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Structure–Reactivity Studies of Intermediates for Mechanistic Information by Subensemble Fluorescence Microscopy Kazuhiro Kitagawa, and Suzanne A. Blum ACS Catal., Just Accepted Manuscript • Publication Date (Web): 24 Apr 2017 Downloaded from http://pubs.acs.org on April 24, 2017
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ACS Catalysis
Structure– Structure–Reactivity Studies of of Intermediates for Mechanistic Mechanistic InforInformation by Subensemble Fluorescence Microscopy Kazuhiro Kitagawa and Suzanne A. Blum* Department of Chemistry, University of California, Irvine, California, 92697–2025, United States Structure–reactivity studies of organometallic complexes have a rich history in aiding mechanism-based reaction design in organometallic and synthetic organic chemistry. Originally developed by physical-organic chemists and later adopted for the emerging field of organometallic chemistry,1 structure–reactivity studies at the molecular level provide the ability to correlate changes in the structure of metal complexes and substrates (e.g., through ligand design, electronic parameters, substrate structure, solvent coordination, etc.) to changes in reactivity of individual steps or in the reaction overall. This ability is then employed to create predictive models for development of new reactions, extension of the chemistry to new substrates, and improvement of catalytic activity, selectivity, or other desirable reaction properties. Often such structure–reactivity studies, however, are hampered by a low quantity of reactive intermediates, especially when organometallic intermediates are involved. These intermediates might not build up to the quantity needed for detection by traditional ensemble analytical techniques.1 Such ensemble techniques are best suited to identifying the major components in mixtures; yet often these reactive components are not the major components.1 This discrepancy leads to long-standing analytical challenges in the field. Thus, structure–reactivity studies are sometimes unable to be performed through direct detection of specific intermediates and instead must be teased out indirectly through measurement of the effects on the overall reaction. In these cases the changes in reactivity of specific intermediates—rather than changes in the reaction overall—are difficult to assign. This difficulty hinders predictive reaction model development and thus reaction design and improvement. Driven by the need to identify and study limited quantities of organometallic species under conditions relevant to catalysts, synthetic organic, and preparative organometallic chemistry, our laboratory and the Goldsmith laboratory have recently reported two subensemble fluorescence microscopy approaches to this problem (Figure 1).2-4 Subensemble fluorescence microscopy is well-suited to detection of minor components due to its high sensitivity—as sensitive as single organometallic complexes—and the option to selectively fluorescently label some reaction components over others, which lets the chemist observe
complexes of interest without interfering signal from all reaction components. As such, it provides a new physicalorganic/mechanistic toolbox for chemists interested in structure–reactivity studies of intermediates that are difficult or impossible to detect by traditional approaches. Although this approach employs physical/analytical tools, the structure–reactivity answers obtained through this research are of interest to those involved in reaction design (i.e., “users” of the data rather than solely “developers” of the microscopy technique), including recently in drug discovery.5 The purpose of this Viewpoint is to familiarize the reader with this recent direction in the field (first appearing in 2016) and is not meant to serve as a comprehensive review of subensemble fluorescence microscopy applied to chemical questions. Such reviews are available elsewhere,68 and we also provide important leading references to primary literature behind these general reviews,9-18 including detailed studies of the effect of the shape of nanoparticle catalysts on activity,19 and review of other (nonfluorescent) types of subensemble microscopy as applied in chemistry20. Readers of this Viewpoint may be particularly interested in studies wherein meta-chloroperoxybenzoic acid (mCPBA) epoxidation kinetics intriguingly suggested a molecular intermediate of unknown structure.21
