Site-Selective Nickel-Catalyzed Hydrogen Isotope Exchange in N

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Research Article Cite This: ACS Catal. 2018, 8, 10210−10218

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Site-Selective Nickel-Catalyzed Hydrogen Isotope Exchange in N‑Heterocycles and Its Application to the Tritiation of Pharmaceuticals Haifeng Yang,†,‡ Cayetana Zarate,† W. Neil Palmer,† Nelo Rivera,‡ David Hesk,‡ and Paul J. Chirik*,† †

Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States MRL, Merck & Co., Inc., Rahway, New Jersey 07065, United States

‡

ACS Catal. Downloaded from pubs.acs.org by UNIV OF SUNDERLAND on 10/08/18. For personal use only.

S Supporting Information *

ABSTRACT: A nickel-catalyzed method for the site-selective hydrogen isotope exchange (HIE) of C(sp2)−H bonds in nitrogen heteroarenes is described and applied to the tritiation of pharmaceuticals. The α-diimine nickel hydride complex [(iPrDI)Ni(μ2−H)]2 (iPrDI = N,N′-bis(2,6-diisopropylphenyl)-2,3-butanediimine) mediates efficient HIE when employed as a single component precatalyst or generated in situ from readily available and air-stable metal and ligand precursors (iPrDI, [(NEt3)Ni(OPiv)2]2 (Piv = pivaloyl) and (EtO)3SiH). The nickel catalyst offers distinct advantages over existing methods, including: (i) high HIE activity at low D2 or T2 pressure; (ii) tolerance of functional groups, including aryl chlorides, alcohols, secondary amides, and sulfones; (iii) activity with nitrogen-rich molecules such as the chemotherapeutic imatinib; and (iv) the ability to promote HIE in sterically hindered positions generally inaccessible with other transition metal catalysts. Representative active pharmaceutical ingredients were tritiated with specific activities in excess of the thresholds required for drug absorption, distribution, metabolism, and excretion studies (1 Ci/mmol) and for protein receptor−ligand binding assays (15 Ci/mmol). The activity and selectivity of the nickel-catalyzed method are demonstrated by comparison with the current state-of-the-art single-site (iridium and iron) and heterogeneous (Raney nickel and rhodium black) catalysts. A pathway involving C(sp2)−H activation by a α-diimine nickel hydride monomer is consistent with the experimentally measured relative rate constants for HIE with electronically disparate pyridines, the pressure-dependence of activity, positional selectivity preferences, and kinetic isotope effects. KEYWORDS: nickel, C−H activation, tritium, pyridine, isotope

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INTRODUCTION Isotopic labeling of pharmaceutical lead compounds, particularly with radioactive nuclei, is a critical component of the drug-discovery pipeline. Studies on drug absorption, distribution, metabolism, and excretion (ADME) are required to establish safety and efficacy.1 For this reason, tritium labeling of drug candidates is increasingly important and one of the most frequently used tools for these studies. Direct hydrogen isotope exchange (HIE) with the final drug molecules is one of the most desirable methods for the preparation of radiolabeled isotopologues to eliminate additional steps associated with the traditional synthesis of radioactive molecules.2 Tritium gas (T2) is the preferred source of the radioactivity due to its availability in high isotopic purity, adaptability to the micromolar scales often used in radiolabeling, and the ability to circumvent the autoradiolysis risks associated with tritiated water.3−5 Transition metal catalysts that selectively promote HIE ideally at minimal pressures of T2 gas and tolerate © XXXX American Chemical Society

functional groups characteristic of active pharmaceutical ingredients (APIs) are therefore highly desirable. Nitrogen-containing heterocycles are among the most prominent structural motifs in bioactive compounds and are present in 59% of FDA-approved pharmaceuticals. Among these, pyridines are the second most common N-heterocycles.6 Traditional methods established for HIE with N-heteroarenes have primarily been limited to deuteration studies with Pd,7 Pt,2,7a Rh,8 and Ru8a,9 catalysts using D2O, CD3COCD3, and tBuOD as the isotope source. Most of these H/D exchange protocols cannot be applied to tritiation, as the equivalent tritiated reagent is not commercially available. Although tritiated water (THO) can be made on demand with moderate to high specific activity, its high radioactivity-to-volume ratio makes its handling far less convenient than tritium gas. Received: September 15, 2018 Published: September 21, 2018 10210

