Distinguishing between Homogeneous and Heterogeneous Catalytic

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Distinguishing between Homogeneous and Heterogeneous Catalytic Activity in C−H Arylation of an Indole with Aryl Halides under “Ligandless” Conditions: Crucial Evidence from Real Catalytic Experiments Elena V. Yarosh, Anna A. Kurokhtina, Elizaveta V. Larina, Nadezhda A. Lagoda, and Alexander F. Schmidt* Downloaded via UNIV AUTONOMA DE COAHUILA on April 18, 2019 at 17:36:34 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

Department of Chemistry, Irkutsk State University, 1 K. Marx Str., Irkutsk 664003, Russia S Supporting Information *

ABSTRACT: The kinetic approach for distinguishing between homogeneous and heterogeneous catalysis mechanisms by the analysis of differential selectivity was applied for direct C−H arylation of an indole with aryl halides under “ligandless” conditions. The differential selectivity of competing arylation of an indole with two aryl iodides or bromides and the differential regioselectivity of a parallel formation of C2- and C3-regioisomers of arylated indoles were studied by the simple method of phase trajectories needed for raw kinetic data only. The results obtained indicated that the selectivities strongly depended on the type (soluble or insoluble) and concentration of the Pd precursor. Considering the pathways of Pd transformations under the reaction conditions, this indicates a substantial contribution of catalysis occurring on the surface of metallic Pd (including nanoparticles). KEYWORDS: C−H arylation, palladium, differential selectivity, phase trajectories, heterogeneous catalysis

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INTRODUCTION Arylation of indoles via direct C−H activation (direct arylation) is a very attractive synthetic approach for obtaining up-to-date pharmaceuticals, agrochemicals, etc.1 Nevertheless, a crucial mechanistic question on the truly homogeneous or heterogeneous nature of catalysis in the reaction has not been precisely identified. However, while the question is not solved, it is impossible not only to develop a rational approach to the elaboration of new catalysts for direct C−H activation methods and to optimize the synthetic protocol under laboratory and technological conditions but also to construct more reliable full mathematical (macrokinetic) models of processes and economical reactor design. Studies aimed at distinguishing these two mechanisms have been conducted (for a review of such papers, see refs 2 and 3 and a recent review on the related cross-coupling processes4); however, the different reaction tests for homogeneity/ heterogeneity as well as different ex situ techniques for detection of a Pd form used in these studies are unable to solve the problem unambiguously. The matter is that the reaction is complicated by the behavior of several consecutive parallel processes including the interconversions of soluble and insoluble Pd forms occurring simultaneously with the catalytic reaction. So, the results of the tradition reaction tests for homogeneity/heterogeneity were subjected to the influence of such processes. Pd dissolution from the surface, as well as its reverse precipitation, leading to the formation of nanoparticles and bulk metal, have been well-established using various methods under the reaction conditions and occur undoubtedly, at the very least, in “ligandless” conditions.2,3 Therefore, any conventional research methods (including kinetic and © XXXX American Chemical Society

operando ones) are ineffective for obtaining reliable results for this reaction. In order to draw any valid conclusions about the nature of the active species, it is necessary to apply an approach leading to results that are independent of the concentration of the active species, which varies in the abovementioned processes. In addition, using any model conditions (i.e., low substrate/catalyst ratio or excluding any components of a reaction system) must be avoided due to crucial influence of all reaction components to each other and, in the first place, to catalyst transformations.2−4 We previously proposed the kinetic study of the differential selectivity of competing reactions because it does not depend on the concentration of the active species and is determined by their nature alone.5 Therefore, a change in the differential selectivity under varying reaction conditions unambiguously points to the changes in the species responsible for catalysis. As a convenient method for the qualitative and quantitative estimation of differential selectivity, the use of the so-called phase trajectories of the reactions was proposed.4−6 To the best of our knowledge, the phase trajectories have not been used as the instrument for mechanistic studies of catalytic reactions earlier; however, they are widely used for the analysis of the dynamical system behavior in physics and engineering. With regard to the catalytic reaction, if two competing substrates are used, the phase trajectory is the interdependence of the concentrations of the products formed from the competing substrates. In this case, the slope of the tangent to any point of the phase trajectory is the ratio of the rates of the competing reactions, Received: February 26, 2019

