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Jan 4, 2011 - tallic chemistry in meeting the needs of the future. Introduction. Demand for energy, materials, medicines, and foodstuffs is expanding ...
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Organometallics 2011, 30, 36–42 DOI: 10.1021/om1010319

The Future, Faster: Roles for High-Throughput Experimentation in Accelerating Discovery in Organometallic Chemistry and Catalysis† Sebastien Monfette, Johanna M. Blacquiere, and Deryn E. Fogg* Department of Chemistry and Center for Catalysis Research and Innovation, University of Ottawa, 10 Marie Curie, Ottawa, Canada K1N 6N5 Received November 1, 2010

High-throughput experimentation has enormous potential to accelerate the discovery and implementation of new methodologies based on organometallic catalysis. A perspective is presented of technical challenges and opportunities for advance. We highlight what we believe to be essential inventions, and key areas for exploration, for progress that will facilitate enlistment of organometallic chemistry in meeting the needs of the future.

Introduction Demand for energy, materials, medicines, and foodstuffs is expanding at an ever-increasing rate. The environmental capacity to sustain these needs, as we know, is not. The tension between these two constitutes one of the major challenges of the 21st century. It also delineates the major arena in which challenges to invention in organometallic chemistry can be anticipated, particularly in the form of new catalytic methodologies for clean, sustainable exploitation of available resources for energy use and for chemical synthesis. A pressing concern in this context is the long induction period that characterizes the discovery and implementation of efficient new catalytic transformations. A canonical model for discovery has evolved along with the field of organometallic chemistry, with which homogeneous catalysis is closely entwined. This standard model begins with catalyst design and proceeds to synthesis (including optimized, high-yield routes to organometallic or inorganic target molecules), purification and testing of the isolated complex(es), and iterative redesign based on both observed catalytic behavior and mechanistic studies that probe the fundamental reactions in the catalytic cycle (e.g., oxidative addition, reductive elimination, insertion, transmetalation, etc.) and elucidate rate-limiting parameters. The success of this approach is beyond question. Homogeneous catalysis has had a tremendous impact on commodity and fine-chemicals synthesis, driven by a level of sustained innovation unmatched in any other area of chemistry. Three Nobel prizes have been awarded in organometallic catalysis in the last 10 years: in asymmetric hydrogenation and oxidation (Noyori, Sharpless, Knowles; 2001),1 in olefin metathesis (Schrock, Grubbs, Chauvin; †

Part of the special issue Future of Organometallic Chemistry. *To whom correspondence should be addressed. E-mail: dfogg@ uottawa.ca. (1) (a) Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008–2022. (b) Knowles, W. S. Angew. Chem., Int. Ed. 2002, 41, 1998–2007. (c) Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2024–2032. (2) (a) Schrock, R. R. Angew. Chem. 2006, 118, 3832–3844. (b) Grubbs, R. H. Angew. Chem., Int. Ed. 2006, 45, 3760–3765. (c) Chauvin, Y. Angew. Chem., Int. Ed. 2006, 45, 3741–3747. pubs.acs.org/Organometallics

Published on Web 01/04/2011

2005),2 and most recently in palladium cross-coupling reactions (Suzuki, Heck, Negishi; 2010). These success stories also illustrate, however, the very long time scale from discovery to such widespread recognition: on the order of 30 years for cross-coupling, 40 years for asymmetric hydrogenation, and 50 years for olefin metathesis. The case of the Hartwig-Buchwald amination;invented in ca. 1995 and implemented in industry in less than 5 years;demonstrates that this time scale can be dramatically reduced where no adequate alternative exists.3 Industrial opportunities bring new urgencies, however, in time-to-market challenges and, increasingly, in not only sourcing suitable renewable-based feedstocks but also devising methodologies for their economically and environmentally sustainable exploitation. Clearly, new ways of thinking are needed to accelerate the pace of progress from discovery to understanding, optimization, and implementation. High-throughput experimentation (HTE) is of enormous interest for its potential to contribute in this regard;or, put another way, to capture the transformative potential of organometallic chemistry to help meet urgent societal needs. Here we present a perspective on the current state of the art for HTE in homogeneous catalysis, and highlight needs and new areas of opportunity in the as-yet underdeveloped interface between organometallic catalysis and organometallic chemistry. Target-driven screening (Figure 1) was the earliest application of HTE in homogeneous catalysis,4-6 and it remains the most extensively deployed. Showcase successes include the collaborative discovery of new, thermally more robust catalysts for the synthesis of isotactic polypropylene by (3) Hartwig, J. F., Palladium-catalyzed amination of aryl halides and related reactions. In Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi, E.-i., Ed.; Wiley: Hoboken, NJ, 2002; Vol. 1, pp 1051-1096. (4) de Vries, J. G.; de Vries, A. H. M. Eur. J. Org. Chem. 2003, 799– 811. (5) Reetz, M. Angew. Chem., Int. Ed. 2001, 40, 284–310. (6) Weinberg, W. H.; Turner, H. W., Impact of High-Throughput Screening Technologies On Chemical Catalysis. In High Throughput Screening in Chemical Catalysis; Hagemeyer, A., Strasser, P., Volpe, A., Eds.; Wiley-VCH: Weinheim, Germany, 2004. r 2011 American Chemical Society

