Synthesis of Bis(indolyl)methanes Using Hyper-Cross-Linked

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Article Cite This: ACS Omega 2018, 3, 2242−2253

Synthesis of Bis(indolyl)methanes Using Hyper-Cross-Linked Polyaromatic Spheres Decorated with Bromomethyl Groups as Efficient and Recyclable Catalysts Reddi Mohan Naidu Kalla,† Sung Chul Hong,*,‡ and Il Kim*,† †

BK21 PLUS Center for Advanced Chemical Technology, Department of Polymer Science and Engineering, Pusan National University, Geumjeong-gu, Busan 609-735, Republic of Korea ‡ Department of Nanotechnology and Advanced Materials Engineering, Sejong University, 209 Neungdong-ro, Gwangjin-gu, Seoul 143-747, Republic of Korea S Supporting Information *

ABSTRACT: Highly uniform and hyper-cross-linked polyphenanthrene and polypyrene microspheres were synthesized by Friedel−Crafts bromomethylation of phenanthrene (Phn) and pyrene (Py) in the presence of zinc bromide as a catalyst, followed by self-polymerization of bromomethylated Phn and Py. The resultant 3-D carbon microspheres consisting of micro-, meso-, and macropores bear peripheral unreacted bromomethyl groups, which are directly utilized as catalysts to efficiently promote the electrophilic substitution reaction of indoles with aldehydes to yield a variety of bis(indolyl)methanes. The important features of this catalysis are easy catalyst synthesis, high product yields, environmental benignity, short reaction time, broad substrate scope, use of nontoxic solvents, and recyclability.

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INTRODUCTION At present, several researchers are focusing their efforts on developing green chemical methods to decrease costs, hazards, waste, and energy consumption using ecological reagents and reaction conditions for chemical synthesis. The realization of several modifications in a single process is consistent with the goals of green and sustainable chemistry.1 In particular, the use of environmentally benign solvents [e.g., water, glycerol, and ethylene glycol (EG)], solvent-free conditions, or nontraditional methods (e.g., ultrasound, grinding, and microwaves) represents a highly potent and green chemical protocol for costeffective synthesis.2 Bis(indolyl)methanes (BIMs) and their derivatives are promising nitrogen-containing compounds that are present in a variety of natural products and synthetic compounds.3 Furthermore, BIMs and their analogues show a wide range of biological and pharmacological activities such as antioxidant, anti-inflammatory, antifungal, antibacterial, antibiotic, and analgesic properties.4 In addition, BIMs reportedly exhibit anticancer activity, preventing the growth of cancerous cells,5 including those of colon,5c cervical, prostate,5a,b pancreatic,5d,e and lung.5f The most significant metabolite of indole-3-carbinol, dimeric 3,3′-bis(indolyl)methane, plays a significant role in inhibiting breast cancer.5g,h Indole−carbazole derivatives are known to act as triplet energy materials,6 whereas oxidized BIMs are used as colorimetric sensors7,8 and dyes.9 Owing to their significant biological and pharmacological properties, there is an increasing interest in a facile route for the © 2018 American Chemical Society

preparation of BIMs. In general, the electrophilic substitution of indoles with carbonyl compounds is usually mediated by Brønsted or Lewis acids,10,11 ionic liquids, or heteropolyacids.12,13 In general, the use of toxic reagents, high catalyst loading, use of expensive catalysts, and volatile organic solvents are among the drawbacks of these methods. Hence, the search for methodologies to reduce the environmental impact of the synthesis of BIMs is of great interest to the pharmaceutical industry. The use of green chemicals or solvent-free conditions, including nonclassical methods using grindstone, microwaves,14 ultrasound,15 and eco-friendly reagents and catalysts,16 is among the most viable alternatives being considered to improve the synthesis of BIMs. In the past few years, porous organic polymers have attracted significant attention for potential applications in gas adsorption,17 sensing,18 catalysis,19−21 proton conduction,22 and energy storage.23 As a result, researchers have attempted to produce a number of novel porous materials such as covalent organic frameworks,24 metal organic frameworks,25 conjugated microporous polymers (MOPs),26 covalent triazine frameworks,27 hyper-cross-linked polymers (HCPs),28 and microporous organic polymers, in addition to traditional porous materials such as zeolites and activated carbon. Among these porous materials, HCPs and MOPs have been most widely Received: December 4, 2017 Accepted: February 9, 2018 Published: February 26, 2018 2242