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DOI: 10.1021/acs.oprd.9b00096 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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which definitively characterizes the differential selectivity.5 Therefore, with the coinciding/differing phase trajectories obtained by varying the reaction conditions, it is possible to make valid conclusions about the coinciding/differing natures of the active species formed in situ during the reaction. Recently we have published the paper dealing with the investigation of differential selectivity of indole direct arylation (with two competing aryl halides, two indoles, and noncompeting variant analyzing differential regioselectivity of C2/ C3-phenyl indole formation) using the phase trajectories.7 With the natures of the cation and anion of the base as well as of inorganic salt (using as additive to the catalytic system) varied, the anionic type of active species has been established. Also, the data obtained allowed concluding of the participation of indole in the electrophilic substitution, at least under “ligandless” conditions. However, the obtained results on the types of elementary steps realized in the catalytic cycle of indole direct arylation and about anionic type of active species did not provide any information about realization of catalysis in the solution phase or on the surface of heterogeneous Pd species. Therefore, to distinguish these two possibilities, an extra study needs to be carried out. It is well-known that the type (soluble or insoluble) as well as concentration of the Pd precursor are the crucial factors influencing the Pd distribution between the soluble and insoluble forms during the catalytic reaction. Additionally, the type and concentration of the precursor also determine the size and/or shape of the Pd metal particles formed in the solution and/or on the heterogeneous support.2,3,8 It is very important that when using “ligandless” reaction conditions (the absence of any strong organic ligands), the Pd molecular complexes in solution remain unchanged when the nature or concentration of the Pd precursor varies.9,10 Therefore, the invariability of the phase trajectories (i.e., of differential selectivity) using soluble and insoluble (for instance, metallic Pd deposited on various supports) Pd precursors indicates unambiguously that the nature of the active species in these reactions is the same and is independent of the precatalyst nature. This rules out the activity of the supported palladium because it is absent in the reaction using homogeneous precatalysts.4−6 Furthermore, any changes in the differential selectivity when moving from a soluble precursor to a supported one become possible only when heterogeneous catalysis occurs. Therefore, the differing phase trajectories obtained by varying the type (soluble or insoluble) and/or concentration of catalyst precursors allow valid conclusions about the considerable contribution of the heterogeneous catalysis mechanism in the formation of the reaction products. It is important to emphasize that possible contributions of homogeneous and heterogeneous mechanisms into observed catalytic activity are likely to vary substantially under the reaction proceeding due to aggregation of Pd and its inverse solubilization. However, the resulting phase trajectories of the reactions differing in such contributions would also be different, as it is under the sole heterogeneous catalytic activity. So, any discrepancy of the phase trajectories observed with varying the factors mentioned above definitely points to the direct participation of heterogeneous Pd in catalysis. It should be particularly noted that such a rapid and efficient approach for distinguishing between the homogeneous or heterogeneous nature of active species needs the concentration of organic reaction products data only (raw GC or GC−MS data), which makes such conclusive methodology become very attractive for kinetic investigations. Moreover, such studies

performed under real catalytic conditions exclude any possible restrictions for the conclusions to be used for real catalytic ones.