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Figure 1. Flow chart outlining three dominant approaches to HTE in homogeneous catalysis: target-driven screening (commonly for catalyst discovery or process optimization), reaction discovery, and mechanistic analysis.

DOW and Symyx,7 and the astonishingly compressed discovery and implementation of a new asymmetric hydrogenation process (25 days from screening to scaleup) by Lefort, de Vries, and co-workers at DSM.8 A more recent approach, for which MacMillan favors the term “accelerated serendipity”, focuses on the discovery of new chemistry: that is, exploiting HTE to discover unexpected reactions or products.9 In either case, Alan Kay’s mantra “If you don’t fail 90% of the time, you’re not aiming high enough”10 applies. That is, a hit or miss screening tactic is adopted, in which misses are discarded and only hits are followed up. As with benchtop methods, the number of hits is normally minute relative to misses. The latter constitute (in conventional experimentation) either failed or only mildly successful experiments; in HTE “mild successes” can themselves be hits or leads for subsequent amplification. A third approach is complementary in its aims: it seeks to harness HTE for efficient compilation of mechanistic data.11,12 This strategy goes beyond hit and miss, capturing all of the data generated from the well plate and using it to formulate the deeper understanding essential to optimize the reaction in hand and to expand fundamental knowledge, on which broader insight rests. Irrespective of the model, the goal of HTE is not to cut down on the number of experiments (on the contrary, this number may well increase) but, by carrying them out much faster and ideally screening them in parallel, to compress the time penalty otherwise associated with large numbers of unsuccessful experiments. (7) Boussie, T. R.; Diamond, G. M.; Goh, C.; Hall, K. A.; LaPointe, A. M.; Leclerc, M. K.; Murphy, V.; Shoemaker, J. A. W.; Turner, H.; Rosen, R. K.; Stevens, J. C.; Alfano, F.; Busico, V.; Cipullo, R.; Talarico, G. Angew. Chem., Int. Ed. 2006, 45, 3278–3283. (8) Lefort, L.; Boogers, J. A. F.; Kuilman, T.; Vijn, R. J.; Janssen, J.; Straatman, H.; de Vries, J. G.; de Vries, A. H. M. Org. Process Res. Dev. 2010, 14, 568–573. (9) Treece, J. L.; Goodell, J. R.; Vander Velde, D.; Porco, J. A., Jr.; Aube, J. J. Org. Chem. 2010, 75, 2028–2038. (10) Crawford, C., On Game Design; New Riders Publishing: New York, 2003; p 440. (11) Boelens, H. F. M.; Iron, D.; Westerhuis, J. A.; Rothenberg, G. Chem. Eur. J. 2003, 9, 3876–3881. (12) Portal, C.; Bradley, M. Org. Biomol. Chem. 2007, 5, 587–592.

The ideal, however, is not yet generally attainable. The scope and sophistication of the robotic hardware and software for experimental design and control generally surpasses that of the analytical capacities integrated into the HT workflow.13 Development of the latter is thus a key area of opportunity. The discussion below examines current and projected needs that would promote recruitment of HTE as a powerful tool to exploit the opportunities created by organometallic chemistry in catalysis.

