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The olefin metathesis reaction is a powerful and widely used catalytic tool to form carbon–carbon double bond. The increasing interest in this reaction in drug discovery and process chemistry is evidenced by the number of commercial applications used at manufacturing scale. Currently, the most applicable catalysts for this transformation are based on ruthenium–carbene complexes. However, with the currently increasing prices of ruthenium, research is directed to the use of more abundant transition metals in catalysis. The use of first-row transition metals in catalysis is an answer to the concern of heavily fluctuating prices and limited availability of precious metals in a market with increasing demand.
In this direction, iron has been suggested as an alternative metal for the olefin metathesis reaction. The advantages of using iron instead of ruthenium are related to the natural abundance, price, and toxicity. The difference in price is a strong motive to employ the use of iron as one kilogram of iron ($0.1401) is 1500 times cheaper than ruthenium ($19933.46). Another argument to choose iron over ruthenium is that in Chapter 232, providing the limits of elemental impurities in pharmaceutical products, substances, and excipients, ruthenium is classified as class 2B, whereas iron is classified as class 4. Thus, residual traces of ruthenium typically need to be below 10 ppm, whereas no assessment is required for iron as a result of its low inherent toxicity. In this light, the article by David Milstein et al. in Nature Catalysis is of interest as it describes the use of an iron-pyridine-based pincer complex as catalyst for the ring-opening metathesis polymerization (ROMP) reaction (doi.org/10.1038/s41929-022-00793-4), yielding the formation of polynorbornene with stereoregularity and high molecular weight (>107 g mol–1).
Figure 1. Ring-opening metathesis polymerization of norbornene catalyzed by 2.
An important consideration of using a newly developed catalyst is the synthetic accessibility of the active catalyst, a factor that can demotivate industry to incorporate new technologies in their manufacturing processes. The three-step synthesis includes the preparation of the pyridine pincer ligand, followed by the formation of the corresponding iron-chloride complex as the catalyst precursor. The active catalyst is formed by the addition of 2 equivalents of trimethylsilylmethyllithium. What stands out in terms of the synthetic applicability of such complex is the air and moisture sensitivity, which requires performing the synthesis in a nitrogen-filled glovebox.
The catalytic activity of iron was tested in ROMP of olefins by using norbornene as the substrate. When 100 equivalents norbornene were added to a benzene solution of 2 at 25 °C, an insoluble polymer formed quickly. This is the first example of iron used as catalyst in ROMP of olefins resulting in a TON of 800 and >99% yield of the desired polymer. However, the limitation of this study is the limited scope of olefins (table 1).
Figure 2: ROMP of cyclic olefins catalysed by iron complexes.
Importantly, the researchers demonstrated that the catalytic activity of this system stems exclusively from the iron complex and not from trace Ru or other trace metal impurities. This has been done by a series of tests including mass spectrometry analysis of the catalyst and by preparation a ruthenium analog complex which showed no ROMP activity. Furthermore, complex 2 catalyzes the ROMP of norbornene in the absence of a stirring bar, showing that deposited metal trace impurities are not involved. We strongly believe that when a different metal is employed in an established metal-catalyzed transformation, control tests and analysis are critical to support that trace impurities are not responsible for the catalytic activity.
Despite the breakthrough of this research, the ruthenium-based catalysts are much more applicable than the newly developed iron-based complexes. Important factors such as the stability of the catalyst and the reduced activity when exposed to air and moisture need to be addressed in the future. As the authors state “This study can be useful to other researchers in the field….I hope that iron- based catalysts can be developed further using this knowledge.” We fully underline these statements.
About InCatT (www.incatt.nl): InCatT B.V. is a company specialized in catalyst screening and catalyst development from initial catalyst-lead finding to process optimization. Over the years we have worked with different industries ranging from Flavor & Fragrance, Bio-based industry, Pharmaceutical, and bulk chemical industry to solve their most challenging projects.
Article: “Iron-catalysed ring-opening metathesis polymerization of olefins and mechanistic studies”
By Satoshi Takebayashi, Mark A. Iron, Moran Feller, Orestes Rivada-Wheelaghan, Gregory Leitus, Yael Diskin-Posner, Linda J. W. Shimon, Liat Avram, Raanan Carmieli, Sharon G. Wolf, Ilit Cohen-Ofri, Rajashekharayya A. Sanguramath, Roy Shenhar , Moris Eisen and David Milstein