Figure 1. The sensitivity of fluorescence microscopy enables probing previously out-of-reach structure–reactivity relationships by looking into the previous "black box" in certain mechanisms.22 It is useful to compare the new technique to some of the established physical-organic chemistry techniques to study low quantities of intermediates. In contrast to the alternative technique of flash photolysis/reaction synchronization,23 fluorescence microscopy does not require that the chemical system contain a laser flash photolysis handle nor
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does it require ultrafast spectroscopy instrumentation, instead relying on more broadly available standard fluorescence microscopy instrumentation. The alternative approach of trapping intermediates to confirm their existence requires (generally irreversible) diversion of the intermediate to an off-reaction-sequence stable compound;1 in contrast, both the formation and the subsequent reactivity of the target intermediate can in principle be studied by fluorescence microscopy. We herein discuss the first two examples2-4 of subensemble fluorescence microscopy applied to studying structure–reactivity relationships in the formation and/or consumption of intermediates in organometallic systems. Case Study 1 examines surface microstructure–reactivity relationships around a well-defined supported molecular N-heterocyclic (NHC) palladium catalyst.4 The challenge with traditional ensemble studies in such systems is correlating surface structures, which may generate as many different microenvironments as there are molecules of catalyst, with the heterogeneous unique reactivity of the catalysts in these microenvironments (Figure 2, left). Traditional ensemble studies inform almost exclusively on the average reactivity of the systems, which for supported molecular catalysts may arise from many effectively different microenvironments (possibly with each giving rise to slightly different catalyst rates and selectivity). Case Study 2 examines molecular structure–reactivity relationships in the propensity of substrates to form intermediates in the synthesis of soluble organozinc reagents, and of those intermediates to subsequently react.2,3 Traditional ensemble studies are hobbled by providing overall reaction rate information in such systems where intermediates do not build up to the quantities needed for detection (Figure 2, right). Thus, the effect of changing structure on the reactivity of a specific intermediate cannot be determined directly by traditional approaches.
Figure 2. Challenges of traditional ensemble experiments that are the circumvented by subensemble experiments, in two types of recently published structure– reactivity studies. In this Viewpoint we delve into how the sensitivity of fluorescence microscopy avoided the limitations of traditional ensemble studies in these two systems. In the key advance shared by both Case Studies, this sensitivity provided the ability to detect and localize small quantities of fluorophore-tagged material of interest in a sea of untagged reagent, solvent, substrate, surface features and/or metal.
Both Case Studies employ readily available wide-field microscopy instrumentation and achieve single-molecule detection. Further, both share the approach of using of a spectator fluorescent tag6,11 to provide sufficient signal-tobackground ratio for detection of ligand-metal complexes that are minor components at points along the reaction coordinate,6,10-14 and the use of microscopy to provide location information and/or spatial resolution on these minor reactive components. Boron-dipyromethene (BOPIPY) fluorophores were employed in both Case Studies as spectator fluorophores. This spectator fluorophore class is exceptionally well suited for studying chemical reactions by fluorescence microscopy. It has a high quantum yield, is excited and fluoresces in the visible region (making it compatible with standard laser optical microscopy systems), is soluble in organic solvents, has pH-independent and solvent-independent fluorescence properties24, is generally chemically inert including that it lacks Lewis basic lone pairs that may bind to transition metals (thus avoiding unwanted interference with the target reaction), and can be synthesized in the laboratory on a scale allowing for downstream synthetic manipulation and with sufficient flexibility for incorporation of synthetic handles.10-14,25 Case Study 1: Surface Microstructure–Reactivity.4 Summary: Studies revealed multiple different reactivity microenvironments during the catalyst initiation step of an NHC palladium complex. In this case, the structural differences leading