Analytical Tools for HT Catalysis: A Snapshot of the State of The Art Where We Come From. The nature of the analytical tools that have been integrated into the HTE workflow has helped to shape the applications of the technology, to an extent perhaps unrecognized. Few methods for parallel, in situ analysis exist, particularly in real time.14 An exception is IR thermography, which offers a qualitative measure of reaction rates in all wells simultaneously, in strongly exothermic reactions. The methodology has been extensively used for polymerization, and has also proved valuable in alkyne hydrogenation and alkene oxidation reactions.6,15 Reaction exotherms may be insufficient, however, at the dilutions required for HT screening of homogeneous catalysts (which can be essential to limit total plate costs): not only is the number of molecules then limited, but the solvent functions as a heat sink. Gas uptake (of, for example, ethylene, again in HTE polymerization) is attractive as a method of quantitatively assaying the progress of reactions, but this is so far feasible only in smaller experimental arrays. The same holds true for gas evolution, which also sets a high bar for detector sensitivity, at normal substrate concentrations. Fluorescence measurements offer considerable power, the scope of which can be expanded to some extent by use of (13) Jaekel, C.; Paciello, R. Chem. Rev. 2006, 106, 2912–2942. (14) an der Heiden, M. R.; Plenio, H.; Immel, S.; Burello, E.; Rothenberg, G.; Hoefsloot, H. C. J. Chem. Eur. J. 2008, 14, 2857–2866. (15) Holzwarth, A.; Schmidt, H.-W.; Maier, W. F. Angew. Chem., Int. Ed. 1998, 37, 2644–2647.

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suitable additives (barring interference by unintended reactions with the catalyst).16-18 Other spectrophotometric techniques, such as IR or Raman spectroscopy, are of interest but are limited at present by probe size and, in some cases, low sensitivity. Unsurprisingly, given these issues, off-line analysis is the norm for screening across broad substrate and reaction classes. Particularly common are integrated GC and LC analysis of organic constituents, used to quantify conversion to products at some fixed time. Individual, serial assays of each well in a 96-well plate create a significant demand even where analysis is rapid, and the analytical stage is commonly the bottleneck in throughput. Emerging methods for multiplexed GC, which can currently handle up to 450 samples/h,19 offer a powerful way to cope with this challenge. Comparably impressive throughput has been described for capillary electrophoresis methods, albeit predominantly for relative assessment of enantioselectivities rather than absolute quantitation.20,21 A general limitation to the use of off-line analytical methods, however, is the need to terminate all reactions in the entire plate at a single, arbitrary reaction time, prior to analysis. More, Better, Faster. Use of HTE for mechanistic insight is a tantalizing goal. Such uses would include, at their simplest, the evaluation of induction periods or differential deactivation rates as factors controlling catalyst performance. Determination of time profiles;routinely employed for rigorous evaluation of catalyst performance in organometallic catalysis;presents a major challenge in HTE.22 Ideally, the progress of each microscale reaction could be assessed in situ, online, in real time, at real dilutions, with the capacity to independently and simultaneously address all 96 wells. The development of suitable analytical methods (and coping with the associated volume of data) represents a formidable challenge for engineers and chemists in the coming years, but one in which success would greatly expand the scope of these methodologies. For the present, the most reliable means of obtaining timeresolved insight is via a “high-throughput quenching” methodology, in which a 96-well plate is converted into a smaller series of time-arrayed experimental sets.23 Within each set, reactions are arrested by robotic addition of a suitable quenching agent, for analysis at a convenient time following the final quenching run. The shortest “query interval” attainable using a single-needle configuration was 30 s: this can be reduced further by use of a multineedle arm for parallel injection. Provided that a suitable catalyst poison (16) Guo, H.-M.; Tanaka, F. J. Org. Chem. 2009, 74, 2417–2424. (17) Rozhkov, R. V.; Davisson, V. J.; Bergstrom, D. E. Adv. Synth. Catal. 2008, 350, 71–75. (18) Copeland, G. T.; Miller, S. J. J. Am. Chem. Soc. 1999, 121, 4306– 4307. (19) Trapp, O. Angew. Chem., Int. Ed. 2007, 46, 5609–5613. (20) Breadmore, M. C.; Hodgson, R.; Kennedy, D. F.; Messerle, B. A. Electrophoresis 2008, 29, 491–498. (21) Reetz, M. T.; Kuhling, K. M.; Deege, A.; Hinrichs, H.; Belder, D. Angew. Chem., Int. Ed. 2000, 39, 3891–3893. (22) A highly parallelized alternative to HTE offers the possibility of compiling large volumes of mechanistic data (including activation parameters) by screening multiple substrates in a single reaction vessel. Opportunities and limitations (in particular, the importance of conducting separate screening reactions for each catalyst system, and caution regarding cross-reactions), were usefully discussed. See: an der Heiden, M. R.; Plenio, H.; Immel, S.; Burello, E.; Rothenberg, G.; Hoefsloot, H. C. J. Chem. Eur. J. 2008, 14, 2857–2866. (23) Blacquiere, J. M.; Jurca, T.; Weiss, J.; Fogg, D. E. Adv. Synth. Catal. 2008, 350, 2849–2855.