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ACS Catalysis

pharmaceuticals at low pressures of T2 gas in N-methyl pyrrolidone solvent.14 Isotopic exchange occurred with predictable selectivity, determined by steric accessibility of the C−H bond, and was maintained in the presence of directing groups. Despite certain advantages over existing technology, application of this method to preparative HIE has been limited by the complexity and expense of the reduced iron precatalyst as well as its extreme air and water sensitivity. Other limitations include deactivation by acidic N−H and O− H bonds or α-unsubstituted pyridinyl rings, which are found in many drug molecules. Efforts in catalyst development have focused on next-generation earth abundant metal complexes prepared from more readily available and ideally air stable sources that are more robust under catalytic conditions. Both cobalt and nickel α-diimine (DI) complexes reported by our laboratory exhibit a rich catalytic chemistry, including the polyborylation of benzylic C(sp3)−H bonds.15,16 A dialkyl cobalt variant proved active for the diastereoselective and enantioretentive deuteration of benzylic C(sp3)−H bonds; however, the compatibility with APIs has not been explored.17 Here, we describe the application of both an isolated and in situ generated nickel hydride [(iPrDI)Ni(μ2−H)]2 for hydrogen isotopic exchange in N-heteroarene containing molecules and the tritiation of APIs (Scheme 1c). Relative rate studies and kinetic isotope effect measurements have provided insight into the mechanism of operation. The nickel method generally promotes hydrogen isotope exchange at two types of C(sp2)−H sites: the α-positions to Nheteroatoms and N-heteroatom directed C−H bonds in an adjacent ring. The ability of the nickel catalyst to incorporate hydrogen isotopes in multiple sites renders it advantageous over single-site labeling methods because (i) it improves the overall isotope enrichment, which is highly desirable for high specific activity radiotracers used in ligand binding studies, and (ii) it provides additional tracking sites, thus reducing the risk of losing metabolically unstable labels.1 Furthermore, the nickel HIE method is a complementary tool to the existing catalysts technologies and allows the labeling of selected Nheteroarenes that cannot be labeled with existing Fe or Ir catalysts.

Seminal studies from Lockley and coworkers describe methods for the H/D exchange of the α-positions of selected N-heterocycles with D2 gas using heterogeneous rhodium and ruthenium black as catalysts,10 which later enables rhodium black as the standard method for tritiation of pharmaceuticals containing N-heteroarenes using T2 gas (Scheme 1A). Scheme 1. Methods for HIE in N-Heteroarenes

However, super stoichiometric amounts of rhodium black are often required to tritiate complex drug molecules; studies of its functional group tolerance has not yet been systematically established, and one report suggested inconsistencies from batch to batch.8a In the realm of metal-catalyzed hydrogen isotope exchange, iridium catalysts, including Crabtree’s catalyst [(COD)Ir(py)PCy3][PF6] (COD = 1,5-cyclooctadiene) and more contemporary variants reported by Kerr and others,11,12 are most widely used. These iridium catalysts enable efficient H/T exchange at C−H bonds directed by various functional groups, including N-heterocycles. With these heterocycles, the C(sp2)−H isotope exchange occurs preferentially at the ortho C(sp2)−H bonds, while the N-heterocycle core generally remains unlabeled (Scheme 1B). Use of Raney nickel for the HIE in N-heterocycles has been reported,2,13 including examples for the tritiation of pharmaceuticals,13a but widespread adoption has been limited because of pyrophoricity of the catalyst, high reaction temperatures, long reaction times, and the requirement for tritiated water (Scheme 1A). As part of our continuing program on exploring earth-abundant, first-row transition metal catalysts for HIE in pharmaceuticals with low pressures of T2 gas, we were interested in developing homogeneous nickel catalyst for efficient HIE in N-heterocycles. This initiative was also inspired by our recent report of a single site iron catalyst that exhibits unique performance in HIE reactions by offering orthogonal site selectivity to iridium. The bis(arylimidazolin-2ylidene)pyridine iron bis(dinitrogen) complex (H4-iPrCNC)Fe(N2)2 was effective for the tritiation of a host of

