During the past century, organometallic chemistry has had an indelible impact in synthesis and catalysis (1), yet its potential is far from being fully realized. Future developments in organometallic chemistry are expected to improve human health and to address sustainability issues in economic development. Three topics are highly pertinent yet challenging: a) catalysis with first-row metals; b) catalytic asymmetric oxidative ether and amine synthesis; c) small molecule activation for organic synthesis. Although there are several prominent pioneering studies in each of these topics, it is too early to claim that these challenges are generally solved. At the first glance, the three challenges listed above are distinct from each other. However, they are closely related, and I believe that solutions will be built on a common set of new principles and key discoveries. Hence, I will discuss my personal perspective on future directions and concepts that I believe will reshape organometallic chemistry.
A. Mechanistic investigations into the nature of M–C species. (M = Fe, Co, Ni, and Cu)
Practical methods for asymmetric C(sp3)–O and C(sp3)–N bond formation have been pursued for decades due to the prevalence of these motifs in natural products and drug molecules. Beyond benzylic and allylic positions (2), catalytic asymmetric C(sp3)–O and C(sp3)– N bond formation is highly challenging. One emerging solution is copper-catalyzed hydroamination; however, this chemistry has the disadvantage of requiring stoichiometric silane and a pre-formed N–O regent (3). Radical couplings catalyzed by first- row transition metals would be a promising approach to address this problem (4). However, it is nearly unknown how to render such reactions enantioselective. Given the fact that the asymmetric radical heteroatom coupling has continued to prove problematic over the decades, despite increasingly massive chiral ligand libraries, it is time to adopt a new approach to tackle this problem beyond high-throughput screening. Surprisingly, the fundamental properties of the M–C bond in the putative organometallic intermediates in radical coupling processes remains largely unknown. A thorough investigation of the properties and the fate of the organometallic intermediate under radical coupling conditions would provide important information about how to achieve chiral induction.
Particularly, it is critical to establish whether the M–C bond is more like a σ bond or more like radical pair. Few fruitful studies have been reported probably due to the instability of the intermediates, the difficulty of characterizing paramagnetic species, and the fast reaction rates of key elementary steps. Thus, rather than relying on purely chemical methods, I propose to address this problem by merging techniques from chemistry and physics. On the chemistry side, metallacycle complexes will be designed by tethering the carbon chain of the substrate onto the ligand to enhance stability. Stoichiometric organometallic reactions will be carried out to understand the elementary steps of C–heteroatom bond formation. Spectrometric experiments that are not typically not employed by chemists will be carried in collaboration with colleagues in physics, such as measuring oxidation state and coordination environment of the metal center by synchrotron radiation and studying the transition state of the key elementary steps by ultrafast laser.
B. Catalytic small molecule activation for organic synthesis
N2 is among the most abundant small molecules and is an ideal potential amination reagent in organic synthesis. The Harbor–Bosch process reshaped agriculture by transforming nitrogen to ammonia using heterogeneous catalysis. However, incorporating nitrogen into more complicated organic molecules by homogeneous catalysis is virtually unknown (5). I propose to develop a polyfunctional catalyst system in which one part of the catalyst can activate N2 and another part can transfer the N atom onto the organic substrate for the sake of realizing amination reactions with nitrogen.
- Hartwig, J. F. Organotransition Metal Chemistry, From Bonding to Catalysis; University Science Books, 2010.
- a) Park, Y.; Kim, Y.; Chang, S. Chem. Rev. 2017, 117, 9247–9301; b) Nasrallah, A.; Boquet, V.; Hecker, A.; Retailleau, P.; Darses, B.; Dauban, P. Angew. Chem. Int. Ed. 2019, 58, 8192–8196; c) Rössler, S. L.; Petrone, D. A.; Carreira, E. M. Acc. Chem. Res. 2019, 10.1021/acs.accounts.9b00209; d) Cheng, Q.; Tu, H.-F.; Zheng, C.; Qu, J.-P.; Helmchen, G.; You, S.-L. Chem. Rev. 2019, 119, 1855–1969.
- Zhu, S.; Buchwald, S. L. J. Am. Chem. Soc. 2014, 136, 15913–15916.
- a) Gui, J.; Pan, C-M.; Jin, Y.; Qin, T.; Lo, J. C.; Lee, B. J.; Spergel, S. H.; Mertzman, M. E.; Pitts, W. J.; La Cruz, T. E.; Schmidt, M. A.; Darvatkar, N.; Natarajan, S. R.; Baran, P. S. Science. 2015, 348, 886–891; b) Crossley, S. W. M.; Obradors, C.; Martinez, R. M.; Shenvi, R. A. Chem. Rev. 2016, 116, 8912–9000.
- Guru, M. M.; Shima, T.; Hou, Z. Angew. Chem. Int. Ed. 2016, 55, 12316–12320.