Hydroformylation or Oxo Synthesis/Process

Hydroformylation, or Oxo Synthesis, is used for the production of aldehydes from alkene compounds. The reaction is catalyzed by organorhodium or organocobalt compounds and adds a hydrogen atom to the C=C bond to form a C-C bond and a formyl group to the molecule, creating an aldehyde. Aldehyde compounds formed by hydroformylation are the basis for synthesis of many other compounds including alcohols, amines, carboxylic acids, etc. Thus, hydroformylation constitutes one of the most important chemical syntheses for producing bulk chemicals. Additionally, hydroformylation using catalysts with specific metal-ligand bonding is used in the chiral synthesis of more complex fine chemicals and pharmaceuticals. Though hydroformylation is considered a major homogeneous catalysis application, there are a number of heterogeneous hydroformylation systems that have been developed, often associated with rhodium complexes supported on various scaffolds.

Hydroformylation is the source for millions of tons of industrial chemicals that are produced each year. The large volumes of 1-alkene produced by the petrochemical industry helps to drive the extensive use of hydroformylation for industrial chemical processes. Though most long-chain, branched-chain and cyclic olefins can be hydroformylated, the most common starting chemicals are ethylene and propylene, which yield propionaldehyde, n-butyraldehyde and iso-butyraldehyde. Propionaldehyde from ethylene can be hydrogenated to form plasticizers, such as diethyl phthalates and long carbon chain alcohols used as surfactants and detergents. There is considerable interest and efforts in developing catalysts for asymmetric hydroformylations, resulting in the formation of enantiomer specific aldehydes. These in turn, are converted into a range of chiral specific molecules containing different functional groups. 

The overall hydroformylation mechanism is well-understood and the various steps in the mechanism result in the formation of either linear or branched aldehydes. Linear aldehydes are preferred in most industrial applications, so there is interest in developing chemistry that enhances the formation of the linear product. Key steps in forming either the linear or branched aldehyde is the insertion of the hydride and alkene ligands. The hydride can add either to the internal double bond carbon or the terminal carbon. In the former case, the linear aldehyde is formed; the latter case results in the formation of the branched aldehyde. Adding bulkier ligands to the metal center is one means of favoring the formation of linear aldehyde. For example, adding a trialkyl phosphine ligand (PR3) to HCo(CO)4 catalyst significantly increases the ratio of linear to branched aldehyde formed.

With respect to the catalyst, new cobalt and rhodium ligand-specific complexes/processes have been developed that enable hydroformylations to occur at lower pressures and temperatures, as well as yield longer catalyst lifetimes. Furthermore, there is significant effort in the development of catalysts and processes that control regioselectivity and enantioselectivity in asymmetric hydroformylations. Rhodium catalysts are generally more effective with respect to rate and can operate at lower temperatures and pressures than cobalt catalysts. However, newer organocobalt catalysts have been developed that approach the effectiveness of the far more costly rhodium complexes. 

Asymmetric hydroformylation is quite attractive, employing readily accessible alkenes and syngas to synthesize enantiomerically-enhanced aldehydes from which enantiospecific compounds with various functionalities can be further synthesized. There are challenges associated with asymmetric hydroformylation, such as depressed reaction rates that occur as a result of the lower reaction temperature required to achieve desired selectivity. To minimize these issues, asymmetric hydroformylations require organometallic catalysts with ligands that are different than those used, for example, in hydrogenation reactions. Ligand classes for asymmetric hydroformylations include mixed phosphine/phosphite, diphosphites, phospholanes, etc.

In addition to the type of catalytic complex used, asymmetric hydroformylations are affected by reaction temperature and CO pressure, either or both potentially altering reaction kinetics. As an example, in asymmetric hydroformylation of styrene, using higher CO pressures favors the formation of branched isomers, whereas lower CO pressure results in linear isomers. In-situ FTIR and Raman spectroscopy are useful techniques for investigating the kinetics of asymmetric hydroformylations catalyzed by metals with novel ligands, as well as for determining the affect of reaction variables on achieved performance. A more complete understanding of the trade-offs between reaction rate and enantiospecificity aids in determining the optimum reaction variables for a specific catalyst complex. 