DOI: 10.1021/acsomega.7b01925 ACS Omega 2018, 3, 2242−2253

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Figure 1. Schematic synthesis of hyper-cross-linked polyaromatic spheres bearing bromomethyl functionality (HCP@CH2Br) and BIM derivatives using HCP@CH2Br as a catalyst.

for the preparation of biologically potent BIMs. Following green protocols, no solvents were used at mild reaction conditions and catalyst recycle feasibility was also examined.

studied because of their unique properties such as large surface area, low skeletal density, and high chemical stability. The HCPs have been synthesized mainly by the hyper-cross-linking of small organic molecules by the Friedel−Crafts alkylation reaction with an external cross-linker.29 Davankov resin is one of the styrenic polymers that are hyper-cross-linked by the Friedel−Crafts reaction.30 However, tedious synthetic processes are required, and the resultant resins bear nonuniform pores. Recently, we fabricated highly uniform HCPs based on a simple Friedel−Crafts alkylation of aromatic hydrocarbons such as naphthalene, anthracene, phenanthrene (Phn), pyrene (Py), and coronene, followed by self-polymerization, as supercapacitor materials, gas absorption, and support for heterogeneous catalysts.31 For several years, we have developed new methodologies for the synthesis of bioactive compounds by following the principles of green chemistry, including the use of neat conditions,32 cheap and recyclable heterogeneous catalysts,33 grindstone method,34 ionic liquid catalysts, and energy-efficient protocols.35 On the basis of our studies on HCPs and the synthesis of bioactive compounds, we found that the HCPs could be a good candidate for the green synthesis of BIMs because HCPs are characterized by easy synthesis and chemical and thermal stability and contain unreacted halogen groups on their surface which can directly catalyze the electrophilic substitution reaction of indoles with aldehydes to yield a variety of BIMs. In this regard, we report the synthesis of HCPs by Friedel−Crafts bromomethylation of Phn and Py in the presence of zinc bromide as a catalyst, followed by selfpolymerization of bromomethylated Phn and Py. The resultant 3-D carbon microspheres bearing unreacted bromomethyl functionality (Figure 1) on the surface contain micropores, mesopores, and macropores and were directly used as a catalyst

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RESULTS AND DISCUSSION Characterization of Polyphenanthrene and Polypyrene. The HCP spheres were prepared by a one-pot protocol without using any templates. Highly uniform spheres of an average diameter of ∼1 μm began to form after 10 min of reactions of Phn or Py with bromomethyl methyl ether (BMME) at 70 °C in the presence of the ZnBr2 catalyst. This initial morphology was retained even after 18 h of reaction. Figure 2d shows the scanning electron microscopy (SEM) images of polyphenanthrene (PPhn) and polypyrene (PPy) spheres after 18 h of reaction. Friedel−Crafts bromomethylation of Phn or Py followed by cross-linking produces energyminimized spherical particles in the 1,2-dichloroethane (DCE) solvent bearing micropores formed by interconnected −CH2− bridges (see Figure 1). It is interesting to note that the HCP spheres intrinsically bear unreacted bromomethyl groups on the surface. The unreacted bromomethyl groups on the surfaces of PPhn (PPhn@CH2Br) and PPy (PPy@CH2Br) spheres were also traced using Fourier transform infrared (FTIR) spectra (Figure 2a). The absorption peaks at 2892 and 2909 cm−1 clearly represent the methylene bridge of PPhn@CH2Br and PPy@CH2Br, respectively. The absorption peaks at 1090, 741, 1099, and 752 cm−1 correspond to the C−H wagging and C− Br stretching vibrations, indicating the existence of unreacted bromomethyl groups. The concentrations of unreacted bromine groups of the PPhn and PPy samples estimated calorimetrically using Hg(SCN)236 were 0.29 and 0.31 mg/L, respectively (see Figure S1 in the Supporting Information). Most of this bromomethyl groups will be removed by 2243