to these reactivity distributions have been inferred by modeling the distribution of initiation kinetics. Detailed discussion: For many heterogeneous catalysts, low reaction selectivity is an obstacle towards practical use. Supported molecular catalystscan exhibit different or lower selectivity than their soluble homogenous molecular counterparts. Thus, the determination of the origin of this difference in supported molecular catalysts compared their soluble versions is an important challenge that could lead to the design of more selective catalysts. Silica-immobilized molecular catalysts attached via silyloxy tethers are one example of such catalysts. The presence of different microstructures on these surfaces are known from surface structure studies,26 but the effect of these microstructures on reactivity distributions are less well understood. In Case Study 1, the kinetics of the series of steps leading to catalytic initiation for a silyloxy-tethered palladium complex were investigated at the single-molecule level (Figure 3). Palladium complexes are typically added to reaction mixtures in the form of stable precatalysts from which ligand dissociation must occur in order to generate the catalytically active unsaturated complex; catalysts in which pyridine is the ligand that dissociates are employed in the suite of cross-coupling and amination chemistry traditional to palladium catalysis. To enable detection, a palladium precatalyst was synthesized, bearing at its pyridine ligand a red BODIPY fluorophore tag. This complex was then immobilized on the glass surface of a microscope slide as a model system for silicasupported molecular catalysts (1). The red fluorophore
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ACS Catalysis then served as a spectator in the reaction. It provided a bright red beacon on the surface of the glass slide at each location where an individual tagged complex 1 was. Since loss of pyridine was part of the catalyst initiation process, loss of the red signal at a single complex correlated with the start of initiation at that individual complex. Thus, although dark intermediate 2 was not directly detected, the kinetics of its formation were approximated by the kinetics of pyridine ligand loss. Figure 4. Surface microstructures inferred from detected reactivity. Squiggly lines depict alkyl chains of neighboring alkyl silyloxy groups codeposited with catalyst 1. This analysis provided the first direct evidence that the many different physical surface microstructures detected in silyloxy tethered molecular complexes displayed different chemical reactivity. Further, hypotheses for which structural heterogeneities gave rise to the reactivity range could be compared against the kinetics data, arriving at a plausible structure–reactivity model.
Figure 3. Overall experimental schematic for Case Study 1. Red-fluorophore-tagged pyridine ligand creates a bright red spot at locations of individual molecules of precatalyst 1 across the surface of a glass coverslip. Disappearance of this red signal correlates with dissociation of the redtagged pyridine ligand. The rate of signal loss increases with increasing isopropoxide concentration, caused by formation of dark intermediate 2. The rate of signal loss under different conditions was then analyzed. Fitting the kinetics with a Weibull analysis27 showed that the distribution of rates could not be coming from a single reactive environment. These different environments were attributed to the presence of different local microstructures on the surface, such that complexes displayed detectably different reactivity. The exact structures of these different microstructures is still unknown; however, data from the kinetic analysis was employed to develop models that allowed evaluation of different hypotheses for their structures. Of particular interest was the effect of isopropoxide concentration on catalyst initiation, given that isopropoxide is known to promote this step in the fully homogeneous system. On the basis of the kinetic effect of the isopropoxide, it was determined that certain local microenvironments experienced saturation kinetics (i.e., lost their dependence on the concentration of added isopropoxide) before other local microenvironments. This difference was then hypothesized to come from variations in the physical structure of the support—the density and orientations of codeposited alkyl silyloxy groups—which allowed for varying numbers of isopropoxide anions to be near the palladium center (conceptually displayed in Figure 4 microstructures 4 and 5).