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RESULTS AND DISCUSSION Deuteration of Heteroarenes. Our studies commenced with the isolated, dimeric nickel hydride [(iPrDI)Ni(μ2−H)]2, a compound initially reported by Yang and coworkers18 and later applied to alkene hydrogenation19 and hydrosilylation20 catalysis by our group. During the course of these investigations, an alternative synthetic route was developed from air-stable Ni(II) bis(carboxylates), free α-diimine, and (EtO)3SiH.20 An alternative nickel precursor, [(NEt3)Ni(OPiv)2]2,16,21 was selected for subsequent in situ studies due to its ease of handling and reliability in catalytic reactions. Application of [(iPrDI)Ni(μ2−H)]2 to HIE with substituted Nheterocycles was initially examined given the prevalence of this substructure in APIs. As shown in Scheme 2, both isolated (blue values) and in situ generated [(iPrDI)Ni(μ2−H)]2 (green values) were effective for the deuteration of a host of substituted pyridines. The standard procedure for the in situ generation of the nickel hydride [(iPrDI)Ni(μ2−H)]2 relied on premixing a THF solution of [(NEt3)Ni(OPiv)2]2, iPrDI, and HSi(OEt)3 in the glovebox for 3 h, resulting in a stock solution that can be immediately used or stored in the freezer for several days for future use.22 With 1 mol % loading and 4 atm 10211

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ACS Catalysis Scheme 2. Ni-Catalyzed Deuteration of Heteroarenesa,b

the adjacent aryl ring. Deuteration of these additional sites likely arises from a directed reaction whereby coordination of the nitrogen of the pyridine promotes activation of the C(sp2)−H bond in an adjacent ring. Notably, the siteselectivity of the nickel method is distinct from (H4-iPrCNC)Fe(N2)2 and other metal complexes, where the C−H bond activation step relies solely on steric control. Optimization of Conditions for Catalytic Deuteration of MK-6096. The successful and distinct HIE reactivity observed with N-containing heteroarenes prompted application of the method to more complex APIs. MK-6096 (Table 1), a potent antagonist of OX(1)R and OX(2)R receptors investigated for insomnia treatment,23 was initially studied due to the electronically and sterically different types of C−H bonds in the molecule and for comparison to reported Fecatalyzed HIE method.14 Both isolated and in situ generated [(iPrDI)Ni(μ2−H)]2 were evaluated. No HIE was observed in control experiments conducted with the omission of the silane (Table 1, entry 1), nickel precatalyst (entry 2), or α-diimine (entry 3).24 While the combination of [(NEt3)Ni(OPiv)2]2 and iPrDI ligand did not yield deuterated product 24 h at 23 °C (entry 1), addition of (EtO)3 SiH to the [(NEt 3)Ni(OPiv)2]2/iPrDI solution (premixed for 3 h) generated an active catalyst for HIE (entry 4). However, the efficiency of the HIE decreases when the catalyst precursors and substrate are added at once without prior premixing (entry 5). The level of deuteration was comparable to that obtained using the standard in situ catalyst activation procedure ,where activity was observed at 23 °C and introduced 2.6 D/molecule (entry 7). Increasing the reaction temperature to 45 °C increased deuterium incorporation (entries 8 and 10; for additional substrates, see Tables S2 and S3) with the value of 0.2 D/ molecule at 23 °C increasing to 3.0 D/molecule at 45 °C when using the isolated precatalyst. This effect is likely a result of a higher concentration of active monomeric nickel hydride at the higher temperature.19,20 Deuteration of Pharmaceuticals. A family of representative pharmaceuticals and other APIs were evaluated for nickel-catalyzed H/D exchange (Scheme 3). Substrates were selected to explore the versatility, site-selectivity, functional

a

3.08 mmol substrates; 1.0 mL of THF were used for reactions. b%D incorporation was determined by 1H NMR and confirmed by quantitative 13C{1H} NMR spectroscopy.

of D2, both conditions promoted HIE; the degree and sites of deuteration were determined by a combination of 1H and quantitative 13C{1H} NMR spectroscopies. The C(sp2)−H bond adjacent to nitrogen was the preferred site of deuteration, and notably, pyridine (1), often a poison for metal catalysts,12e,14 was well tolerated. Selective deuteration of this position was successfully maintained in the presence of methyl groups in a range of substitution patterns as generally high isotopic incorporation was observed with 2, 3, 4, and 5. With (−)-nicotine (6), higher deuterium incorporation was observed at the less sterically hindered α-position, but the hindered site also remained reactive toward HIE. The nickel-catalyzed method also offers supplementary siteselectivity with 2-(p-tolyl)pyridine (9) and quinoline (10), where, in addition to deuteration of the C−H bond adjacent to nitrogen, exchange was also observed in the C(sp2)−H bond in Table 1. Optimization of Conditionsa,b