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have not been previously reported in the literature. Accordingly, the PPy@CH2Br-catalyzed synthesis of BIMs offers several advantages in terms of easy operational procedure, high product yields, good stability of the catalyst, and recyclability (vide infra). All synthesized BIMs were confirmed by IR, 1H, and 13C NMR spectroscopies. In their 1H NMR spectra, the −NH proton signals typically appeared as a singlet in the region of 10.81−7.41 ppm. The Ar−CH proton signal also appeared as a singlet in the region of 6.48−5.56 ppm, confirming product formation, and the remaining proton signals were observed in the expected regions. In the 13C NMR spectra of the products, the Ar−CH carbon signals were observed in the region of 54.1−32.2 ppm, confirming the formation of BIMs (Supporting Information).37 For further investigations into the effect of operational conditions, a series of reactions of indole (1.0 mmol) with benzaldehyde (0.6 mmol) were performed under different conditions (Table 2). First, the reaction was performed under neat conditions using 5 mg of PPhn@CH2Br and PPy@CH2Br as the catalyst with constant stirring at room temperature (rt) for 1 h and under an open atmosphere. The target BIM (1) was obtained in 25 and 40% yields, respectively (entries 1 and 2). To increase the product yield, the amount of catalyst was increased to 5 and 10 mg, resulting in 50 and 73% yields, respectively, of 1 (entries 3 and 4). Increasing the reaction temperature to 40 and 60 °C, BIMs were obtained in 75, 85, 90, and 96% yield (entries 5−8). Phn and Py were tested as catalysts for the reaction; however, the yield was only 20 and 25%, respectively (entries 9 and 10). It is worth noting that the carbonized PPhn (PPhn−C) and PPy (PPy−C) samples of PPhn@CH2Br and PPy@CH2Br samples, respectively, show no catalytic activities at rt (entries 11 and 12). To compare the effect of bromomethyl group on the activity, we synthesized PPy@CH2OMe using dimethoxymethane as a cross-linker bearing no bromomethyl groups on the periphery. The PPy@ CH2OMe sample shows reasonable but much lower catalytic activities, 35 and 68% at 25 and 60 °C, respectively (entries 13 and 14), than those of the PPy@CH2Br sample obtained at the same conditions. These results clearly demonstrate that the bromomethyl moieties on the surface of PPhn@CH2Br and PPy@CH2Br samples play an important catalytic role in this reaction medium. The higher catalytic activity of PPy@CH2Br than PPhn@CH2Br is thus related with the higher concentration of CH2Br groups of the PPy@CH2Br sample than that of PPhn@CH2Br. The optimum yield (96%) of BIM 1 was achieved by reacting 1.0 mmol of the indole with 0.6 mmol of the aldehyde under neat condition at 60 °C for 1 h with 10 mg of the PPy@CH2Br catalyst (entry 8). Table 2 shows that the catalytic activity of PPy@CH 2 Br for the electrophilic substitution of indole is dependent on the reaction temperature. To further investigate the kinetics, the yield versus time plots of this catalytic reaction are prepared at 25, 40, 50, and 60 °C (Figure 3). At all temperatures, the yields increase sharply at the early period of reaction and the extent of increment falls as the time goes by. These kinetics are a typical case observed for the heterogeneous catalytic reactions involving the adsorption of reactants and surface reactions (vide infra). Next, we aimed to verify the effect of the neat method and different solvents in accelerating the catalytic reaction. The effects of the various solvents were compared, and the results are presented in Table 1 (entries 8 and 15−21). The reaction conducted in water using PPy@CH2Br at 60 °C for 1 h resulted in only a 50% yield of the target BIM. When the same

Figure 2. (a) FT-IR spectra, (b) XRD patterns, (c) TGA thermograms, (d) SEM images, (e) nitrogen adsorption and desorption isotherms, and (f) pore size distribution of PPhn@ CH2Br and PPy@CH2Br.

calcination at a high temperature. X-ray powder diffraction (XRD) spectra of PPhn@CH2Br and PPy@CH2Br samples (Figure 2b) show the amorphous nature of the samples. The thermogravimetric analysis (TGA) curves of both PPhn and PPy spheres (Figure 2c) show a sharp weight loss at ∼500 °C; the overall weight loss at 800 °C is 28.6 and 34.8%, respectively. The larger weight loss of PPy is presumably due to the existence of a larger amount of organic components that can be calcined, such as bromomethyl groups and loosely cross-linked aromatic rings. The PPhn@CH2Br and PPy@CH2Br samples with no thermal treatments were further investigated by nitrogen adsorption−desorption experiments. The nitrogen absorption−desorption isotherms of both samples are type IV curves (Figure 2e), and the Brunauer−Emmett−Teller (BET) surface areas of PPhn@CH2Br and PPy@CH2Br are estimated to be 550 and 628 m2 g−1, respectively, indicating a highly porous structure bearing micro-, meso-, and macropores. PPy@CH2Br-Catalyzed Synthesis of BIMs. The synthesized PPy@CH2Br sample was tested as potential HCP-based solid catalysts for the synthesis of BIMs. As shown in Table 1, 35 biologically potent BIMs could be synthesized in high yields (83−96%) using PPy@CH2Br catalysts under neat conditions. Among the synthesized BIMs, compounds 6−11 and 23−28 2244