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EXPERIMENTAL SECTION General Considerations. All reactants and solvents were obtained from Sigma-Aldrich or Acros (grade p.a.) and were used as received without further purification or drying. The qualitative and quantitative analysis of the C2- and C3-arylated products was performed by gas chromatography (GC, Chromatec Crystal 5000.2 instrument fitted with a flame ionization detector [FID] and a 15 m HP-5 methyl phenyl siloxane capillary column) or GC−MS (Shimadzu GC−MS QP-2010 Ultra, ionization energy of 70 eV, 0.25 μm × 0.25 mm × 30 m GsBP-5MS column, with He as the carrier gas). The recorded mass spectra were compared with those available in the literature (Wiley, NIST, and NIST05 comparison libraries). Samples for GC and GC−MS analyses were collected at different reaction time points. Concentrations of C2- and C3arylated products were determined by GC−MS based on the relative area of GC−MS signals referred to an internal standard (naphthalene) calibrated to the corresponding pure compound. To estimate the reproducibility of the data, each experiment was performed three times. For phase trajectories plotted, the appropriate polynomial fitting of the experimental data was used in order to be convinced in phase trajectories overlapping/changing. Catalyst Preparation. Pd/C was prepared using Pd(OAc)2 at a Pd loading of 4 wt %. The support material (“sibunit”, 1 g) was suspended in 20 mL of toluene. Pd(OAc)2 was added, and the suspension was stirred for 30 min at 95 °C. Completeness of Pd(OAc)2 adsorption was controlled by the observation of changes in intensity of the absorption band in solution at 300 nm. Then 0.04 mL of formic acid was added to reduce palladium on the carbon surface, and the suspension was stirred for 20 min until discoloration occurred. The resulting catalyst was filtered and washed with acetone. The catalysts were used after drying in a vacuum. The procedure for Pd/Al2O3 synthesis was analogous to those for Pd/C. Pd black was obtained by the reduction of a 2.5 M solution of Pd(acac)2 in DMF by an equimolar amount of NaBH4 under Ar. 11 The completeness of Pd(acac)2 reduction was controlled by the observation of changes in the intensity of the absorption band in solution at 330 nm. The resulting catalyst was precipitated by hexane and washed by ethanol. The catalysts were dried in a vacuum and stored under Ar. Competing Direct Arylation of Indole by Two Aryl Halides. Two competing aryl halides (1.25 mmol each), indole (2.5 mmol), base (NaOAc, if another is not specified, 1.625 mmol), naphthalene (0.5 mmol, as an internal standard for GC and CG−MS analyses), and 1.6 mol % Pd precursor (0.04 mmol) were introduced into a glass reactor equipped with a magnetic stir bar and a septum inlet. Five mL of a DMF and water mixture (4/1) was added; the mixture was placed in a preheated oil bath (140 °C). The reaction was performed with vigorous stirring at the specific temperature for 4−6 h. The following Pd compounds were used in order to investigate the influence of the catalyst precursor nature on the differential selectivity: PdCl2, Pd/C, Pd/Al2O3, Pd black. The following concentrations of PdCl2 were used in order to investigate the influence of the catalyst precursor concentration B

DOI: 10.1021/acs.oprd.9b00096 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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the competing conditions (see Figure 2b demonstrating the similarity of regioselectivities obtained under competing and noncompeting conditions). The latter result indicates the absence of any mutual influence of the additional aryl halide (used under competing conditions) on the formation of the active species responsible for the parallel formation of the C2and C3-phenylindoles. The second important feature of the phase trajectories plotted by using the concentrations of the C2- and C3regioisomers was the clearly defined nonlinearity of some of them, particularly, using PdCl2 (Figures 1c and 2a). When the parallel formation of two products from one common intermediate of a catalytic cycle or from a common intermediate and a common reagent (that corresponds to regioisomers formation) occurs, strictly linear phase trajectories should, in theory, be expected (constant slope of the tangent to any point of the phase trajectory),5 as opposed to the formation of two products from one common intermediate of a catalytic cycle and two different competing reagents (sum of C2- and C3-arylated products from competing aryl halides). In the most common case, the ratio of the rates of product formation in competing reactions, which corresponds to the slope of the phase trajectory, consists of the ratio of the rate constants of the definite steps of these reactions and the ratio of the competing substrates concentrations varying in the course of the reaction. If the parallel (noncompeting) formation of two regioisomers occurs, the competing substrates are absent, and the common reagent (indole, in this case) acts as “competing substrates” reacting with the common intermediate of the parallel catalytic cycles. As a result, the ratio of the substrate concentrations is canceled in the ratio of the rates of the regioisomers formation.5 Therefore, the rate ratio becomes equal to the ratio of the rate constants only, which should be invariable during the reaction if the nature of the active species does not change. Consequently, the phase trajectory plotted using the concentrations of the parallel (noncompetingly) forming products of the reaction should be strictly linear. Therefore, nonlinearity of the phase trajectories for the parallel formation of regioisomers (Figures 1c and 2a) is direct evidence for the change in active species during the catalytic reaction,7 and according to the above text, at least one species should be heterogeneous. The size and/or shape of the heterogeneous Pd forms depend strongly on the concentration of the Pd complexes in solution due to the nonlinear agglomeration kinetics.12,13 Therefore, the differential selectivity of the competing aryl iodides was also investigated by varying the concentration of the soluble precursor. It follows from the data obtained that the selectivity was virtually insensitive to the changes in the concentration (Figure 3a). However, the coincidence of the phase trajectories should be interpreted with caution (in contrast to their difference, which points unambiguously to the changes in the differential selectivity). The constancy of the phase trajectories can result from both the differential selectivity invariance and its slight changes along with the simultaneously insufficient sensitivity of the analytical method used. In such situations, the maximum possible factors capable of influencing the type of active species should be varied. As we analyzed the regioselectivity of the C2and C3- phenylindoles, its slight but reproducible change with a varying concentration of the soluble precursor can be considered as evidence for heterogeneous catalysis (Figure 3b). In order to widen the set of factors capable of influencing the amount, size, and/or shape of the insoluble Pd species, we