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can be identified (for key criteria, see later), this methodology enables straightforward access to HTE kinetics and thus a more accurate picture of catalyst performance (i.e., total productivity, induction periods, selectivity, and lifetime), as well as mechanistic analysis. A subsequent, related protocol24 utilized multiple sampling from individual reaction wells, with transfer of the aliquots to a second well plate loaded with a quenching agent and held at -20 °C. This eliminates the need for sets of identical reactions and thus expands the number of parallel reactions that can be monitored. The minimum “query interval” of course increases with the number of reactions: this figure approaches 1 h for a 96-well plate sampled with a standard single-tipped needle, once the necessary rinsing stage is incorporated, but this can be reduced by use of a multitipped needle (see above). More seriously, repeated piercings of the same gasket degrade the Teflon and rubber seal: in our hands, even a single piercing led to loss of solvent for experiments at reflux, and the resulting variability in concentration compromised the data. Whatever protocol or quenching agent is adopted, it is essential to confirm that quenching is immediate and quantitative, as the proportions of substrate and product otherwise continue to evolve prior to analysis, leading to inaccuracies in conversion and selectivity data. Feeling Our Way in the Dark. Using HTE to discover unknown reactions presents a new challenge, in that the targets for analysis are not defined a priori: that is, analytical capabilities must be selected to meet an unknown need. While broad-spectrum analytical methods will facilitate detection of a suitably wide range of potential products, some products will inevitably escape observation by any one technique, and use of multiple methods is therefore highly desirable. UV-detected supercritical fluid chromatography (SFC) requires a suitable chromophore, for example, while even workhorse GC-FID methods are restricted by the requirement for volatility and would discard (e.g.) promising new materials25 that could potentially be detected by LCMS. Quantitation of observed species cannot be considered at the discovery stage in this kind of inquiry, as calibration curves will not exist, and multiple products of interest may be present in different wells. A problem of higher precedence, moreover, is that of speciation. In essence, the problem of product analysis is shifted upstream: before quantitation can be undertaken, qualitative identification must be addressed. MacMillan, Beeler, Porco, and others have demonstrated the power of GC-MS and LC-MS to expedite product identification, where coupled with spectral matching software and extensive databanks.26 Following assignment of structures, and decisions regarding which targets to pursue, more reliable quantitative assays can be undertaken.

(24) Kuhn, K. M.; Bourg, J.-B.; Chung, C. K.; Virgil, S. C.; Grubbs, R. H. J. Am. Chem. Soc. 2009, 131, 5313–5320. (25) In fact, GC-FID can also give grossly misleading results in screening ruthenium metathesis catalysts for the synthesis of large and medium rings by ring-closing metathesis, depending on concentration and the time point chosen for interrogation of reactions. See: Monfette, S.; Fogg, D. E. Chem. Rev. 2009, 109, 3783–3816. These and other challenges specific to olefin metathesis will be discussed in a subsequent publication. (26) Beeler, A. B.; Su, S.; Singleton, C. A.; Porco, J. A., Jr. J. Am. Chem. Soc. 2007, 129, 1413–1419.

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Figure 2. Potential feedback loop between control software and reaction well plate. A plate detector monitors the progress of reaction; the software recognizes when a specified target conversion is reached (red vial), and it then instructs the robot to dispense a quenching reagent or relevant additive, and/or alters reaction conditions.