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ACS Omega Table 1. PPy@CH2Br-Catalyzed Synthesis of a Series of BIMs (1−35)

compound G R yield (%) compound G R yield (%) compound G R yield (%) compound G R yield (%) compound G R yield (%)

1 H H 96 8 2-OH-3-Cl H 92 15 2-Br H 90 22 4-NO2 Me 94 29 2-CN Me 91

2 2-Cl H 93 9 2-OH-3-tBu H 84 16 3-Br H 92 23 3,5-Me Me 93 30 4-OMe Me 95

3 4-Me H 92 10 2-OH-3-OMe-5-NO2 H 88 17 4-Br H 96 24 PPhn Me 83 31 2-NO2 Me 92

4 3,5-OMe H 91 11 2-OH-Np H 96 18 H Me 93 25 2-OH-3-Cl Me 90 32 2-Br Me 91

5 4-NO2 H 93 12 2-CN H 95 19 2-Cl Me 94 26 2-OH-3-tBu Me 91 33 3-Br Me 95

6 3,5-Me H 95 13 4-OMe H 93 20 4-Me Me 95 27 2-OH-3-OMe-5-NO2 Me 90 34 4-Br Me 96

7 PPhn H 85 14 2-NO2 H 91 21 3,5-OMe Me 92 28 2-OH-Np Me 93 35 4-OH Me 87

Table 2. Optimization of the Synthesis of BIM 1 by the Reaction of 1 mmol of Indole with 0.6 mmol of Benzaldehyde at Various Conditions

entry

catalyst

catalyst amount (mg)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

PPhn@CH2Br PPy@CH2Br PPhn@CH2Br PPy@CH2Br PPhn@CH2Br PPhn@CH2Br PPy@CH2Br PPy@CH2Br Phn Py PPhn−C PPy−C PPy@CH2OMe PPy@CH2OMe PPy@CH2Br PPy@CH2Br PPy@CH2Br PPy@CH2Br PPy@CH2Br PPy@CH2Br PPy@CH2Br

5 5 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10

a

temperature (°C)

solvent

yield (%)a

25 25 25 25 40 60 40 60 40 40 25 25 25 60 60 100 60 60 60 60 60

neat neat neat neat neat neat neat neat neat neat neat neat neat neat H2O H2O PEG-400 glycerol EG toluene benzene

25 40 50 73 75 85 83 96 20 25 nrb nr 35 68 50 50 51 48 45 88 86

Figure 3. Yield vs time plots of the synthesis of BIM 1 in the presence of PPy@CH2Br at different temperatures. The yields were measured by comparing 1H NMR spectra of the samples taken at specific reaction times.

experiment was conducted at 100 °C, the product yield remained unchanged. Therefore, water was replaced with other eco-friendly solvents such as poly(ethylene glycol) (molecular weight = 400; PEG-400), glycerol, and EG. These solvents also resulted in low product yields of about 50% (entries 17−19). When the same reactions were conducted in the presence of toluene and benzene, the product yields were recorded to be 88 and 86%, respectively, which indicates that the product yields were low in protic solvents in comparison to those in nonprotic solvents. To investigate the applicability and limitations of PPy@ CH2Br catalysis, the protocol was extended to other examples under optimized conditions. Initially, diverse aromatic/ heterocyclic aldehydes were reacted with indole with conventional heating and under neat conditions, affording BIMs in good to excellent yields within 1 h. These results are summarized in the Experimental Section (see also the

Isolated yields. bNo reaction.