Investigating Hydroformylation Catalysts and the Effect of Reaction Conditions on Reaction Performance

With respect to homogenous catalysts, in-situ molecular spectroscopy provides structural information on active reaction species present, some which may be transient. By measuring carbonyl band shifts in rhodium and cobalt hydroformylation catalysts, substantial insight into mechanism and catalytic pathways can be inferred. In-situ spectroscopy also directly measures the affect of reaction variables such as temperature and pressure on hydroformylation activity and selectivity. The diamond Attenuated Total Reflectance (ATR) sensors associated with ReactIR technology easily handle hydroformylation reaction conditions. Raman spectrometers can measure catalytic reactions non-invasively through quartz windows in pressure reactors. In either case, the information is obtained in real time without disturbing reaction condition. Raman spectroscopy has proven useful in investigating heterogeneous hydroformylation reactions.

EasyMax chemical reactors are available with pressure vessels ranging in size from 50 mL to 100 mL. The 50 mL vessel will handle pressures up to 200 bar; the 100 mL vessel accommodates pressures to either 60 bar or 100 bar. These elevated pressure vessels enable measurement of catalytic processes such as hydrogenation reactions and hydroformylations. EasyMax provides unparalleled automated control of reaction conditions and is ideal for chemical synthesis, parameter screening and characterization. Both ReactIR and ReactRaman in-situ molecular spectroscopic technology seamlessly integrate with EasyMax high-pressure vessels. iC software automatically manages reactor temperature, pressure, mixing and dosing rate, as well as controls the molecular spectroscopic measurements.

• Si-min Yu, William Snavely, Raghunath V. Chaudhari, Bala Subramanian, “Butadiene hydroformylation to adipaldehyde with Rh-based catalysts: Insights into ligand effects”, Molec. Catalysis, 2020, 484, 110721
• Drew M. Hood, Ryan A. Johnson, Alex E. Carpenter, Jarod M. Younker, David J. Vinyard, George G. Stanley, “Highly active cationic cobalt(II) hydroformylation catalysts”, Science, 2020, 367(6477), 542-548
• J. M. Dreimann, E. Kohls, H. F. W. Warmeling, M. Stein, L. F. Guo, M. Garland, T. N. Dinh, A. J. Vorholt, “In-situ infrared spectroscopy as a tool for monitoring molecular catalyst for hydroformylation in continuous processes”, ACS Catal., 2019, 9(5), 4308–4319
• Andreas Jörke, Andreas Seidel-Morgenstern, Christof Hamel, “Rhodium-BiPhePhos catalyzed hydroformylation studied by operando FTIR spectroscopy: Catalyst activation and rate determining step”, J. Mol. Catalysis A: Chem., 2017, 426 Part A, 10-14
• Sebastian Schmidt, Eszter Baráth, Christoph Larcher, Tobias Rosendahl, Peter Hofmann, “Rhodium-Catalyzed Hydroformylation of 1,3-Butadiene to Adipic Aldehyde: Revealing Selectivity and Rate-Determining Steps”, Organometallics 2015, 34, 5, 841–847
• László T. Mika, László Orha, Eddie van Driessche, Ron Garton, Katalin Zih-Perényi, István T. Horváth, “Water-Soluble-Phosphines-Assisted Cobalt Separation in Cobalt-Catalyzed Hydroformylation”, Organometallics 2013, 32, 19, 5326–5332
• Daniela Fuchs, Géraldine Rousseau,  Lisa Diab, Urs Gellrich, Bernhard Breit, “Tandem Rhodium‐Catalyzed Hydroformylation–Hydrogenation of Alkenes by Employing a Cooperative Ligand System“, Angew. Chem. 2012, 51(9), 2178-2182
• Jaroslav Keybl and Klavs F. Jensen “Microreactor System for High-Pressure Continuous Flow Homogeneous Catalysis Measurements”, Ind. Eng. Chem. Res. 2011, 50, 11013–11022
• Benjamin Hentschel, Gregor Kiedorf, Martin Gerlach, Christof Hamel, Andreas Seidel-Morgenstern, Hannsjörg Freund, Kai Sundmacher, “Model-Based Identification and Experimental Validation of the Optimal Reaction Route for the Hydroformylation of 1‑Dodecene”,  Ind. Eng. Chem. Res. 2015, 54, 1755−1765

ReactIR Shows Active Catalyst Species and Tracks Key Intermediates Providing Kinetic and Mechanistic Information

Andreas Jörke, Andreas Seidel-Morgenstern, Christof Hamel, “Rhodium-BiPhePhos catalyzed hydroformylation studied by operando FTIR spectroscopy: Catalyst activation and rate determining step”, J. Mol. Catalysis A: Chem., 2017, 426 Part A, 10-14n.