1 2 3 4 5 6 7 8 9 10

[Ni] (%)

conditions

temp (°C)

D/molecule

D incorporation (1, 2, 3) (%)

25 25 25 25 25 10 25 25 25 25

[(NEt3)NiOPiv)2]2/ iPrDI iPr DI/HSi(OEt)3 [(NEt3)Ni(OPiv)2]2/HSi(OEt)3 [(NEt3)Ni(OPiv)2]2/iPrDI, then HSi(OEt)3 [(NEt3)Ni(OPiv)2]2/iPrDI/HSi(OEt)3 (no premixed) standard in situ generation conditionsc standard in situ generation conditionsc standard in situ generation conditionsc [(iPrDI)Ni(μ2−H)]2 [(iPrDI)Ni(μ2−H)]2

23 23 23 23 23 23 23 45 23 45

0.0 0.0 0.0 2.6 1.6 0.5 2.6 3.2 0.2 3.0

no incorporation no incorporation no incorporation 97, 58, 7 63, 20, 12 23, 0.8, trace 92, 65, 8 98, 92, 36 7.3, 0.4, trace 98, 65, 35

a

Reactions were conducted with 0.14 mmol substrate in 0.5 mL of THF. b%D incorporation was determined by 1H NMR and confirmed by quantitative 13C{1H} NMR spectroscopy. cStandard in situ generation conditions: [(NEt3)Ni(OPiv)2]2/iPrDI/HSi(OEt)3 in THF, 3 h.22 10212

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ACS Catalysis Scheme 3. Ni-Catalyzed Deuteration of Pharmaceuticalsa,b

substrate possesses a potential amide directing group, deuteration of tropicamide (15) with Crabtree’s27 and Kerr’s catalysts were unsuccessful (20 Ci/mmol were obtained with [ 3 H]varenicline, [ 3 H]MK-6096, [ 3 H]MK-7622, [ 3 H]etoricoxib, and [3H]papaverine, resulting from exchange of multiple C−H bonds. The specific activity was improved by increasing the catalyst loading, as shown with the tritiation of MK-5395. The utility of in situ generated nickel precatalyst for tritiation is also highlighted by H/T exchange of famciclovir, a pioneering example of using one-step HIE method to install tritium on structures containing nucleobase analogues.26 By comparison, relatively low specific activities of 1.9 and 2.7 Ci/ mmol were obtained for famciclovir and imatinib, respectively, presumably due to the presence of −NH sites competing for H/T exchange. However, these levels are sufficient for metabolic studies.

Relative Rates of Hydrogen Isotope Exchange for 4Substituted Pyridines. The utility of both in situ generated and isolated [(iPrDI)Ni(μ2−H)]2 in HIE prompted additional investigations to elucidate the nature of the active C−H functionalization catalyst and the mode of operation. Initial studies were conducted with representative 4-substituted pyridines containing electron-donating and -withdrawing groups with the goal of understanding the electronic preferences of the substrate in nickel-catalyzed HIE (Scheme 7). The deuteration reaction was conducted to approximately Scheme 7. Relative Rates of H/D Exchange with 4Substituted Pyridines

10% conversion to avoid potential complications from isotope effects, and the progress of each reaction was determined by a combination of LC-MS and 1H NMR spectroscopy. Deuteration occurred 1.6 times faster with 4-CF3-substituted pyridine as compared to pyridine itself. By contrast, the more electronrich 4-picoline underwent H/D exchange with a relative rate 10214