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ACS Omega Table 3. Comparison of PPy@CH2Br with Various Catalysts for the Synthesis of BIMs entry

catalyst

condition

time (h)

yield (%)

refs

1 2 3 4 5

graphene oxide Na2CO3 NaOH Fe3O4@Fe2O3−SO3H PPy@CH2Br

H2O H2O/CH2Cl2 EtOH−H2O (1:1) neat neat

3 3 2 2 1

92 70 85 100 96

38 39 40 41 this work

Supporting Information) were similar to those of the fresh catalyst.

Supporting Information). No remarkable reactivity differences were observed by the presence of electron-withdrawing or electron-donating groups in the benzaldehyde ring. As an exception, the heterocyclic substrate, 1-phenyl-1H-pyrazole carboxaldehyde, gave the respective BIM in a lower yield (85%) compared to the other aldehydes. The fused aromatic 2hydroxy naphthaldehyde gave a 96% yield within 1 h, and 2methylindole also reacted smoothly with all aldehyde derivatives, except for heterocyclic 1-phenyl-1H-pyrazole carboxaldehyde, which gave a lower yield (83%). The performance of PPy@CH2Br was compared with that of the reported catalysts for the synthesis of BIMs (Table 3). Recently, Wang and co-workers38 reported the use of graphene oxide for the synthesis of BIMs in the presence of water. They used a large amount of catalyst (150 mg) and used tedious flash chromatography for product isolation. Sodium carbonate was also used for the synthesis of BIMs;39 however, harmful dichloromethane was used as a cosolvent and flash chromatography was used for the separation of the product. Sodium carbonate acts as an alkali because when dissolved in water, it dissociates into the weak acid carbonic acid and the strong alkali sodium hydroxide. Direct use of NaOH achieved an 85% yield in 2 h.40 Kothandapani and co-worker reported magnetically separable sulfonic acid (Fe3O4−OSO3H)-catalyzed one-pot synthesis of BIMs.41 Even though multistep synthesis of the catalyst was involved, this catalyst gave stoichiometric yields of diverse BIMs. Compared to the reported catalysts, the synthesis of PPy@CH2Br is straightforward, the catalyst gives high yield (96%) in 1 h and is recyclable (vide infra), and laborious workup procedures are not needed. The leaching components of the catalyst into the liquid medium can be one of the crucial aspects regarding the deactivation of heterogeneous catalysts in liquid media. There are several ways of accomplishing the detection of the phenomenon of leaching, such as sampling of the reaction liquid and chemical analysis, contacting the catalyst with the reaction medium, activity measurement of the soluble species, and careful characterization of the used solid. Here, we tested the activity of the soluble species. The PPy@CH2Br catalyst was separated out of the reactor by filtration after 20 min of reaction during the synthesis of BIM 1 with the reaction conditions given in entry 8 of Table 2. The reaction was kept for 4 h at 60 °C with the solution mixture bearing no catalyst. The 55% yield obtained at 20 min of reaction remained almost unchanged, that is, 56% after 3 h of reaction, demonstrating that there was no remarkable leaching of active catalyst components. The recyclability of PPy@CH2Br catalysis was also examined. The catalyst was recovered by adding ethyl acetate (EA) (10 mL) to the reaction mixture; the insoluble PPy@CH2Br was separated by centrifugation, washed twice with EA (5 mL), and finally dried under vacuum. The catalyst was recyclable up to five runs (Figure 4).The morphology and chemical functionality of the recycled catalyst (see Figure S1,

Figure 4. Effect of recycling the PPy@CH2Br catalyst on the yield of the compound 1.

The chemoselectivity of the reaction was also investigated. Indole (1 mmol) was reacted with benzaldehyde (0.6 mmol) in the presence of acetophenone (0.6 mmol) at 60 °C for 5 h using 10 mg of the PPy@CH2Br catalyst. The only product obtained was BIM 1 derived from benzaldehyde (96%), whereas BIM 1′ derived from acetophenone was not observed (Scheme 1). Standard free energies of formation (ΔGf°) of BIM 1 and BIM 1′ were computed each by a vibrational evaluation as a function of temperature using DMol3 package. The calculations for ΔGf° were performed using the methodology of computing the total electronic energy of molecules and their individual atomic constituents using the density functional theory (DFT) method (BLPY).42 As shown in Scheme 1, the resulting computed ΔGf° values for BIM 1 and BIM 1′ are 24.69 and 38.46 kcal/mol, respectively. The positive signs of the free energy indicate that these reactions will not occur spontaneously at rt, and the ΔGf° value of BIM 1 is considerably less than that of BIM 1′, indicating that BIM 1 must be formed first upon continuous reaction of a mixture of 2 mol of indole and 1 mol of benzaldehyde and acetophenone. Mechanistic Aspect of HCP-Catalyzed Synthesis of BIMs. To get insights on the driving force of the high efficiency of PPy@CH2Br-catalyzed synthesis of BIMs, the structure, electronic properties, and chemical reactivity of pyrene, pyrene dimeric species, and their derivatives bearing bromomethyl groups in different positions and numbers were theoretically studied by using DFT calculations and are illustrated in Figure 5. The energies of frontier orbitals, the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO), are also calculated, and the results are summarized in Table 4 together with computed minimum energy values. Even though the PPy@CH2Br catalyst contains a large number of CH2Br on the surface of the highly cross-linked PPy matrix, the DFT studies may help to understand the catalytic role of PPy@CH2Br. The ground-state geometry 2246