Case study 2: Molecular Structure–Reactivity.2,3 Summary: Subensemble studies enabled detection of a previously unobserved intermediate in a lithium chloride assisted formation of organozinc complexes from zinc metal. This detection then enabled study of the structurereactivity relationship of the initial oxidative addition step independent from a subsequent lithium chloride assisted solubilization step. Detailed discussion: Organozinc complexes are wellestablished reagents in synthetic organic chemistry, including as Negishi cross-coupling partners.28 These reagents have recently become more accessible due to advances by the Knochel laboratory, who found that the addition of LiCl to reagent preparations significantly increased the number of suitable substrates for direct insertion of organohalides to commercial zinc powder.29
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b. Structures Known
Reactivity Detected -35 oC
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c. Detection of Single Organozinc Complexes, 8a
Figure 5. a. Overall experimental schematic for Case Study 2. Oxidative addition leads to previously notdetected surface intermediate 8a. b. Determination of the effect of the structure of the starting organoiodides 7a and 7b on the temperature of oxidative addition reactivity to form intermediate 8a and 8b. c. A single zinc particle appears dark against a brighter background; Sensitivity is suitable for detection of single organozinc complexes on the surface of this particle (intensity vs. time graph available in citation 3). Figure reprinted in part from citation 3. In this study, a green BODIPY fluorophore was attached to an organoiodide probe molecule 7 (Figure 5a). Treatment of commercial zinc powder (6) with this probe gave rise to a previously unobserved surface intermediate, 8, detectable as bright green spots on otherwise dark zinc particles. Each green spot in Figure 5b was the signal from many fluorophore-tagged intermediates 8a derived from probe 7a, however, detection of 8a at the singlemolecule/single-intermediate level was also possible under modified imaging conditions (not shown). Through a series of experiments, this intermediate was assigned as oxidative addition product 8a. Subsequent treatment of 8a with lithium chloride lead to removal of the bright green spots via solubilization consistent with production of 9a. Previous ensemble bench-scale synthetic experiments established that aryl iodides lacking electron withdrawing groups underwent the full sequence (top black arrow, Figure 5a) of multistep starting material to product transform at 50 oC, whereas alkyl iodides underwent this full sequence at ambient temperature. Without the ability to detect—and therefore measure rate of formation and consumption of—small quantities of intermediates on the surface of the zinc (8), determination of the specific step to
which the temperature difference originated could not be directly experimentally determined. Now with the ability to detect intermediate 8 in hand, the structure–reactivity relationships in Steps 1 and 2 (Figure 5a) were independently experimentally determined. Specifically, in order to attribute the difference in the observed bulk reactivity to a specific step, two organoiodides were separately tagged with green BODIPY fluorophores. The critical molecular structure difference of these two probes was the connection point of the iodide: sp3 carbon in alkyl iodide 7a or sp2 carbon in aryl iodide 7b. Microscopy studies showed that alkyl iodide 7a was more reactive towards oxidative addition in the first step on the reaction coordinate, proceeding at ambient temperature to generate intermediate 8a (Figure 5b, appearing as bright green spots on the surface of otherwise dark zinc particles). In contrast, aryl iodide 7b was less reactive in this first step to form intermediate 8b, requiring 60 oC to produce intermediate 8b. The sensitivity provided by wide-field fluorescence microscopy was sufficient to detect single complexes of 8a (Figure 5c). Specifically, Figure 5c shows a single zinc particle that appeared dark against a lighter green background. The light green background was caused by fluorophores in solution that were diffusing rapidly and from out-of-focus neighboring zinc particles. The zinc particle appeared dark on account of physically blocking the