Watching catalysts at work: Understanding the Power of Phosphite Ligands in Rh-catalyzed Hydroformylation through operando FlowNMR Spectroscopy

Hydroformylation is an industrially important chemical reaction that involves the addition of carbon monoxide and hydrogen to an olefin (alkene) to produce an aldehyde at perfect atom economy (i.e. with zero waste generated). Aldehydes are extremely versatile building blocks in the chemical industry that can be further processed to produce plasticizers, synthetic lubricants and fuel additives. Among the transition metals known to promote (catalyze) hydroformylation, rhodium (Rh) and cobalt (Co) are the most widely utilized due to their exceptional activity and selectivity in facilitating this transformation.

To tune and optimize the efficiency and selectivity of the hydroformylation process, researchers introduce ligands into the catalyst system. Ligands are carefully designed molecules that bind to the metal center of the catalyst, influencing its reactivity and determining the products formed. The role of ligands is critical in controlling the reaction’s selectivity and enhancing its overall efficiency. In hydroformylation reactions, phosphine and phosphite ligands have garnered significant attention for their impact on catalytic performance.

Phosphine ligands, such as triphenylphosphine (PPh₃), have been extensively studied and employed in hydroformylation catalysis. However, these ligands suffer from limitations such as susceptibility to oxidation and the formation of inactive catalyst species. In contrast, phosphite ligands offer distinct advantages over phosphines. Due to their distinct steric and electronic properties they accelerate the overall rate of the reaction and deliver very high selectivities. Furthermore, phosphite ligands exhibit superior resistance to oxidation, a crucial attribute that preserves the catalyst’s integrity and long-term activity.

However, despite their advantages, phosphite ligands can induce an unintended side reaction known as isomerization. Isomerization involves the rearrangement of the carbon skeleton within the olefin substrate, leading to the formation of undesired isomers and disrupting the desired product ratio. This competitive isomerization reaction vies with the primary hydroformylation pathway, ultimately compromising overall selectivity and producing low-value side products.

Understanding why a given ligand is effective in promoting fast and selective hydroformylation with minimal catalyst deactivation under certain reaction conditions is very difficult due to the complexity of the hydroformylation reaction. Many reaction intermediates are highly sensitive to a number of factors such as moisture, oxygen, temperature, and gas pressure and composition. A minor change in any of these conditions can lead to a significant shift in the speciation of the catalyst, rendering it very challenging to unravel the intricate details of how the ligand influences the reaction pathway.

To gain deeper insights into the mechanism of hydroformylation reactions and circumvent the challenges posed by sensitive intermediates, researchers typically employ non-invasive analytical methods. Infrared spectroscopy (IR) for example provides valuable information about certain functional groups within the reaction mixture and has long been used to monitor the progress of carbonylation reactions in situ. The amount of information about the catalyst itself that IR spectroscopy can provide is limited, however. In a more recent development, in situ nuclear magnetic resonance (NMR) spectroscopy has emerged as a powerful tool, enabling researchers to monitor the reaction in real-time and providing crucial information about reaction intermediates at the same time.

A new study published in the peer-reviewed journal ChemCatChem showcases the efforts of a collaborative team of researchers from prestigious institutions: Alejandro Bara-Estaún, Catherine Lyall and John Lowe led by Professor Ulrich Hintermair from the University of Bath, along with Professor Paul Pringle from the University of Bristol, Professor Paul Kamer from the Leibniz Institute for Catalysis, and Professor Robert Franke from Evonik Industries and the Ruhr-Universität Bochum. The research team investigated in depth the complexity of phosphite ligands within rhodium-catalyzed hydroformylation reactions. The study’s primary objective was to unravel the underlying mechanisms that contribute to the high catalyst activity and selectivity observed in the presence of phosphite ligands as compared to PPh₃ (a model system which the team have studied previously).

To achieve this ambitious goal, the authors harnessed the power of multi-nuclear FlowNMR spectroscopy. FlowNMR spectroscopy is a sophisticated technique that seamlessly merges flow reaction setups with the capabilities of high-resolution NMR spectroscopy. This innovative approach enables non-invasive real-time monitoring of reactions, facilitating the detection and characterization of reactive intermediates that play a pivotal role in the reaction pathway. In their carefully designed experiments, the authors employed a setup comprising a glass reactor connected to a cutting-edge FlowNMR apparatus. To ensure the highest precision and accuracy, the setup was meticulously purged with dry argon to eliminate any traces of air or moisture that could potentially interfere with the reaction. NMR spectra were systematically recorded throughout the reaction process using a state-of-the-art high field NMR spectrometer equipped with a high sensitivity cryoprobe. The use of internal standards paired with careful selection of acquisition parameters and calibration spectra to account for flow effects ensured accuracy and precision of the data obtained.

The research team succeeded in uncovering important insights into the intricate catalytic dance of hydroformylation. By carefully studying the reaction intermediates and the species actively participating in the reaction, they were able to establish a compelling connection between the intrinsic properties of the ligands used and the rate and selectivity of the hydroformylation reaction. Depending on the specific ligand type and quantity used, the authors observed variations in key reaction intermediates that could be correlated with productive catalysis. Ligands such as triphenylphosphite and biphephos readily bound to the [Rh(acac)(CO)₂] precursor leading to swift catalyst activation into hydrido-carbonyl complexes that catalyzed the hydroformylation reaction. In contrast, using sterically demanding phosphite ligands such as alkanox led to an extended unproductive activation time ranging from 8 to 12 hours under identical conditions.

Moreover, the authors reported the relationship between the concentration of CO in the reaction solution and the hydroformylation reaction’s outcome. Elevated concentrations of CO correlated with enhanced reaction rates and heightened selectivity, underscoring the pivotal role of CO availability in shaping the reaction’s trajectory by favoring the formation of more reactive reaction intermediates with less phosphite ligands bound to the Rh center which can capture and stabilize the metal again after turnover to protect it from deactivation. With bidentate phosphites, the geometry of their coordination to the metal could be observed to correlate with the product distribution obtained (i.e. the regioselectivity of the reaction), a concept that long been postulated and observed in model reactions but never seen “live” during the reaction before.

In conclusion, the study conducted by Ulrich Hintermair and his colleagues adds a new layer of understanding to the interplay between phosphite ligands and rhodium catalysts in hydroformylation reactions. The results obtained prove useful not only for efficient application of hydroformylation catalysts on industrial scale, but also constitute a solid foundation for the rational design and development of new ligands and catalysts with tailored properties. Prof. Hintermair points out that the further development and application of operando FlowNMR techniques supplemented with orthogonal analytical techniques as pursued in the Dynamic Reaction Monitoring Facility at the University of Bath can be expected to produce more exciting advances in other areas of homogeneous catalysis.