From the discovery of the Ziegler Natta polymerization catalyst, which underpins modern synthetic materials, to the discovery of the Haber-Bosch synthesis of ammonia, which enables the large-scale production of fertilizer essential to global food production, organometallic chemistry and catalysis are two of the main drivers of human innovation.
The advent of enantioselective catalysis utilizing transition metal complexes has revolutionized organic synthesis enabling the efficient construction of complex organic molecules with unprecedented efficiency. The general principles governing enantioinduction and catalytic activity for a wide range of important catalyst structures and reactions have been established thanks to the pioneering work of luminaries in the field of asymmetric catalysis such as Knowles, Noyori, and Sharpless as well as the monumental contributions of Heck, Negishi, and Suzuki, in the field of catalytic cross-coupling reactions utilizing transition metal complexes.
Thanks to the large number of powerful chemical transformations, which have been developed using transition metal complexes, the field of synthetic chemistry has largely moved beyond the question of whether any particular molecular structure can be made, to the pursuit of developing methods that enable structures to be prepared with increasing efficiency and stereocontrol, utilizing readily available starting materials.
In this vein, the development of enantioselective multicomponent coupling reactions that enable diverse product motifs to be prepared efficiently, in a modular fashion from simple and readily available chemical building blocks will increasingly drive innovation at the forefront of modern organometallic chemistry and catalysis.
Engaging renewable chemical resources is vitally important as increasing global energy demands decrease available hydrocarbon-based materials. Yet, renewable chemical feedstocks, such as phenols, are chronically underutilized due to the mechanistic challenge of engaging these often less-reactive compounds in pharmaceutical and industrial processes designed around the use of non-renewable reagents. Developing new catalytic processes specifically designed to engage abundant and inexpensive renewable reagents will provide an arena in which to craft innovative approaches to challenging problems of measurable and imminent importance to society.
I anticipate that the promise this area of research holds will be proportional to the challenges the organometallic chemistry community will encounter in its pursuit. It will become increasingly necessary to combine the principles of rate acceleration and stereocontrol that have been traditionally segregated into the separate domains of organometallic synthesis and transition metal catalysis with those of enzymatic- and organocatalysis. The design of new catalysts and cooperative multi-catalyst systems, which combine the potent reactivities of transition metal complexes with the principles underpinning rate acceleration and enantiocontrol in non-covalent organocatalysis, will become increasingly important.
Discoveries in merging organometallic chemistry with photoredox catalysis and electrochemistry as pioneered by Macmillan, Baran, and others will become increasingly prominent and have a lasting impact on organic synthesis.
In addition to advances in these areas, discoveries in the merging of machine learning with large chemical data sets will likely fundamentally reshape the world in the coming century. Organic and organometallic reactions, which, in contrast to enzymatic and organocatalytic reactions, often involve well-defined covalent interactions and discreet intermediates of moderate size, will likely serve as a training ground for this emerging technology and be the earliest domain of chemistry to substantially benefit from these advances. Researchers such as Sigman have pioneered merging parameterized data sets with computational predictive modeling. Machine learning can harness data sets generated by industry and academia to generate programs that can accurately interpret and predict chemical reactions. This has implications for improving reaction discovery, planning chemical routes, and guiding reaction optimization, fundamentally improving all areas affected by chemistry.
Synthetic and methodological advances in organometallic chemistry have enabled the preparation of new plastics, drug molecules, fine chemicals, and other consumer products(1). The tangible benefits of fundamental studies ranging from olefin polymerization to cross-coupling demonstrate the significant impact that organometallic compounds can have on daily life. This precedent emphasizes that future solutions to global energy and environmental challenges will require contributions from organometallic chemists. Target reactions such as the reduction of CO2 to useful feedstocks and the oxidation of water to hydrogen-based fuels are of tremendous global importance and have spurred the development of novel molecular catalysts(2,3). The current synthetic toolkit for designing selective and efficient catalysts includes ligand properties such as donor strength, steric bulk, lability and back-bonding, among others (1). An expansion of this toolkit to include oriented electric fields built into organometallic molecules would expand the scope of organometallic reactions and prove a powerful tool for controlling reactivity and selectivity.