fluorescence from the solution, thus forming a "shadow" under itself that created a dark narrow gap between the particle and the glass coverslip. This area was therefore relatively dark, with low background. Thus the comparitively faint signal from individual complexes could be observed on the surface of the zinc without being overwhelmed by the signal of the background solution. Subsequent study of the lithium chloride assisted solubilization step demonstrated that both 8a and 8b were removed from the surface through solubilization at ambient temperature. Thus, the observed difference in the reaction barriers in the bench-scale ensemble reaction for the full sequence could be assigned experimentally to originate exclusively from the first oxidative addition step in the multistep reaction sequence. The second step remained significantly faster than oxidative addition for both the alkyl and aryl structures. Thus, structure–reactivity relationships for individual steps were experimentally determined. These relationships were previously obscured because intermediate 8 had not built up to a quantity sufficient for detection by tradition ensemble spectroscopic techniques. Current Status and Future Directions. Consideration of the current state of the technology with respect to structure–reactivity questions to organic, inorganic, organometallic, and catalysis is of interest here. We here consider the equipment and skill sets needed, current challenges, and promising directions. Broad availability of equipment. The palladium studies were performed in the Goldsmith laboratory using an inhouse-built microscopy system. While potentially offering advantages in signal-to-background, time resolution, local-
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ACS Catalysis ization ability, and customization, such systems so far have been limited to researchers with skills in microscopy instrument building. The zinc studies were performed in our laboratory using a commercial system, more readily accessible to those with training solely in organic/inorganic/catalytic synthesis. Some university campuses have user facilities with similar commercial equipment capable of the required imaging; these user facilities are likely to be geared towards the imaging of fluorescently labeled biological or biochemical samples, including at the single-molecule level. Expansion of applications by chemists is becoming increasingly possible by hijacking this equipment. Several descriptions of these microscopes are readily available in the literature, including in the Supporting Information sections of the papers described in the case studies,2,3,4 and elsewhere6,7,30, such as an excellent fundamental comparison of wide-field and confocal imaging approaches suitable for beginners31. These systems are becoming increasingly easy to use, and an increasing number of examples of applying subensemble fluorescence microscopy to chemical systems is providing the needed groundwork for broader adoption within the synthetic/physical-organic and -inorganic chemistry communities, which have traditionally relied on other technologies for mechanistic investigation. Combination of multidisciplinary skills is still helpful; however, training in application areas of organic/organometallic/catalytic chemistry are the most important skills for the next generation of structure– reactivity studies. This training equips scientists with the knowledge of what the real problems and mechanistic questions are in these fields. Organic synthesis skills for probe design remains helpful. Through synthetic skills,
new probe molecules can be constructed that contain fluorophores tethered to reactive functional groups of interest to enable the study of additional reactions. This skill set may also allow for iterative studies to test the effect of tether lengths, molecular sizes, and/or functional groups of probe molecules on the kinetics and/or qualitative observations from fluorescence experiments—in other words to determine if and how the probe molecules effect the reaction. Similarly, standard synthetic skills in spectroscopic characterization of soluble molecular organic and organometallic species aid in confirming that starting materials with tethered fluorophore probes are capable of producing the otherwise analogous target products.2,3 While innovations in microscopy, potentially developed by specialists, will likely play a role to enable new measurements on mechanisms, the current advanced state of microscopy does not require a physical-chemistry training in order to study intermediates with application areas in synthetic chemistry. The current instrumentation allows most of the microscopy techniques and imaging software to be learned “on the job”. As the technology becomes increasingly available in user facilities and with commercial systems, the application of these microscopy tools to chemical questions is expected to become increasingly available to industrial and academic chemists—even those