Where Next? Beyond the Frontier Give the Robot a Brain. In addition to providing richer, more relevant data, a potentially very powerful role can be conceived for real-time, online analytical methods in enabling iterative feedback. Installation of a feedback loop between the reaction vessel, the analytical tools showing the progress of reaction, and the control27 software (Figure 2) would greatly expand control at the single-well level. The robot could then be instructed, for example, to quench individual reactions once reagents are fully consumed, thereby terminating further reactions that could lead to false negative results. Likewise, a suitable chemical trigger could be added once the reaction is complete, in order to initiate a second, tandem catalytic transformation in situ. By minimizing catalyst-specific decomposition, this would permit more efficient “capture” of the catalyst to be harnessed in the second step, yielding a truer picture of performance. Other interventions might include changes in reaction conditions to trigger a reaction cascade. Such methods have the potential to significantly expand the intelligence built into walk-away operation, and thereby to create a step change in the efficiency and scope of HTE methods. Moving the Lens: Viewing Organometallic Chemistry in HTE? The metal species present in catalytic reactions (the concentrations of which are normally much lower than those of the organic constituents) are typically reported on indirectly. We infer much about their behavior and performance from the readily examined distribution of organic products, but rarely interrogate them. Direct observation of the inorganic chemistry occurring at the metal center during catalysis, as well as the organic reactions (Figure 3), would transform insight and greatly expedite the process of catalyst design. The fundamental issue at this stage is one of feasibility. The issue lies not in interfacing the instruments but rather in improving the reporting ability of the detection methods available (or inventing new ones). Methods for interrogating catalyst species in “live” reactions are at an early stage of development, even for benchtop catalysis. Recent advances in mass spectrometry (MS), however, are creating new opportunities.28 These can be expected to open up new vistas once implemented into HTE workflows, as mild MS ionization methods offer the capacity to enable detection of both organic and catalyst species. The former, although present in higher amounts, need not interfere with observation of (27) Westerhuis, J. A.; Boelens, H. F. M.; Iron, D.; Rothenberg, G. Anal. Chem. 2004, 76, 3171–3178. (28) Henderson, W.; McIndoe, J. S. Mass Spectrometry of Inorganic and Organometallic Compounds; Wiley: Hoboken, NJ, 2005.

Figure 3. Proposed interrogation of both organic and organometallic constituents of a HT plate can provide complementary data to establish structure-performance relationships.

transition-metal complexes if the latter are maintained intact and the molecular weight difference is sufficient. Matrix-assisted laser desorption-ionization (MALDI) and electrospray ionization (ESI) MS are complementary methods that have been shown to greatly simplify structure elucidation in organometallic chemistry. Both instrument types have been coupled to gloveboxes and thus permit examination of catalytic reactions in progress under rigorously anaerobic and anhydrous conditions.29,30 A breakthrough in MALDI analysis was the discovery that polyaromatic hydrocarbons (PAHs) can function as “organometallic-friendly” matrices, enabling detection of the intact molecular ion for a wide range of transition-metal complexes;whether neutral or charged;including highly reactive catalysts.29 The PAHs effect ionization of the metal complexes by charge transfer,31 circumventing the problems of ligand protonolysis that bedevil the standard aromatic acid matrices (which ionize by protonation). Matrices that permit observation of metals in their highest oxidation states and that can cope with very low coordination numbers without extensive formation of matrix adducts, will expand the scope of the methodology further. ESI-MS permits examination of charged complexes, species that can readily be oxidized, or ones that can be associated with a charged component. It is typically a gentler ionization method than MALDI (if more vulnerable to contaminants, particularly at the high dilutions required): this facilitates observation of labile metal complexes,28 which can also be subjected to gas-phase screening via tandem MS-MS techniques.32 Reek and co-workers, noting that the stability of catalytic intermediates should relate inversely to catalyst reactivity, have proposed an ESI-MS protocol for screening one-pot, multicatalyst reactions, in which the less abundant ions are identified as the most active catalysts.33 The idea is attractive and potentially powerful, particularly where gas-phase response factors (29) Eelman, M. D.; Blacquiere, J. M.; Moriarty, M. M.; Fogg, D. E. Angew. Chem., Int. Ed. 2008, 47, 303-306; Angew. Chem. 2008, 120, 309-312. (30) Lubben, A. T.; McIndoe, J. S.; Weller, A. S. Organometallics 2008, 27, 3303–3306. (31) Macha, S. F.; McCarley, T. D.; Limbach, P. A. Anal. Chim. Acta 1999, 397, 235–245. (32) Chen, P. Angew. Chem., Int. Ed. 2003, 42, 2832–2847. (33) Wassenaar, J.; Jansen, E.; van Zeist, W.-J.; Bickelhaupt, F. M.; Siegler, M. A.; Spek, A. L.; Reek, J. N. H. Nat. Chem. 2010, 2, 417–421.