on the differential selectivity: 0.008 mmol (0.32 mol %), 0.02 mmol (0.8 mol %), 0.04 mmol (1.6 mol %), 0.08 mmol (3.2 mol %). The experiment with HCOONa or NaBH4 (0.5 mmol) and with NBu4Br (0.8 mmol) was performed using 1.6 mol % of PdCl2. Noncompeting Direct Arylation of Indole by Iodobenzene. Indole (2.5 mmol), iodobenzene (2.5 mmol), base (1.625 mmol), naphthalene (0.5 mmol, as an internal standard for GC and CG−MS analyses), and 1.6 mol % Pd precursor (0.04 mmol) were introduced into a glass reactor equipped with a magnetic stir bar and a septum inlet. Five mL of a DMF and water mixture (4/1) was added; the mixture was placed in a preheated oil bath (140 °C). The reaction was performed with vigorous stirring at the specific temperature for 4−6 h. The following Pd compounds were used in order to investigate the influence of the catalyst precursor nature on the differential selectivity: PdCl2, Pd/C, Pd/Al2O3, Pd black.

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RESULTS AND DISCUSSION In order to measure the differential selectivity of competing aryl halides, the phase trajectories should be plotted using the sums of C2- and C3-arylated indoles forming from each competing aryl halide. When competing arylation of indole by iodobenzene and 4-iodoanisole (Scheme 1) was performed Scheme 1. Direct Arylation of Indole by Competing Aryl Iodides or Aryl Bromides

using soluble (PdCl2) and several insoluble (including those deposited on heterogeneous supports) Pd precursors, the phase trajectories were different (Figure 1a). As indole arylation accompanied by the parallel formation of C2- and C3-arylated regioisomers of the reaction products, the phase trajectories were also plotted using the concentrations of the C2- and C3-phenylindoles formed from iodobenzene to measure the differential regioselectivity (Figure 1c). According to the data obtained, the regioselectivity of the products formed form one aryl halide and indole was also dependent on the type of precursor used. Such result unambiguously points to heterogeneous nature of active species or, at least, their significant contribution to catalytic activity along with homogeneous ones. As a single phase trajectory for the experiments with homogeneous and heterogeneous precatalysts would rule out supposition about activity of supported palladium (because it is absent with homogeneous precatalysts),4 the sole explanation for different phase trajectories in such situation is participation of heterogeneous Pd in catalysis. It should be noted that the regioselectivities of the C2- and C3-phenylindoles obtained under noncompeting conditions (i.e., the reaction where only iodobenzene and indole were present, as shown in Scheme 2) were also dependent on the type of precursor used (Figure 2a). Also the regioselectivities were similar to those obtained under C

DOI: 10.1021/acs.oprd.9b00096 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Figure 1. Phase trajectories of the reaction of indole with competing iodobenzene and 4-iodoanisole (Scheme 1) plotted by using (a, b) sum concentrations of the corresponding C2- and C3-arylated products and (c, d) concentrations of C2- and C3-phenylindoles, under varying the nature of the Pd precursor: PdCl2 (⧫), Pd/C (■), Pd/Al2O3 (▲), Pd black (Δ), PdCl2 + HCOONa (◊), PdCl2 + NaBH4(●).

8%. At the same time, the rates of arylated indoles accumulation decreased twice. A similar tendency of an increase in the rates of formation of arenes and a decrease in the rates of formation of the arylated indoles was observed using NaBH4 as a reductant. However, as the value of differential selectivity (i.e., slope of a phase trajectory) is determined only by the ratio of the consumption rates of two substrates (or two intermediates) competing for a common intermediate (or reagent) in the particular catalytic step, any side transformations of reactants proceeding at any another step of the catalytic cycle (or outside it at all) cannot affect the differential selectivity of the step. Therefore, any changes of the observed differential selectivity (i.e., discrepancy of the phase trajectories) are resulted from a change in the selectivitydetermining step and not from any other changes in the reaction system. So, the differential selectivity changes observed with both the addition of the reductant and various natures and concentrations of the precursor used unambiguously pointed to the change in active species associated with the considerable contribution of the heterogeneous catalysis mechanism (including catalysis by nanoparticles). It can be assumed that the relative contributions of homogeneous and heterogeneous catalysis can considerably vary when aryl bromides having a different reactivity (and as a result, a different ability to retain Pd in solution as well as to