Although proposed to have dramatic effects on catalytic rates and product selectivity in enzymatic(4) and heterogeneous systems(5,6), the application of electric fields in organometallic and inorganic complexes has only been preliminarily explored(7,8). Through the polarization of electron density, electric fields can be expected to alter catalyst properties and reaction mechanisms. For example, catalyst characteristics such as nucleophilicity, redox potential, and the arrangement of molecular orbitals will all be sensitive to where electron density is localized within a molecule. Additionally, the energy of polar transition states and intermediates will be responsive to the orientation of an electric field. By selectively stabilizing one transition state or intermediate over another, electric fields have the potential to accelerate reaction rates, change the preferred mechanism, and even disfavor off-cycle pathways. Combining these effects suggests that electric fields have the potential to completely alter the product distribution, speed, and overpotential of a reaction. These factors are generally applicable to catalytic reactions and especially important for electrochemical CO2 reduction as multiple products can be formed (2). Before any of these applications can be realized, more investigation is required in order to map out the ways in which electric fields influence reactivity. Organometallic complexes are the ideal platform for exploring the relationship between electric fields and catalysis due to their well-defined reaction sites and tunable ligand environments.
The incorporation of non-coordinating charged groups into a rigid ligand scaffold should result in an electric field in the corresponding complexes(9). The synthetic groundwork for preparing such complexes has already been demonstrated by zwitterionic systems incorporating ligands with carboxylate(10), borate(11), ammonium(7), and cation binding functionalities(8). The remaining challenge is to orient the resulting electric field in a direction that facilitates the desired reaction and/or catalyst properties. Developing structure activity relationships between the location of a charged group and the resulting effect on rates and catalyst properties is the first step towards the rational design of catalysts with internal electric fields. One of the most commonly used parameters for quantifying substituent effects is the Hammet parameter, an empirical measure of how various ligand substituents alter reaction equilibria such as the pKa of carboxylic acids(12). This parameter has been further broken down into contributions from resonance (in aromatic systems) and inductive/electrostatic effects. However, most substituents which have been studied are neutral, and charged substituents frequently deviate from the typical correlations(12). Although inductive and electrostatic effects have historically been considered together, an important challenge for quantifying the effect of electric fields exerted by charged groups is deconvoluting these contributors. Developing an empirical and quantitative method of relating electrostatic field effects to charged groups at specific distances and angles would provide synthetic chemists with the basis to rationally design electric fields into ligand scaffolds. Concurrent studies characterizing the influence of charged ligands on fundamental organometallic reaction steps, such as oxidative addition or ligand substitution, would provide a foundation for predicting how ligand imposed electric fields might alter more complicated reaction mechanisms. Drawing from these studies, a library of commercially-available charged ligands with known electric field effects could be prepared. This would provide synthetic chemists with a straightforward method for investigating electric field effects in catalytic screening experiments.
Organometallic complexes with distal charges are uniquely suited for probing electric field influences as every molecule will exert the same electric field on the reaction site, allowing ensemble measurements to accurately reflect interactions with the intramolecularly defined electric field. In contrast, the determination of field-reactivity relationships in heterogeneous metal and metal oxide systems is complicated by the presence of surface defects, which can lead to inhomogeneity in the effective field over the surface(5). Overall, the design of molecules which optimize the internally applied electric field to facilitate a reaction would provide a new approach towards driving catalysis. The future of organometallic chemistry is to explore the influence of electric fields on reactivity and apply this knowledge to address chemical challenges of global importance.
- R. H. Crabtree, The Organometallic Chemistry of the Transition Metals, John Wiley & Sons, Inc., Hoboken, 5th edn., 2009.
- R. Francke, B. Schille and M. Roemelt, Chem. Rev., 2018, 118, 4631.
- J. D. Blakemore, R. H. Crabtree and G. W. Brudvig, Chem. Rev., 2015, 115, 12974.
- S. D. Fried and S. G. Boxer, Annu. Rev. Biochem., 2017, 86, 387.
- F. Che, J. T. Gray, S. Ha, N. Kruse, S. L. Scott and J.-S. McEwen, ACS Catal., 2018, 8, 5153.
- S. Ciampi, N. Darwish, H. M. Aitken, I. Díez-Pérez and M. L. Coote, Chem. Soc. Rev, 2018, 47, 5146.
- I. Azcarate, C. Costentin, M. Robert and J.-M. Savéant, J . Am. Chem. Soc, 2016, 138, 16639.
- T. Chantarojsiri, J. W. Ziller and J. Y. Yang, Chem. Sci., 2018, 9, 2567.
- A. H. Reath, J. W. Ziller, C. Tsay, A. J. Ryan and J. Y. Yang, Inorg. Chem., 2017, 56, 3713.
- R. Puerta-Oteo, M. V. Jiménez and J. J. Pérez-Torrente, Catal. Sci. Technol., 2019, 9, 1437.
- J. M. Smith, Comments Inorg. Chem., 2008, 29, 189.
- C. Hansch, A. Leo and R. W. Taft, Chem. Rev., 1991, 91, 165.