who may have never thought to reach for a microscope before. Future types of questions. 1) Multiple ligands. Organometallic chemistry, especially in the field of catalysis, gains its richness in reactivity and selectivity from the chemist’s ability to make small structural changes in substrate and at the metal center though altering the ligands, which then correlate to changes in reaction outcome. The two case studies herein characterized the presence of one red- or green-fluorophore tagged ligand at the metal center at a specific point or points along the reaction coordinate. The ability to characterize more than one ligand in order to reveal the more complete coordination sphere at metal complexes at the time of reactivity/selectivity is a tantalizing prospect that has not yet been achieved but is clearly within reach. 2) Higher concentrations. Most questions in industrial and academic catalysis in condensed phase pertain to systems with relatively high concentrations of reagents. Subsensemble fluorescence microscopy studies have been limited to systems wherein the fluorescent probe molecule is relatively dilute: ~1 nM for single-molecule studies, for example. This dilution is required so that the fluorescence signal from the solution's background does not swamp out the comparatively faint signal from the small numbers of molecules of interest. Addressing the discrepancy between the low concentration of fluorescent probe required for subensemble studies and the typical higher concentration of reactants under synthetically relevant conditions has been done in a few ways in chemical reaction systems:6-19 a) doping in a small amount of fluorophore-tagged reagent into a system with high concentrations of otherwise analogous untagged reagents, b) using small quantities of reagents and extrapolating that the events are likely consistent with those that occur at higher concentrations, c) rinsing, flowing, or decanting excess probe, d) employing a probe that is nonfluorescent until the target reaction occurs, e) attaching the probe directly to the glass slide and employing a large excess of untagged reagent compared to this probe (e.g., silyloxy tethered palladium complex 1 in Figure 3), f) physically blocking the background fluorescence of the solution (e.g., with zinc and intermediate 8a in Figure 5c), and g) combinations of multiple of these approaches. A number of additional techniques to overcome concentration limits have been developed by the microscopy community but have not yet been applied to the subsensemble study of chemical reactions, presumably in part because of the somewhat more advanced microscopy instrumentation needed.32 A recent technique that achieves 1 mM detection of single binding events at biomolecules through combined fluorescence resonance energy transfer (FRET) and zero-mode waveguide approaches holds future potential as one way to achieve higher concentrations of reagents in suitable chemical systems.33 Conclusion. Subensemble fluorescence microscopy has brought its sensitivity to bear at the interface of organometallic, organic, inorganic and catalytic chemistry to reveal structure–reactivity relationships in the formation and consumption of intermediates that were previously ob-
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scured by ensemble averaging. This technique generated unique types of reaction information spanning surface microenvironments around molecular catalysts to organic substrate/organometallic intermediate reactivity studies. These two examples bridge the areas of homogeneous and heterogeneous chemical reactivity through studying multistep, multiphase processes. Tools, applications, and results in this area of structure–reactivity studies of intermediates are new, rapidly evolving, and relevant to synthetic chemistry “users,”5 as well as microscopy “developers”.