Scheme 2. Noncompeting Direct Arylation of Indole by Iodobenzene

compared the phase trajectories obtained using the soluble precursor PdCl2 with and without the addition of sodium formate, which is a typical reductant used in aryl halide coupling reactions.12 It is well-known that an additive of a reductant influences the concentration of Pd(0) complexes in solution, and therefore, the amount, size, and shape of the Pd metal particles formed as a result of Pd(0) complexes agglomeration. The differential selectivity of competing aryl halides as well as the differential regioselectivity of the C2- and C3-arylated indoles formed from one aryl halide were found to be affected by the HCOONa as well as NaBH4 addition (see Figure 1b, d). It should be noted that the concentration of a reductant added also affected the differential selectivity and regioselectivity. It is worth noting separately that the addition of HCOONa led to a slight increase in the amount of benzene formed in the side reaction of iodobenzene reduction from 5 to D

DOI: 10.1021/acs.oprd.9b00096 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Figure 2. Phase trajectories (a) of the reaction of noncompeting direct arylation of indole with iodobenzene (Scheme 2) plotted by using concentrations of C2- and C3-phenylindoles under varying the nature of the Pd precursor: PdCl2 (⧫), Pd/C (■), Pd/Al2O3 (◊), and Pd black (Δ) and (b) of the reaction of noncompeting direct arylation of indole with iodobenzene (Scheme 2) (■) and the reaction of competing direct arylation of indole with iodobenzene and 4-iodoanisole (Scheme 1) (□) using Pd/C plotted by using concentrations of C2- and C3-phenylindoles shown for comparison.

Figure 3. Phase trajectories of the reaction of indole with competing iodobenzene and 4-iodoanisole (Scheme 1) plotted by using (a) sum concentrations of the corresponding C2- and C3-arylated products and (b) concentrations of C2- and C3-phenylindoles, under varying the concentration of PdCl2: 3.2 mol % (Δ), 1.6 mol % (⧫), 0.8 mol % (◊), and 0.32 mol % (●).

Figure 4. Phase trajectories of the reaction of indole with competing bromobenzene and 4-bromoanisole (Scheme 1) plotted by using (a) sum concentrations of the corresponding C2- and C3-arylated products and (b) concentrations of C2- and C3-phenylindoles, under varying the concentration of PdCl2: 3.2 mol % (Δ), 1.6 mol % (⧫), 0.8 mol % (◊), and 0.32 mol % (●).

enable dissolution of metallic Pd) are used instead of aryl iodides. When we carried out indole arylation with competing bromobenzene and 4-bromoanisole under “ligandless” conditions (Scheme 1), the substrates conversions using heterogeneous precursors were insufficient to use the data obtained for formulating any decisive conclusions on the differential selectivity patterns. Therefore, experiments with a varying concentration of the soluble catalyst precursor PdCl2

were performed. The differential selectivity of the competing aryl bromides (Figure 4a) as well as the regioselectivity of the C2- and C3-phenylindoles (Figure 4b) were sensitive to the concentration of Pd, indicating the considerable contribution of heterogeneous catalysis under these reaction conditions as well. In order to validate the conclusion, additional experiments using another pair of competing aryl bromides, i.e., E

DOI: 10.1021/acs.oprd.9b00096 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Figure 5. Phase trajectories of the reaction of indole with competing bromobenzene and 4-bromochlorobenzene (Scheme 1) plotted by using (a) sum concentrations of the corresponding C2- and C3-arylated products and (b) concentrations of C2- and C3-phenylindoles, under varying the concentration of PdCl2: 3.2 mol % (Δ), 1.6 mol % (⧫), 0.32 mol %(○), and using additives of HCOONa (◊) and NBu4Br (●).

Figure 6. Phase trajectories of the reaction of indole with competing bromobenzene and 4-bromochlorobenzene (Scheme 1) with Na2CO3 as a base, plotted by using (a) sum concentrations of the corresponding C2- and C3-arylated products and (b) concentrations of C2- and C3phenylindoles, under varying the concentration of PdCl2: 3.2 mol % (▲), 1.6 mol % (⧫), 0.32 mol % (○).