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a minimal pressure of T2 is desired to minimize the amount of radioactive waste. Determination of Kinetic Isotope Effects and Mechanistic Outlook. To further understand the nickel-catalyzed HIE process and the nature of the C(sp2)−H activation step, kinetic isotope effects were measured. Because the reaction is reversible, there are potential isotope effects involved with the C−H bond undergoing exchange but also the gas being used and the isotopologues formed during the course of the reaction. Attempts to observe catalytically relevant intermediates during turnover have been unsuccessful; only the nickel hydride dimer was observed. Using isolated [(iPrDI)Ni(μ2− H)]2, an experiment was designed whereby the relative rates of HIE in pyridine and pyridine-d2 were measured using subatmospheric pressure of T2 gas. The tritiated pyridine products were treated with stoichiometric HCl to convert them to the nonvolatile pyridinium salts, which were well suited for analysis by LC-MS (+ESI) for determination of the net tritium enrichment. To the best of our knowledge, this is the first time that kinetic isotope effects for catalytic HIE process were studied using T2 gas. Comparison of the initial rates of reaction of pyridine and pyridine-d2 established a primary kinetic isotope effect of 3.47 ± 0.24 at 23 °C (Scheme 10, A vs B). This value is comparable to the primary isotope

constant half of parent pyridine. Thus, more electron-deficient substrates undergo more rapid HIE. Monitoring the Site Selectivity of the Deuteration of 2-(p-Tolyl)pyridines. The site selectivity of the deuteration of 2-(p-tolyl)pyridine with in situ generated [(iPrDI)Ni(μ2− H)]2 was monitored by 1H NMR spectroscopy as a function of time to determine if the activation of any of the C−H bonds (pyridinyl versus tolyl ring) was kinetically preferred. Deuteration occurred at essentially the same rate at both the N-heteroarene positions and the directed sites (Scheme 8). While by no means definitive, this observation argues against degradation to heterogeneous nickel for the deuteration of the α-position in N-heteroarenes. Scheme 8. Deuteration of 2-(p-Tolyl)pyridine at Different Time Intervals

Scheme 10. Kinetic Isotope Effects for Ni-Catalyzed HIE in Pyridine

Inverse Pressure Dependence. The influence of the pressure of D2 gas was investigated in the deuteration of MK6096 as a representative substrate. With isolated [(iPrDI)Ni(μ2−H)]2, decreasing the D2 pressure from 1 to 0.37 atm increased the amount of deuterium incorporation from 64 to 86% in the pyrimidine ring (position 1, Scheme 9) and from 15 to 27% in the likely directed position (position 2). This is an important, favorable feature for tritiation applications where Scheme 9. Inverse Pressure Dependence in Deuteration of MK-6096 Using 25 mol % of [(iPrDI)Ni(μ2−H)]2

effect of 3.7 (25 °C) measured with the iridium catalyst, [Ir(COD)(PPh3)(IMes)][PF6], for the deuteration of acetophenone with D2 and the converse hydrogenation of acetophenone-d5 with H2.11d In addition, the relative rate of deuteration of natural abundancepyridine was measured at the same pressure of 0.15 atm of D2 gas and was found to be 2.4 times faster than the corresponding tritiation (Scheme 10, B vs C). The significant kinetic isotope effect between between D2 and T2 addition is consistent with the observations of higher degrees of deuteration relative to tritiation of all substrates under identical conditions. Both KIE values are in agreement with the hypothesis that involves rate determining C−H activation and a pre-equilibrium of D2 (or T2) activation.29 Consistent with precedent from [(iPrDI)Ni(μ2−H)]2-catalyzed enyne cyclization30 and hydrosilylation,20 it is likely the N-heterocycle induces dissociation of [(iPrDI)Ni(μ2−H)]2, resulting in an unobserved nickel hydride monomer as the active species, presumably with substrate coordinated.29 The combined KIE, relative rates of deuteration of 4-substituted pyridines, and observed pressure dependence are consistent with the putative nickel hydride monomer promoting turn10215

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ACS Catalysis over-limiting C(sp2)−H oxidative addition, analogous to proposed H−H and Si−H bond cleavage pathways with the same precatalyst19,20 and C(sp2)−H bond activation with a related Ni(I) complex.31 Based on the current data, a concerted pathway cannot be ruled out as a viable pathway for the C−H bond cleavage step.29,32 The selectivity of the reaction is likely determined by the acidity of the C−H bonds and their proximity to the nickel center in the putative active monomeric species. The more rapid labeling of electrondeficient N-heteroarenes may be a consequence of the more facile activation of the C−H bonds in this class of substrates. The inverse pressure dependence likely derives from a competition for the nickel active site between free D2 or T2 and the substrate.33 The open coordination sites in the putative monomer may also enable directed C−H activation, which is in contrast to the iron catalyst, where selectivity is exclusively dictated by steric effects.14