Buchwald Research Group (MIT)
Application for the 2019 Ereztech Young Organometallic Scientists Award
Organometallic chemistry was born at the intersection of two disciplines, as a hybrid of organic and inorganic chemistry. Accordingly, the field has always been characterized by a fluid adaptability and fearlessness toward expanding its boundaries. These same qualities will propel organometallics in the forthcoming decades, steering its practitioners not only to uncover better solutions for its most prominent problems, but also to continuously redefine its scope to address increasingly interdisciplinary challenges.
Many prior eminent successes of organometallics were products of matchmaking: that is, discerningly pairing fundamental insights with appropriate applications. Research in coordination chemistry and chiral ligands produced asymmetric hydrogenation; investigation of mysterious byproducts in Ziegler–Natta catalysis enabled the development of olefin metathesis; and a purely academic curiosity, the Pd-catalyzed conjugate addition of organomercury compounds, gave rise to revolutionary cross-coupling technologies. Looking forward, the advent of metallaphotoredox reactions, the ever-growing lexicon of selective C–H activation transformations, and the renaissance of preparative electrochemistry represent recent examples of concepts that have proven their power yet await their respective occasions for disruptive impact. As we continue to discover and harness new fundamental processes, we are repeatedly reminded that the interface of organometallics with synthetic chemistry remains ripe with opportunity.
But the field stands poised for revolutionary progress well beyond organic fine chemical manufacturing. The role of metal complexes in some modern applications could hardly have been imagined a generation ago. For instance, the invention of palladium-mediated bioconjugation reactions have provided exceptionally rapid and selective tools for linking peptides, small molecules, and even proteins with biomolecules, carrying tremendous potential to enable transformative technologies for medicine and chemical biology. The frontiers of organometallic synthesis are also primed to profoundly affect our understanding of heterogeneous catalysis and reaction engineering at surfaces. Advances in our ability to synthesize well-defined and monodisperse multimetallic complexes have yielded model complexes midway between single-metal homogeneous catalysts and many-metal solid-state catalysts. Soon, this reductionist approach may play a significant part in illuminating the workings of surface catalysis and revising theories of metal–metal bonding. Finally, besides by human ingenuity, the goals of our field will be driven to reinvention also by necessity. Depleting resources and the continual devastation of the environment by human behavior demands radical change, in which organometallic chemists will play a leading, indispensable function. Our response so far includes the development of first-row metal replacements for their precious counterparts, an increased emphasis on “green” reagents such as molecular hydrogen and oxygen, and the advancement of energy technologies based on organometallic processes such as photochemical water splitting.
In short, the organometallic horizon is bright because it is broad. Thanks to its history of adaptation, we can rest assured that the field will rise to the manifold challenges on its skyline. Our confidence should be further bolstered by parallel breakthroughs in adjacent fields of science and engineering. Notable contemporary advances include: first, the exponentially rising power of computation, as well as increasingly sophisticated methods for relativistic DFT, linearly scaling coupled cluster, and machine learning; and second, drastically improved and cost-efficient instrumentation and techniques for characterization, including MicroED and the crystalline sponge method, which can elucidate structural information where previously tedious (or impossible) single-crystal X-ray diffraction was the sole resort.
Of particular importance is the marriage of automation, computational power, and human intelligence, quickly emerging as a radical, new concept not only in chemistry, but in all scientific contexts and in research more generally. Traditionally, besides by shrewd insight and logical deduction, many of the breakthroughs in organometallic chemistry have come by serendipity. It is hard to imagine that big-data approaches to automated reaction discovery and synthetic planning will not have a transformative and accelerating influence on this process, especially since machine-learning methods have already produced significant progress in other disciplines. For instance, might a computer one day tell us what catalysts to make next, what experiments to run, what published work might be relevant, or how to make important complexes that have eluded synthesis? Moreover, can a machine automatically make these catalysts, run these experiments, read these papers, and synthesize unprecedented substances? Each of these hypothetical tools is a current topic of vigorous research, and I hope not only to take advantage of them in my future research, but to participate in their development and maturation.
At the same time, these exciting prospects are accompanied by some tougher, long-term issues that our community must address. For instance, how much of the scientific process should be automated? Of course, the delegation of routine tasks such as literature searching, route planning, and reaction screening to machines might enable the scientist to be a more efficient and creative. At the other extreme, if computers could demonstrate true learning and participate in the creation of knowledge and conceptual advances in chemistry, we might wonder: is any role left for human expertise, and what would that expertise look like? The answer to these questions affects not only the future of organometallic chemistry, but all of academia and society more broadly.
As a concluding remark, I note that the innovations or challenges mentioned above are meaningless without the training of new generations of inspired, broad-minded, and socially conscientious organometallic scientists. For early-career chemists, the impact of recognition and encouragement from corporations like Ereztech and public institutions cannot be overstated. With their support, these students can assume their future roles as leaders in organometallic chemistry and catalysts in bringing the vision outlined above to fruition.