endogenous anions formed as a result of aryl bromide conversion), the composition of molecular complexes should not be affected by such additive. In contrast, it is likely that the Pd nanoparticle size and/or shape are sensitive to the presence of a stabilizer; therefore, the regioselectivity changes when using such additive (Figure 5b) indicate catalysis proceeding on the surface of such particles. Considering all of the phase trajectories obtained using the C2- and C3-phenylindoles (i.e, the differential regioselectivity) under both competing and noncompeting conditions, it should be kept in mind that all of the experiments described above were performed using NaOAc as the base. However, it was demonstrated previously that the regioselectivity of the C2and C3-phenylindoles is strongly dependent on the nature of the base used.7,14,15 So, in order to validate the conclusions drawn using NaOAc, we carried out the experiments aimed at distinguishing between homogeneous and heterogeneous catalysis mechanisms under competition of bromobenzene and 4-bromochlorobenzene using Na2CO3 as the base. As it follows from the data obtained, varying the PdCl2 concentration did not lead to considerable changes in the differential selectivity of the competing aryl bromides, at least, at the

bromobenzene and 4-bromochlorobenzene, were carried out. Under these conditions, varying the homogeneous precursor concentration did not lead to visual changes in the differential selectivity of the competing aryl bromides (Figure 5a). However, the phase trajectories obtained using soluble PdCl2 with and without the addition of sodium formate were different, indicating the participation of heterogeneous palladium forms in catalysis for these substrates as well (see inset in Figure 5a). As additional evidence for the reaction proceeded through heterogeneous catalysis, the obvious sensitivity of the differential regioselectivity of the C2- and C3-phenylindoles in these experiments to varying the precursor concentration and the addition of HCOONa should be considered (Figure 5b and inset). Furthermore, the regioselectivity changed when the additive NBu4Br was used (Figure 5b). It is well-known that such compounds play dual roles in the catalytic systems of aryl halides coupling; i.e., they make both soluble Pd molecular complexes and nanoparticles more resistant to agglomeration (i.e., act as nanoparticle stabilizers) and facilitate the dissolution of Pd metal particles.9,12 Since bromide anions are present in the system even when the NBu4Br additive was not added (i.e., they are F

DOI: 10.1021/acs.oprd.9b00096 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Author Contributions

reaction beginning (Figure 6a), analogously to the situation when NaOAc was used as the base. However, differential regioselectivity of C2- and C3-phenylindoles in these experiments changed (Figure 6b) pointing to catalysis proceeding on heterogeneous palladium forms, as it was for the experiments using NaOAc. Therefore, it can be concluded that participation of heterogeneous Pd occurs in the indole direct C−H arylation irrespectively on the nature of a base used. It is worth noting that the results obtained with both aryl iodides and bromides cannot ultimately disprove the partial progress of the reaction in solution through the homogeneous pathway along with the heterogeneous one. Indeed, the nonlinearity of the phase trajectories plotted using the concentrations of the C2- and C3-phenylindoles can result from changes during the reaction, owing to the relative catalytic contributions of a few (two, as a minimum) distinct active species possessing different reaction selectivities. Some of these species may be homogeneous. It is especially topical to take into account the results of the related cross-coupling reactions, which demonstrate catalysis by multiple-type active species using different catalyst precursors.8,16−19 However, the described results unambiguously indicate a considerable contribution of heterogeneous catalytic activity being able to determine the observed differential selectivity of the reaction.

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Russian Foundation for Basic Research (16-29-10731_ofi_m).

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CONCLUSION The convenient method of distinguishing between homogeneous and heterogeneous catalysis by the measurement of differential selectivity using a pair of competing substrates was applied for direct C−H arylation of indole. Patterns of differential selectivity using competing aryl iodides or bromides as well as of differential regioselectivity of C2- and C3phenylindoles were studied under varying the factors affecting the heterogeneous Pd species formed under the reaction conditions. The kinetic data obtained under real catalytic conditions unambiguously point to the considerable contribution of catalysis on the surface of the heterogeneous Pd forms (including nanoparticles generated in situ). Because the nonlinearity of the phase trajectories describing the regioselectivity of the C2- and C3-phenylindoles clearly indicates the participation of more than one distinct active species in catalysis, at least one heterogeneous active species is contributing considerably to catalysis. The data obtained are urgent from a practical view also because it allows for estimating the possibility of the development of a truly heterogeneous catalytic system for the industrial application of the process under consideration including pharmaceutical synthesis.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.9b00096. Raw GC−MS kinetic data (PDF)

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REFERENCES

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Alexander F. Schmidt: 0000-0002-1881-7620 G

DOI: 10.1021/acs.oprd.9b00096 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

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DOI: 10.1021/acs.oprd.9b00096 Org. Process Res. Dev. XXXX, XXX, XXX−XXX