1.0 equiv of iPrDI ligand, and 6.0 equiv of HSi(EtO)3 in THF with a total [Ni] concentration of 0.035 M. When isolated [(iPrDI)Ni(μ2−H)]2 was used, a 0.2 mL of THF solution was prepared containing 25 mol % of [Ni]. To a 1 mL roundbottom flask charged with a magnetic stir bar was added the desired drug molecule (7 μmol, 2−3 mg), 0.15 mL of THF, and 50 μL of the premade [Ni] stock solution. Tritium gas (1.0 Ci, 120 mmHg) was admitted into the reaction vessel after evacuation of the N2 atmosphere, and the reaction mixture was stirred at specified temperature for 20 h. After this time, the volatile components were removed by successive evaporation from ethanol, and the crude product was analyzed by radio-HPLC. The crude product was subsequently purified by semipreparative reverse phase HPLC.

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ASSOCIATED CONTENT

S Supporting Information *

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.8b03717. Additional experimental details, catalyst optimization studies, and characterization data for all isotopically labeled products (PDF)

CONCLUSION In summary, nickel-catalyzed direct hydrogen isotope exchange methods were reported utilizing either isolated or in situ generated precatalysts. The methods offer site selectivity distinct from that observed using other homogeneous and heterogeneous HIE catalysts and a broad functional group compatibility, including free hydroxyl groups and nitrogen-rich heterocycles commonly found in pharmaceutical compounds. These features coupled with the activity at low tritium pressure and the availability of catalyst precursors render this new method attractive for commercial and drug-discovery pipeline applications.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Cayetana Zarate: 0000-0002-4002-6147 Paul J. Chirik: 0000-0001-8473-2898

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Notes

The authors declare no competing financial interest.

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EXPERIMENTAL SECTION General Procedure for the Deuteration of Pharmaceuticals. Isolated [(iprDI)Ni(μ−H)]2 was prepared according to reported procedures.19 For the in situ method, a stock solution was prepared containing 0.5 equiv of [(NEt3)Ni(OPiv)2]2, 1.0 equiv of iPrDI ligand, and 6.0 equiv of HSi(EtO)3 with a total [Ni] concentration of 0.031 M in THF. To a thick-walled glass vessel charged with a magnetic stir bar was added the desired amount of substrate and catalyst. The vessel was sealed, transferred out of the glovebox, and attached to a high-vacuum line, and the contents of the vessel were frozen by submersion in liquid nitrogen (77 K). Following evacuation of the N2 atmosphere, 1 atm of D2 gas was admitted into the vessel. The vessel was then sealed, and the reaction mixture was thawed (upon thawing of sealed vessel to 298 K, the pressure reaches ∼4 atm of D2) and then stirred at 45 ± 1 °C for 24 h. After this time, the vessel was opened to air and diluted with 1 mL of MeOH. Unless otherwise specified, the reaction mixtures were analyzed following removal of the nickel by filtration through a thin pad of alumina. The solvent was removed in vacuo, and the residue was analyzed using 1H NMR spectroscopy without further purification. The amount of deuterium incorporation was determined by the decrease of 1H NMR signal intensities. For certain substrates (e.g., (−)-nicotine), degree of deuterium incorporation was further confirmed with the appearance of deuterium coupled 13C signals in the quantitative 13C{1H} NMR spectrum. General Procedure for Tritiation of Pharmaceuticals. A stock solution of in situ generated precatalyst was prepared in the glovebox by mixing 0.5 equiv of [(NEt3)Ni(OPiv)2]2,

ACKNOWLEDGMENTS A United States National Science Foundation (NSF) Grant Opportunities for Academic Liaison with Industry (GOALI) grant (CHE-1564379) is acknowledged for financial support. H.Y. thanks the Merck & Co., Inc., Kenilworth, NJ, United States postdoctoral fellow program for support. C.Z. acknowledges support from a Foundation Ramon Areces Fellowship. W.N.P. acknowledges Eli Lilly for partial support through a graduate fellowship. We thank Ingrid Mergelsberg, Sumei Ren, and Andrew Hoover for helpful discussions and Jonathan M. Darmon for assistance with preparation of the manuscript.

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REFERENCES

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DOI: 10.1021/acscatal.8b03717 ACS Catal. 2018, 8, 10210−10218