ReactIR measurements were performed on the hydroformylation of 1-decene by a rhodium catalyst having the diphosphite molecule, BiPhePhos, as a ligand. In-situ IR measurements of the transformation of the precursor Rh compound, Rh(acac)(CO)₂ to the activated HRh(BiPhePhos)(CO)₂ catalyst, were of special interest. This later complex was identified as the major catalyst intermediate as the hydroformylation proceeded, and catalyst degradation via oxidation was not observed since P=O bonds were not present in the IR spectra. The authors report that the turn over frequency indicates that the Rh-BiPhePhos catalyzed hydroformylation is first order with respect to 1-decene concentration and that the rate determining step is the olefin coordination.

The precursor Rh complex exhibited Rh-CO bands at 2085 cm^-1 and 2014 cm^-1 and these bands disappear when BiPhePhos is introduced indicating replacement of CO by the diphosphite ligand. After H₂ is introduced, CO vibrations at 2077 and 2017 are observed consistent with the literature assignments for the Rh-hydridodicarbonyl complex. When the olefin is injected, the C=C band at 1643 cm^-1 is observed, which disappears as the hydroformylation proceeds concurrent with the formation of the intense undecanal C=O band at 1729 cm^-1. The normalized ratio of these bands provide the conversion measurement of the 1-decene and calculation of the turn over number. 

ReactIR Provides Insight into Reaction Pathways, Catalyst Selectivity and Activity

Si-min Yu, William Snavely, Raghunath V. Chaudhari, Bala Subramanian, “Butadiene hydroformylation to adipaldehyde with Rh-based catalysts: Insights into ligand effects”, Molec. Catalysis, 2020, 484, 110721

The authors report that butadiene hydroformylation to adipaldehyde via organorhodium catalysis is an option for producing C₆ compounds, such as adipic acid and hexamethylenediamine. For this reason, they sought to improve adipaldehyde yield by gaining insight into reaction pathways and to determine how reaction conditions affect activity and selectivity. Rh complexes with eight different ligands were systematically investigated using data acquired from in-situ IR measurements. They report that for hydroformylation of butadiene at 80 °C and 14 bar syngas (molar CO/H₂ = 1) pressure, the ligand/Rh ratio, rhodium concentration, butadiene concentration and syngas pressure do not affect adipaldehyde selectivity. However, they found that the selectivity is highly dependent on the type of ligand employed and the bite angle of the ligand. Based on the ReactIR data, they propose that lower selectivity may result from the formation of the stable rhodium η³-crotyl complex with the various Rh complexes.

ReactIR Provides Insight into Catalyst Species, Activity and Stability

Drew M. Hood, Ryan A. Johnson, Alex E. Carpenter, Jarod M. Younker, David J. Vinyard, George G. Stanley, “Highly active cationic cobalt(II) hydroformylation catalysts”, Science, 2020, 367(6477), 542-548

The authors report the development of cobalt catalysts for hydroformylation of alkenes to form aldehydes that are nearly as active as costly rhodium-based catalysts. These novel cationic cobalt(II) bisphosphine hydrido-carbonyl catalysts are hundreds of times more active than the original neutral cobalt catalysts, HCo(CO)₄ and HCo(CO)₃(PR₃) and operate under milder conditions such as lower pressures. They report that for simple linear alkenes, these catalysts have low linear-to-branched (L:B) regioselectivity, but high L:B selectivity for internal alkenes with alkyl branches. Furthermore, they find that the new catalysts are resistant to degradation and have long usable lifetimes.

In-situ IR measurements under actual reaction conditions reveal the presence of several active cationic catalyst species and provide insight into the stability of the catalyst as a function of time. ReactIR measurements show few changes in the carbonyl region of the spectra between 33 and 96 hours. The resulting catalyst solution was tested and found to be as effective for hexene hydroformylation as a fresh catalyst precursor sample.