What is metal catalysis?
Metal catalysis exploits a transition metal to effect a particular chemical transformation that may not be readily available without the metal present, and has become well-established as a key means for bond-forming processes in the pharmaceutical, agrochemical and industrial materials industries. Transition metals are commonly used because they can access a range of different oxidation states, which are often required within the mechanistic pathway. In fact, metal catalysis has had such an impact upon the world that several Nobel Prizes in Chemistry have been awarded in this field (Sharpless, Meldal and Bertozzi in 2022 for “the development of click chemistry and bio-orthogonal chemistry”; Heck, Negishi and Suzuki in 2010 for “palladium-catalysed cross-couplings in organic synthesis”; Grubbs, Schrock and Chauvin in 2005 for “the development of the metathesis method in organic synthesis”).
There are two types of catalyst: heterogeneous and homogeneous. In a heterogeneous process the catalyst remains in a different state to the reaction mixture throughout the reaction, with the catalyst usually a solid and the reaction mixture a solution. An example of a heterogeneous catalyst is Pd/C, which is used during hydrogenation reactions. In a homogeneous process, the catalyst is the same state as the reaction mixture (usually in solution), either by virtue of its physical state, or that it dissolves in a solvent.
Scheme 1: General overview of a reaction using a transition metal catalyst where various oxidation states are accessed.
Key considerations
The use of metal catalysts to effect key transformations within flow has rapidly expanded. Catalysts can either be flowed through a system alongside the reagents, or immobilised onto a solid support system. Methods for immobilisation including covalent and ionic bonding, adsorption, or encapsulation [1]. Although immobilisation was seen as game-changing due to the possibility to re-use and recycle the catalyst, an increasing body of evidence suggests that if the catalytic cycle generates soluble species e.g. Pd(II) some leaching of metal can occur, although it is important to note that this issue does not affect all metal-mediated reactions; hydrogenation, for example, rarely leads to leaching [1]. Leaching means that catalytic activity decreases over time and the leached metal needs to be removed, especially in pharmaceuticals where there are strict limits on heavy metal content in the final product. Recent work has focussed on addressing this issue, with non-leaching, encapsulated, silica-supported palladium catalysts available for both Suzuki-Miyaura and Heck cross-couplings [2].
Benefits of continuous flow for metal catalysis
Despite the issue of leaching, significant advantage is offered by flow chemistry when using metal catalysis, including the opportunity to work with gases more safely and at high pressure (for example during carbonylation), rapid scale-up, temperature control, and rapid optimisation of reaction conditions and library generation. In addition, in-line purification and scavenging of leached metals is possible. Finally, the high concentration of catalyst and increased mass transfer in a microreactor means that reaction rates and turnover numbers (TON) are often elevated when compared with batch mode.
Oxidative Heck coupling
Larhed and co-workers disclosed a palladium(II)-mediated oxidative Heck reaction, where an aryl boronic acid was coupled with an alkene to generate a range of products [3]. Aryl boronic acids are commonly used as Suzuki–Miyaura substrates within medicinal chemistry due to their ease of preparation and the broad array that are commercially available, therefore expansion of their use to Heck couplings is valuable. Products were produced rapidly in good yields, with electron-poor and electron-rich substrates tolerated and telescoping to give a two-step vinylation–arylation procedure in one operation also possible, Scheme 2. In addition, the example highlighted shows that excellent chemoselectivity could be achieved with an aryl boronic acid undergoing oxidative addition in the presence of an aryl bromide.
Scheme 2: Continuous flow arylation of n-butyl acrylate with an arylboronic acid.
Suzuki–Miyaura coupling
Lipschultz, in collaboration with Novartis, disclosed a Suzuki–Miyarua coupling using a Vapourtec E-Series and a heterogeneous nanocatalyst comprising of Fe/Pd nanoparticles encapsulated in the surfactant TPGS-750-M, Scheme 3 [4]. Addition of 2-MeTHF allowed for in-line separation and processing of the products. In this case the Vapourtec E-Series reactor provided advantage over other systems as it could be equipped with a peristaltic backpressure regulator, which avoided the clogging issues when processing suspended nanoparticles.
Scheme 3: Micelle-catalysed biaryl couplings using Fe/Pd nanoparticles. NB NP denotes nanoparticle.
Carbonylation
Flow chemistry can facilitate the use of gases safely, without the risk of explosion. Leadbeater and Mercadante used continuous flow to effect palladium-catalysed alkoxycarbonylation of aryl iodides using 0.5 mol% Pd(OAc)2 at 120 °C, with no additional ligands required [5]. Products were generated in good yield and a range of substrates were tolerated, with the formation of both ethyl and propyl esters.