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can be established, though complications may arise from “off-cycle” speciation (e.g., differential rates of formation and decomposition and intercatalyst interactions). This approach may benefit from synergic developments in which ESI-MS is used to interrogate both substrate and catalyst species in “live” catalytic reactions in solution. The McIndoe group recently described the extraction of kinetic data by simultaneously monitoring the concentrations of substrate, product(s), and intermediates in Schlenk-flask reactions coupled directly to the mass spectrometer. Quantitative analysis of the active catalysts and/or resting states, in parallel with organic constituents, would offer great power, where suitable response factors can be generated; even relative data, however, would be highly valuable in monitoring catalyst recruitment and decomposition. HTE interfacing of both MALDI and ESI-MS instruments via robotic sampling from the multiwell plates can be envisaged (though see above for the risks associated with perforation of current gasket-sealed covers). Required stages of dilution (for ESI-MS) or mixing with matrix and spotting onto the target plate (for MALDI-MS) are readily adapted to robotic handling. Complementary techniques that can give insight into the nature of the metal species are desirable. A classic method, which fell into abeyance in organometallic chemistry with the explosion in NMR methods, is electronic spectroscopy. Time-dependent density-functional theory is restoring the luster of this once-vital method, for analysis of predefined structures. While in situ UV-vis methods can potentially permit selective observation of d-d transitions and hence changes in transition-metal geometries, spin states, and electronic structures, including paramagnetic complexes, speciation is a problem. Multiple metal complexes are commonly present in solution, in proportions dependent on the susceptibility of the catalyst to decomposition, side reactions, etc. Where the resting state is the repository for the bulk of the added catalyst, however, the situation is more clear-cut, and UV-vis (in conjunction with TD-DFT) may be valuable in identifying the nature of this species, as well as watching (e.g.) catalyst deactivation. Otherwise, major challenges remain in the direct observation of organometallic species in catalysis, even using conventional, bench-scale, one-by-one screening. A further problem lies in the timehonored question of whether the observable species are in fact those performing the catalysis. In situ monitoring of catalyst species thus remains an ambitious goal in HTE. As a more immediately achievable, practical, and perhaps more broad-based approach, the standard HTE output;that is, catalyst performance as indicated by the yields and selectivities for organic products;can be treated as a guide to uncover organometallic chemistry that could reward exploration on the bench scale.

Telling Us Where to Dig: New Synthetic Targets Catalyst Synthesis. The question here is simply this: can we benefit from inverting the conventional process of catalyst design? “Hits” identified from HT screening can offer a potentially very powerful, informed guide for directed, bench-scale organometallic synthesis, as well as mechanistic inquiry. Such an approach, for which Chen coined the term “screening-before-synthesis”,32 tends to be regarded as running counter to the de novo design strategies that have played such a decisive role in development of the field, and some will

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Figure 4. Iterative, benchtop catalyst development (black) and ways in which HTE can accelerate discovery or refinement. Data obtained from screening in situ generated catalysts (red) can guide catalyst synthesis efforts; these and data from screening “prefabricated” catalysts (blue) can guide catalyst (re)design.

Figure 5. Inverse relationship between structural scope and structural definition in catalyst screening programs: (a) prefabricated catalysts; (b) in situ catalyst assembly; (c) in situ ligand and catalyst assembly.

reject it on this basis. From an alternative perspective, HT screening can be seen as inserting one powerful step upstream in the classic “iterative redesign” approach to catalyst discovery and mechanistic elucidation (Figure 4). HTE outcomes can provide a lead, but the nature of the key organometallic species remains to be identified, synthetic routes will require improvement and redesign, rigorous mechanistic studies must still be undertaken, and imagination and creativity in recognizing and elaborating on key structural elements will remain essential. Synthetic Methods. Beyond new catalyst targets for synthetic efforts, the needs of HTE programs can highlight new research goals. A case in point is the paucity of efficient, clean, quantitative methods for in situ catalyst assembly. Such methods, which eliminate the reliance on prefabricated catalysts in screening programs (Figure 5a,b), can expedite or expand the scope of inquiry, as well as reducing screening costs. Required, however, are more and better metal precursors, proligands, and synthetic methodologies. Little attention to date has focused on the design of versatile, soluble, reactive organometallic precursors that can be rapidly and quantitatively recruited for in situ catalyst synthesis at room temperature, without liberation of byproducts that can skew catalyst performance, and without decomposition over the time scale of plate assembly. Many of the metal complexes commonly used as starting materials in benchtop synthesis are limited in their utility for HTE by poor lability, which necessitates thermal labilization. This is problematic because the outcomes of catalysis in (e.g.) a ligand screening survey will be affected by unrecognized induction periods and variable extents of recruitment and decomposition. More generally, in situ catalyst yields (and hence the results of HT screening) depend on incubation time: too short an interval may lead to competing catalysis by the precursor, whereas too

