, rhodium and iridium metal catalysts that are coordinated with specific ligands are used to achieve asymmetric synthesis hydrogenation. In the latter case, alkanes are formed from double or triple bond carbon moieties. In all cases the choice of the catalyst greatly influences a hydrogenation reaction, as well as the catalyst concentration, solvent, substrate purity, temperature, and pressure. 

The use of hydrogenation reactions in industrial and commercial applications are numerous and well known. In food products, liquid food oils are hydrogenated to form solid edible fats. In the petroleum industry, various hydrocarbons are hydrogenated using catalysts to form alkanes in gasoline, and hydrogenation of coal provides an alternative source of fuel. Hydrogenation of carbon monoxide is used to form bulk methanol and the Haber-Bosch process uses metal catalysts to synthesize ammonia from nitrogen and hydrogen.

In fine chemicals used or produced in the pharmaceutical chemistry, hydrogenation reactions are equally important. A classic example is the use of chlorotris(triphenylphosphine)rhodium, Wilkinson’s catalyst, to reduce alkenes and alkynes without affecting other functional groups in a molecule. Another family of catalysts with Josiphos diphosphine ligands, are used for enantioselective hydrogenation reactions. There are many specifically tailored catalysts for hydrogenations that use transition metals with chiral ligands that transfer chirality to the target compound.   

Hydrogenations reactions are often performed under potentially challenging conditions including elevated pressure and temperature in the presence of catalysts. This makes monitoring critical for two closely linked reasons: 1. Optimized Yield; and, 2. Safe Operation. Safe reactions are well controlled reactions, which produce intended products and minimize unwanted and potentially hazardous side products. As in so many reactions, understanding reaction initiation, mechanism, conversion, and endpoint, as well as impurity or byproduct profile, enables faster decisions about what changes to chemical conditions or process parameters need to be made. 

The use of in situ FTIR reaction monitoring and reaction calorimetry reduces the number of experiments and time to scale-up a process, increase safety, selectivity and yield, reduces cycle time and minimize byproduct formation.  Furthermore, for accurate quantitative  measurement of reaction species and impurity profiles by off-line HPLC,  EasySampler allows automated, unattended sampling of hydrogenation reactions at pressure and temperature as well as automated quench and dilution of the removed samples, to support offline HPLC measurements 

Chemical Synthesis Reactors and Reaction Calorimetry

• Precise, automated control to test and optimize reaction parameters
• Measure heat flow under actual reaction conditions – pressure, temperature, dosing, agitation, etc. 
• Ensure safe and optimized reactions - support safe scale-up

FTIR Spectrometers

• Real-time tracking of reaction progress; follow reactants, reagents, intermediates, products and by-products
• Measure reaction species in the presence of solid particles and bubbles
• Obtain key kinetic and mechanistic information
• Eliminate difficulty of off-line measurements of reactions at pressure and temperature – minimize sample extraction and interference of reaction equilibria  

Inline Automated Sampling

• Sample and quench hydrogenation reactions under process conditions at pre-selected times
• Provide samples for offline HPLC analysis of impurity profiles, kinetics and to meet regulatory requirements
• Support quantitative HPLC measurement of reaction species in order to calibrate IR trend plots

ReactIR FTIR spectroscopy is an in situ technique that provides instantaneous information and enables actionable decisions to be made in real-time. Since ReactIR probe technology is impervious to damage by most reaction conditions, solid particles, and gases, it offers advantages over alternative analytical methods:

• Investigate homogeneous and heterogeneous hydrogenations under actual reaction conditions, including at elevated pressure and temperature
• Identify, track and measure reactants, reagents, products, reaction intermediates and by-products produced in hydrogenations
• Rapidly acquire data-rich information for determining reaction kinetics, understanding reaction mechanism and pathway
• Test and develop ideal reaction conditions for optimizing end-product yield and minimize side products
• Quickly screen catalysts and conditions for specific hydrogenation reactions
• Eliminate the introduction of air, moisture or disturbing reaction equilibria resulting from sample extraction

Learn how scientists at the University of Tokyo were able to leverage In Situ Spectroscopy to perform a Tandem Hydroformylation/Hydrogenation.

Probe-based automated, unattended sampling provides  representative reaction samples over extended periods of time – even under pressure.

At Novartis, researchers were able to gain a better mechanistic understanding of the factors affecting hydrogenation reactions and by-products. By adding quantitative HPLC measurements throughout the course of the hydrogenation reaction, where sampling had previously been impossible, assumptions were quickly corrected and a realistic mechanistic model drawn resulting in improved productivity and shortened timelines.

See how EasySampler enabled this insight. 

Hydrogenation processes are typically strongly exothermic, which is why a comprehensive safety and kinetic investigation, based on heat flow calorimetry, hydrogen uptake measurements, and online spectroscopy (mid-IR) are conducted before scale up. Predicting large scale process behavior, such as temperature or reaction time, and its impact on residual intermediate and impurity levels can be performed in the laboratory using a Reaction Calorimeter. Process scenarios based on mass and heat transfer, as well as full kinetic characterization, can lead to enhanced catalyst stability, optimum process temperature profile and reaction time.