Ley and co-workers also used a tube-in-tube reactor based on Teflon® AF-2400, which allows passage of gas (in this case carbon monoxide) into a stream of solvent [6]. This system was efficient in the flow carbonylation of aryl iodides and bromides with a variety of nucleophiles. The work was further extended such that sequential introduction of two gases (carbon monoxide and a gaseous nucleophile) was achieved, allowing dimethylaminocarbonylation of aryl iodides.
The key advantage that flow offers in this case is the ability to use a toxic gas (CO) at high pressure while only requiring a small volume of gas at any one time. This both reduces any risk in terms of toxicity, as well as from explosion [6]. In addition, the tube-in-tube reactor allows for careful control of gas flow, reducing the likelihood of catalyst poisoning by excess CO [5].
Negishi coupling
The possibility to combine palladium-catalysed coupling with photochemistry through use of the Vapourtec photochemical reactor means that light-mediated cross-couplings can also be accessed. In one such example, a visible-light-induced Negishi coupling is enabled by activation of the Pd(0)-Zn complex, leading to deactivated aryl iodides undergoing coupling with organozinc species, Scheme 4 [7].
Scheme 4: Use of a visible-light-induced Negishi coupling to prepare functionalised aromatic rings.
During scale-up, the organozinc species was also generated in flow by pumping ethyl bromoacetate over activated zinc, and then combining this stream with a solution of methyl 2-bromobenzoate, Pd(dba)2 and JohnPhos. Yields were significantly improved for the flow procedure when compared with batch (97% in flow vs 36% in batch).
Other metal-mediated reactions
The use of palladium within organic chemistry is well-established, but other transition metals can also be used for generation of important intermediates. For example, click-chemistry using copper-catalysis, as well as oxidative cleavage of alkenes using ruthenium and Stille polycondensation have all been disclosed.
More unusually, an InCl3-mediated Povarov reaction between various aryl imines and cyclopentadiene, which was generated by continuous distillation from the dimeric precursor, has been developed [8]. This is particularly impressive, as distillation was combined with flow chemistry, allowing the immediate generation and use of cyclopentadiene, an unstable species. A range of tetrahydroquinolines were produced on gram-scale in under 1 hour.
References
[1] Immobilized Transition Metals as Catalysts for Cross-Couplings in Continuous Flow—A Critical Assessment of the Reaction Mechanism and Metal Leaching (D. Cantillo and C. O. Kappe, ChemCatChem., 2014, 6, 3286 – 3305) https://doi.org/10.1002/cctc.201402483
[2] Robust and reusable supported palladium catalysts for cross-coupling reactions in flow (W. Reynolds, P. Plucinski and C. G. Frost, Cat. Sci. Technol., 2014, 4, 948 – 954) https://doi.org/10.1039/c3cy00836c
[3] Continuous Flow Palladium(II)-Catalyzed Oxidative Heck Reactions with Arylboronic Acids (L. R. Odell, J. Lindh, T. Gustafsson and M. Larhed, Eur. J. Org. Chem., 2010, 2270 – 2274) https://dx.doi.org/10.1002/ejoc.201000063
[4] Continuous slurry plug flow Fe/ppm Pd nanoparticle-catalyzed Suzuki–Miyaura couplings in water utilizing novel solid handling equipment (A. B. Wood, S. Plummer, R. I. Robinson, M. Smith, J. Chang, F. Gallou and B. H. Lipschutz, Green Chem., 2021, 23, 7724 – 7730) https://doi.org/10.1039/d1gc02461b
[5] Continuous-flow, palladium-catalysed alkoxycarbonylation reactions using a prototype reactor in which it is possible to load gas and heat simultaneously (M. A. Mercadante and N. E. Leadbeater, Org. Biomol. Chem., 2011, 9, 6575 – 6578) https://doi.org/10.1039/c1ob05808h
[6] A General Continuous Flow Method for Palladium Catalysed Carbonylation Reactions Using Single and Multiple Tube-in-Tube Gas-Liquid Microreactors (U. Gross, P. Koos, M. O’Brien, A. Polyzos and S. V. Ley, Eur. J. Org. Chem., 2014, 6418 – 6430) https://doi.org/10.1002/ejoc.201402804
[7] Photoinduced Palladium-Catalyzed Negishi Cross-Couplings Enabled by the Visible-Light Absorption of Palladium–Zinc Complexes (I. Abdiaj, L. Huck, J. M. Mateo, A. de la Hoz, M. V. Gomez, A. Díaz-Ortiz and J. Alcázar, Angew. Chem. Int. Ed., 2018, 57, 13231 – 13236) https://doi.org/10.1002/anie.201808654
[8] Integrating reactive distillation with continuous flow processing (M. Baumann, React. Chem. Eng., 2019, 4, 368 – 371) https://doi.org/10.1039/c8re00217g
