Potential Applications of N-Heterocyclic Carbene- Metal Complexes in Industrial Processes

In 1991, Arduengo et al. reported the isolation of a stable N-heterocyclic carbene (NHC), which was the early beginning of numerous explorations in their application in diverse fields.[2] From these beginnings, N-heterocyclic carbenes have gained numerous attention, and today they are the most famous and powerful two electron-donating ligands in the modern era of organometallic chemistry. NHCs have found several applications not only organometallics chemistry, but also have great relevance to commercial processes. N-heterocyclic carbenes can bind to a plethora of main-group elements, non-metals, and semimetals as well as many d-block elements. In contrast to the wellestablished trivalent phosphines (PR3), N-heterocyclic carbenes display a strong σ-donating and weak p-accepting ability.[3,4]This remarkable eminence of NHCs made them their significance in diverse fields, for instance in the organometallic chemistry, and especially in homogeneous catalysis. The majority of applications of N-heterocyclic carbenes can be divided mainly into two parts; a) effective tools for the stabilization of various novel organometallic species, b) applications in homogeneous catalysis as ancillary ligands.

The applicability of low-valent and low-coordinate NHCs as twoelectron donors for various transition metals can be viewed by their characteristic sigmadonating ability of -hybridized lone-pair and empty pz-orbital can act as the acceptor orbital which can be filled by the filled p-orbital of transition metal atoms.[4] This short article emphasizes industrially relevant applications of carbenes supported various metal complexes.[1] Some of those widely used carbenes and their metal complexes are depicted in Figure 1 and Chart. As shown in the above chart, several ruthenium–NHC complexes have been synthesized by various groups and employed in the field of ring-closing and ring-opening metathesis.[5]This ring-closing metathesis technique of ruthenium-NHCs has been widely employed in different pharmaceutical companies for large-scale synthesis of various types of drug candidates. KOS-1584 (Figure 2) is a promising anticancer agent that is used to inhibit the growth of tumor cells in the human body[6] and it has been reported that the rutheniumNHC complexes (as shown in Figure 2) play a major role in the synthesis processes.[7]

Similarly, SB-462795 (Figure 3) has been recently developed as an effective cathepsin K inhibitor and proved an important therapeutic potential in the treatment of osteoporosis[8]. Ruthenium-NHC complex containing a supported C, O-chelating (as shown in Figure 3) ligand have been successfully employed as a catalyst in the ring-closing metathesis process to form a seven-membered ring in the synthesis of SB-462795.[7]TMC-435 (Figure 4) is a capable drug candidate used in combination with other medications for the treatment of hepatitis C.[9]To achieve the ring-closing metathesis in the preparation of TMC-435, ruthenium-NHC complexes (Figure 4) have been effectively used by many research groups and it has been reported that the ruthenium-NHC complexes have shown a much better efficiency in comparison to many other catalysts.[7]

Interestingly, palladium-based catalysts are often used in many industrial processes for variouspurposes, especially in the Sonogashira coupling reactions, Suzuki-Miyaura, and MizorokiHeck couplings, which are used to synthesize drug molecules and many other useful chemicals.[10] Similarly, the palladium-NHC complexes have been employed as catalysts for the telomerisation reactions on industrial scales. In addition, mesityl-carbene (IMes) supported palladiumNHC complexes (Figure 5) are also widely used as catalysts for the telomerisation of butadiene involved in the 1-octene process.[7]In this article, the exact number of NHC-metal complexes are not updated which have been employed in the different industrial process for various applications, however, the above reports clearly show the importance of NHCs and their metal complexes in several industrial activities. Lastly, it can be concluded that many more large-scale applications of NHCs and their metal complexes will appear in the near future with some new ideas and inventions.

REFERENCES

[1] C. S.J. Cazin (Ed.) Catalysis by Metal Complexes, Springer Netherlands, Dordrecht, 2011.

[2] A. J. Arduengo, R. L. Harlow, M. Kline, J. Am. Chem. Soc. 1991, 113, 361.

[3] a) A. Doddi, M. Peters, M. Tamm, Chem. Rev. 2019; b) M. N. Hopkinson, C. Richter, M. Schedler, F. Glorius, Nature 2014, 510, 485.

[4] H. V. Huynh, Chem. Rev. 2018, 118, 9457.

[5] E. Colacino, J. Martinez, F. Lamaty, Coord. Chem. Rev. 2007, 251, 726.

[6] E. T. Lam, S. Goel, L. J. Schaaf, G. F. Cropp, A. L. Hannah, Y. Zhou, B. McCracken, B. I. Haley, R. G. Johnson, S. Mani et al., Cancer Chemother. Pharmacol. 2012, 69, 523.

[7] O. Briel, C. S. J. Cazin in Catalysis by Metal Complexes (Ed.: C. S.J. Cazin), Springer Netherlands, Dordrecht, 2011, pp. 315–324.

[8] H. Wang, H. Matsuhashi, B. D. Doan, S. N. Goodman, X. Ouyang, W. M. Clark, Tetrahedron 2009, 65, 6291.

[9] Å. Rosenquist, B. Samuelsson, P.-O. Johansson, M. D. Cummings, O. Lenz, P. Raboisson, K. Simmen, S. Vendeville, H. de Kock, M. Nilsson et al., J. Med. Chem. 2014, 57, 1673.

[10] D. S. McGuinness, K. J. Cavell in Catalysis by Metal Complexes (Ed.: C. S.J. Cazin), Springer Netherlands, Dordrecht, 2011, pp. 105–129.