• Zhang, Y-M., Yuan, M-L., Liu, W-P., Xie, J-H., Zhou, Q-L., “Iridium-Catalyzed Asymmetric Transfer Hydrogenation of Alkynyl Ketones Using Sodium Formate and Ethanol as Hydrogen Sources”, Org. Lett. 2018, 20, 4486−4489
• Ehnes , C., Lucas, M., Claus, P., “Effects of Various Solvents and Amines on the CO2 Hydrogenation to Formic Acid”, Chem. Ingen. Tech., 2017, 89(3), 303-309.
• Ehnes , C., Lucas, M., Claus, P., “In‐situ ATR‐IR Spectroscopy: Monitoring Hydrogenation of CO2 and Formation of Formic Acid”, Chem. Ingen. Tech., 2016, 88(10), 1474-1479.
• Liu, W-P., Yuan, M-L., Yang, X-H., Li, K., Xie, J-H., Zhou, Q-L., “Efficient Asymmetric Transfer Hydrogenation of Ketones in Ethanol with Chiral Iridium Complexes of SpiroPAP Ligands as Catalysts” ChemComm, 2015, 51, 6123-6125
• Hamilton, P., Sanganee, M., Graham, J., Hartwig,T., Ironmonger,A., Priestley, C., Senior, L., Thompson, D., Webb, M., “Using PAT To Understand, Control, and Rapidly Scale Up the Production of a Hydrogenation Reaction and Isolation of Pharmaceutical Intermediate”, Org. Proc. Res. Dev., 2015, 19 (1), pp 236–243
• Mitchell, C., Strawser, J., Gottlieb, A., Millonig, M., Hicks, F., Papageorgiou, C., “Development of a Modeling-Based Strategy for the Safe and Effective Scale-up of Highly Energetic Hydrogenation Reactions” Org. Process Res. Dev. 2014, 18, 1828−1835
• Crump, B., Goss, C., Lovelace, T., Lewis, R., Peterson, J., “Influence of Reaction Parameters on the First Principles Reaction Rate Modeling of a Platinum and Vanadium Catalyzed Nitro Reduction”, Org. Process Res. Dev. 2013, 17, 1277−1286
• Richner, G., van Bokhoven, J., Neuhold, Y-M., Makoscha M.,Hungerbuhler,K., “In situ infrared monitoring of the solid/liquid catalyst interface during the three-phase hydrogenation of nitrobenzene over nanosized Au on TiO2”, Phys. Chem. Chem. Phys., 2011,13, 12463-12471
• Littler, B., Looker, A., Blythe, T.,“Optimization of a Hydrogenation Process using Real-Time Mid-IR, Heat Flow and Gas Uptake Measurements”, Org. Process Res. Dev., 2010, 14, 1512–1517
• Casey, C., Beetner, S., Johnson, J., “Spectroscopic Determination of Hydrogenation Rates and Intermediates during Carbonyl Hydrogenation Catalyzed by Shvo's Hydroxycyclopentadienyl Diruthenium Hydride Agrees with Kinetic Modeling Based on Independently Measured Rates of Elementary Reactions”, J. Am. Chem. Soc., 2008, 130 (7), pp 2285–2295
• Blackmond, D., Ropic, M., Stefinovic, M., “Kinetic Studies of the Asymmetric Transfer Hydrogenation of Imines with Formic Acid Catalyzed by Rh−Diamine Catalysts”, Org. Process Res. Dev., 2006, 10 (3), pp 457–463

The authors report the use of a chiral spiro iridium catalyst for the asymmetric transfer hydrogenation of various alkynyl ketones to chiral propargyl alcohols with high yield and enantioselectivity.  They found that when using HCO2Na as the hydrogen donor, the alkynyl ketone converted to propargylic alcohol with 97% e.e.  To improve the speed of the hydrogenation they used HCO2Cs, since the cesium compound has higher solubility in ethanol than the equivalent sodium compound. 

In situ FTIR spectroscopy was used to track the asymmetric transfer hydrogenation and provide insight into the reaction mechanism.  The results show that HCO2Cs was converted to cesium ethyl carbonate (EtOCO2Cs) after providing hydrogen, and that the spectral peak for the ketone disappeared over time.  Information provided by the spectra indicate that the formate salt and EtOH serve as the hydride and proton sources, respectively.  

Zhang, Y-M., Yuan, M-L., Liu, W-P., Xie, J-H., Zhou, Q-L., “Iridium-Catalyzed Asymmetric Transfer Hydrogenation of Alkynyl Ketones Using Sodium Formate and Ethanol as Hydrogen Sources”,  Org. Lett. 2018, 20, 4486−4489. DOI:10.1021/acs.orglett.8b01787