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long an interval may lead to false negatives associated with catalyst decomposition. Ultimately, the problem is that the screening data do not report solely on the desired property (activity, selectivity, ...) but on that property weighted by catalyst concentration. Where high catalyst activity is accompanied by higher fragility, as is commonly the case, the validity of the data may be significantly compromised. The problem is hardly confined to HTE, but is magnified in this context. Classic precursors are suitable in some cases: in rhodium chemistry, for example, [Rh(COD)2]X and [RhCl(COE)]2 (COD = 1,5-cyclooctadiene; COE = cyclooctene) are readily converted into catalyst precursors by reaction with one bidentate or two monodentate ligands. Less satisfactory is the situation in ruthenium chemistry, where in situ generated catalysts are typically derived from [RuCl2( p-cymene)]2 or [RuCl2(COD)]n; of these, the p-cymene dimer is by far preferable, but neither meets the criterion of fast, efficient liberation of the core “RuCl2” motif at room temperature. Even in iridium chemistry (often regarded as closely similar to that of rhodium), in situ preparation of catalysts is frequently unreliable, even from (e.g.) [IrCl(COE)]2, particularly with monodentate ligands. Palladium chemistry sees much use of Pd(OAc)2, but reduction to liberate the desired Pd(0) has the undesired effect of oxidizing 1 equiv of any added phosphine. Where Pd2(dba)3 is used instead, the dba ligand is released very slowly. (A more convenient alternative may be CpPd(allyl), which eliminates 5-allylcyclopentadiene). A general need is thus the design of new “Lego-block” precursors, which will support click-on coordination of the members of a ligand library, without ligand- or additive-dependent variations in the efficiency of recruitment. Parallel issues exist with the design of proligands for in situ installation (Figure 5c), especially for ligands that require use of potentially interfering reagents or byproducts (e.g., H2IMes or other N-heterocyclic carbenes, which must be liberated from a parent salt by treatment with a strong base). More generally, ligand synthesis is one of the chief bottlenecks in expanding catalyst diversity, especially in asymmetric catalysis. Methods for self-assembly of bidentate ligands, as described in recent reviews,34,35 offer a partial solution. HT screening of rhodium catalysts generated in situ from such combinatorially assembled supramolecular ligands enabled the identification of suitable catalysts for the asymmetric hydrogenation of several industrially relevant, challenging prochiral olefins.36 Finally, controlled, reproducible addition of solids, such as inorganic bases, can still be problematic, particularly on a microscale, 96-well format, although further improvements in slurry- and solid-handling capabilities can be anticipated. Invention of new precursor complexes and new reagents may thus emerge as goals stimulated by HTE, realization of which would also benefit conventional synthetic inorganic practice. An ever-present risk, where catalysts are assembled in situ, lies in discrepancies between the products presumed from simple stoichiometries, and those actually present. Extraction of robust structure-performance relationships from catalytic data necessitates benchtop organometallic synthesis, as discussed above, for more rigorous exploration of the behavior and properties of well-defined catalyst systems. An intriguing study by Bercaw and Labinger points toward the