AUTHOR INFORMATION Corresponding Author *
[email protected] ACKNOWLEDGMENT The writing of this Viewpoint was supported by the U.S. Department of Energy, Office of Basic Energy Sciences (DESC0016467) and the Japan Society for the Promotion of Science through a research fellowship (JP15J03538) to K.K.
REFERENCES Blum, S. A.; Tan, K. L.; Bergman, R. G. J. Org. Chem. 2003, 68, 4127– 4137. 2 Feng, C.; Cunningham, D. W.; Easter, Q. T.; Blum, S. A. J. Am. Chem. Soc. 2016, 138, 11156–11159. 3 Feng, C.; Easter, Q. T.; Blum, S. A. Organometallics 2017, DOI: 10.1021/acs.organomet.6b00910. 4 Ng. J. D.; Upadhyay, S. P.; Marquard, A. N.; Lupo, K. M.; Hinton, D. A.; Padilla, N. A.; Bates, D. M.; Goldsmith, R. H. J. Am. Chem. Soc. 2016, 138, 3876–3883. 5 Zhao, W.; Zhao, D.; Guizzetti, S.; Schwindeman, J. A.; Daniels, D. S. B.; Guerrero, C.; Knight, J. Org. Process Res. Dev. 2016, 20, 1691. 6 Cordes, T.; Blum, S. A. Nature Chem. 2013, 5, 993–999. 7 Blum, S. A. Phys. Chem. Chem. Phys. 2014, 16, 16333–16339. 8 Chen, P.; Zhou, X.; Shen, H.; Andoy, N. M.; Choudhary, E.; Han, K.-S.; Liu, G.; Meng, W. Chem. Soc. Rev. 2010, 39, 4560–4570. 9 Roeffaers, M. B .J.; Sels, B. F.; Uji-i, H.; De Schryver, F. C.; Jacobs, P. A.; De Vos, D. E.; Hofkens, J. Nature 2006, 439, 572–575. 10 Esfandiari, N. M.; Wang, Y.; Bass, J. Y.; Cornell, T. P.; Otte, D. A. L.; Cheng, M. H.; Hemminger, J. C.; McIntire, T. M.; Mandelshtam, V. A.; Blum, S. A. J. Am. Chem. Soc. 2010, 132, 15167–15169. 1
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Canham, S.; Bass, J.; Navarro, O.; Lim, S.-G.; Das, N.; Blum, S. A. Organometallics 2008, 27, 2172–2175. 12 Esfandiari, N. M.; Wang, Y.; Mcintire, T. M.; Blum, S. A. Organometallics 2010, 30, 2901–2907. 13 Hensle, E. M.; Blum, S. A. J. Am. Chem. Soc. 2013, 135, 12324–12328. 14 Esfandiari, N. M.; Blum, S. A. J. Am. Chem. Soc. 2011, 133, 18145–18147. 15 Ristanović, Z.; Kerssens, M. M.; Kubarev, A. V.; Hendriks, F. C.; Dedecker, P.; Hofkens, J.; Roeffaers, M. B. J.; Weckhuysen, B. M. Angew. Chem. Int. Ed. 2015, 54, 1836–1840. 16 Wang, N.; Tachikawa, T.; Majima, T. Chem. Sci. 2011, 2, 891–900. 17 Decan, M. R.; Impellizzeri, S.; Marin, M. L.; Scaiano, J. C. Nature Commun. 2014, 5, doi:10.1038/ncomms5612. 18 Sambur, J. B.; Chen, T. Y.; Choudhary, E.; Chen, G. Q.; Nissen, E. J.; Thomas, E. M.; Zou, N. M.; Chen, P. Nature 2016, 530, 77–80. 19 Andoy, N. M.; Zhou, X.; Choudary, E.; Shen, H.; Chen, P. J. Am. Chem. Soc. 2013, 135, 1845–1852. 20 Stavitski, E.; Weckhuysen, B. M. Chem. Soc. Rev. 2010, 39, 4615–4625. 21 Rybina, A.; Lang, C.; Wirtz, M.; Grußmayer, K.; Kurz, A.; Maier, F.; Schmitt, A.; Trapp, O.; Jung, G.; Herten, D.-P. Angew. Chem., Int. Ed. 2013, 52, 6322–6325. 22 Figure 1 includes graphics designed by Freepik from Flaticon. 23 Bromberg, S. E.; Yang, H.; Asplund, M. C.; Lian, T.; McNamara, B. K.; Kotz, K. T.; Yeston, J. S.; Wilkens, M.; Frei, H.; Bergman, R. G. B.; Harris, C. B. Science 1997, 278, 260–263. 24 Asaoka, M.; Kitagawa, Y.; Teramoto, R.; Miyagi, K.; Natori, Y.; Nakano, M. Chem. Lett. 2017, 46, 536–538. 25 Hensle, E. M.; Esfandiari, N. M.; Lim, S.-G.; Blum, S. A. Eur. J. Org. Chem. 2014, 3347–3354. 26 Coperet, C.; Chabanas, M.; Saint-Arroman, R. P.; Basset, J.-M. Angew. Chem., Int. Ed. 2003, 42, 156–181. 27 Flomenbom, O.; Velonia, K.; Loos, D.; Masuo, S.; Cotlet, M.; Engelborghs, Y.; Hofkens, J.; Rowan, A. E.; Nolte, R. J.; Van der Auweraer, M.; de Schryver, F. C.; Klafter, J. Proc. Natl. Acad. Sci. U. S.A. 2005, 102, 2368–2372. 28 Phapale, V. B.; Cárdenas, D. J. Chem. Soc. Rev. 2009, 38, 1598–1607. 29 Krasovskiy, A.; Malakohov, V.; Gavryushin, A.; Knochel, P. Angew. Chem., Int. Ed. 2006, 45, 6040–6044. 30 Roeffaers, M. B. J.; De Cremer, G.; Uji-I, H.; Muls, B.; Sels, B. F.; Jacobs, P. A.; De Schryver, F.; De Vos, D. E.; Hofkens, J. PNAS, 2007, 104, 12603–12609. 31 Roeffaers, M. B. J.; Hofkens, J.; De Cremer, G.; De Schryver, F. C.; Jacobs, P. A.; De Vos, D. E.; Sels, B. F. Catal. Today 2007,126, 44–53. 32 Holzmeister, P.; Acuna, G. P.; Grohmann, D.; Tinnefeld, P. Chem. Soc. Rev. 2014, 43, 1014–1028. 33 Goldschen-Ohm, White, D. S.; Klenchin, V. A.; Chanda, B.; Goldsmith, R. H. Angew. Chem., Int. Ed. 2017, 56, 3299–2402.
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