potential to apply HTE methods to organometallic synthesis, as well as catalysis.37 Fast, quantitative, accurate structural elucidation is the obvious difficulty: the study noted the limitations of X-ray crystallography (throughput, selectivity, deposition of crystalline material unrepresentative of the bulk reaction), but a potential role for MS analysis can clearly be seen. Where suitable metal precursors do not yet exist, screening of prefabricated catalysts is the sole option. While this adds to plate costs and total experimental time (unless commercial catalysts are used), direct structure-performance relationships can then be obtained. Quenching Agents. As noted above, robust “high-throughput quenching” methods enable access to kinetic data in HTE, eliminating the misleading inferences inevitable in analysis at a fixed, arbitrary time. They are also essential to completely extinguish alterations in product distributions while reactions are queued for analysis. A rigorous set of criteria for assaying potential quenching agents has been advanced: these include the rapid, quantitative annihilation of all catalyst activity (including any arising from decomposition of the quenching agent or the quenched catalyst) over the time required to complete and analyze the plate.29 The design and discovery of broad-spectrum quenching agents that meet these criteria constitute an additional new research target. Mining the Data. Access to large volumes of data brings statistical data analysis into the realm of feasibility. Extraction of clusters of related results, and correlation of these with (e.g.) structural or experimental parameters, could greatly expand understanding and rates of progress. In a recent review, Rothenberg examined the concepts and basics of data mining for such purposes, with an emphasis on validation methods that help to “separate knowledge from garbage” for catalyst (re)design.38 Also of considerable interest are promising new directions that could combine statistical analysis with computational evaluation of catalyst structure.39 HTE for the Masses: Making It Affordable. Decades ago, in a context far removed, science fiction visionary William Gibson said: “The future is here. It’s just not evenly distributed yet.” The truth of this statement, as it relates to HTE, is due in large part to the high costs associated with the suite of powerful tools required;the robotic and arraybased hardware, the software to drive it, the gloveboxes to house it, and the integrated tools to analyze their output; and, importantly, the skilled technicians essential to supervise operation, maintenance, and training. Prices are falling for basic systems, however, and even the most sophisticated and costly instrumentation is becoming more common in industry, although it remains rare in academia. Countering the latter scarcity, however, is the academic motivation to harness such powerful tools as a means of stimulating and enabling collaboration. Most exciting is the potential to bring major, diverse strengths to bear on problems of compelling interest, by enlisting researchers with widely different expertise. Such initiatives will undoubtedly expand the sophistication of catalyst and process design: in the context of synthetic methodologies, they also have potential to expand the

(34) Goudriaan, P. E.; van Leeuwen, P. W. N. M.; Birkholz, M.-N.; Reek, J. N. H. Eur. J. Inorg. Chem. 2008, 2939–2958. (35) Breit, B. Angew. Chem., Int. Ed. 2005, 44, 6816–6825. (36) Meeuwissen, J.; Kuil, M.; van der Burg, A. M.; Sandee, A. J.; Reek, J. N. H. Chem. Eur. J. 2009, 15, 10272–10279.

(37) Bercaw, J. E.; Day, M. W.; Golisz, S. R.; Hazari, N.; Henling, L. M.; Labinger, J. A.; Schofer, S. J.; Virgil, S. Organometallics 2009, 28, 5017–5024. (38) Rothenberg, G. Catal. Today 2008, 137, 2–10. (39) Fey, N. Dalton Trans. 2010, 39, 296–310.

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relevance and diversity of substrate screening beyond the all-too-common set of “model compounds”. Accelerated expansion of organometallic-catalyzed methodologies; whether for synthesis or energy use;is one highly desirable outcome; another, with potential for transformative impact, lies in training the next generation of organometallic chemists to “think in high-throughput”. The latter will undoubtedly be a core, enabling factor in enlisting these powerful tools to bring the future closer, faster.

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horizon. As these needs are met, and as HTE becomes more widely accessible, we anticipate that it will become a powerful means of capturing and expanding the creativity and vision of the organometallic community;in the ways suggested, perhaps, and undoubtedly also in ways we do not yet imagine. What we must do, to realize them, is cultivate this opportunity with imagination, with vision, and with inventive vigor. In the words of theologian Leonard Sweet, “The future is not something we enter. The future is something we create.”

Conclusions High-throughput robotic tools, integrated analytical instrumentation, and the software to instruct and couple them are at the early stages of adoption by researchers in homogeneous catalysis. We believe that organometallic chemistry can profit greatly from HTE, and have outlined above some of the needs and possibilities that can be descried on the

Acknowledgment. The NSERC of Canada is thanked for financial support, including CGS-D awards to S.M. and J.M.B. Profs. Hans de Vries and Scott McIndoe are thanked for insightful comments; Jay Conrad is thanked for stimulating discussions and for his pioneering role in establishing the High-Throughput Facility at the University of Ottawa.