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ACS Omega Scheme 1. Chemoselectivity of the Reaction

Figure 5. Frontier orbitals of molecules of pyrene and its derivatives bearing a bromomethyl group in different positions and methylene-bridged pyrene dimer and its derivatives bearing different numbers of bromomethyl group together with electrostatic potential (ESP)-fitted charges for selected atoms. The HOMO and LUMO are also shown.

Table 4. Calculated Values of the Energies of Frontier Orbitals HOMO and LUMO, Band Gap, Chemical Hardness (η), Electronic Chemical Potential (μ), and Electrophilicity Parameter (ω) for the Molecules of Pyrene and Its Derivatives and Methylene-Bridged Pyrene Dimer (dPy) and Its Derivatives compd

EHOMO (eV)

ELUMO (eV)

band gap (eV)

η (eV)

μ (eV)

ω (eV)

total E (Ha)

pyrene 1-BrCPy 2-BrCPy 4-BrCPy dPy BrCdPy (BrC)2dPy (BrC)3dPy

−4.560 −5.208 −5.163 −5.223 −4.696 −4.936 −4.994 −5.050

−1.925 −2.796 −2.550 −2.710 −2.219 −2.512 −2.794 −3.131

2.635 2.421 2.613 2.513 2.477 2.415 2.200 1.919

1.3175 1.2105 1.3065 1.2065 1.2385 1.2075 1.1000 0.9595

3.2425 4.0020 3.8565 3.9665 3.4575 3.7240 3.8940 4.0905

4.0024 6.6154 5.6918 4.9541 4.8261 5.7425 6.8924 8.7192

−615.193505 −3227.704344 −3227.706018 −3227.703681 −1268.352276 −3880.893642 −6493.398121 −6493.398121

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Scheme 2. Proposed Mechanism for the Synthesis of BIMs in the Presence of PPy@CH2Br or PPhn@CH2Br as a Catalyst

its derivatives, the values of EHOMO decrease in the order Py > 2-BrCPy > 1-BrCPy > 4-BrCPy, whereas those of ELUMO decrease in the order Py > 2-BrCPy > 4-BrCPy > 1-BrCPy. Thus, the band gap decreases in the order Py > 2-BrCPy > 4BrCPy > 1-BrCPy. For dPy and its derivatives, the values of both E HOMO and E LUMO decrease as the number of bromomethyl substituents increases. Thus, the same trend is seen for the band gap. Chemical hardness (η) measures the resistance of a compound to electron charge transfer.44 From Table 4, 1-BrCPy from monomeric species and (BrC)3dPy from dimeric species have the lowest η values, and therefore they are the most soft and the most reactive compounds in each series. The similar interpretation is possible with the value of ω, since the smaller the value of the more stable is the compound.47 The value measures the capacity of a species to accept electrons. Thus, 4-BrCPy is the strongest nucleophile, whereas 1-BrCPy is the strongest electrophile among monomeric Py species bearing a bromomethyl group. The electrophilicity increases as the number of bromomethyl groups increases among dPy derivatives. Thus, it is safe to assume that as the number of bromomethyl groups increases, the number of active sites and the electrophilicity of the hydrogen atoms on the benzylic positions increase, which influences the catalytic activity in an affirmative way. Considering the experimental results and DFT calculations of the model compounds, a plausible mechanism for the PPy@ CH2Br-catalyzed synthesis of BIMs can be proposed, as shown in Scheme 2. In the initial step, benzylic hydrides on PPy@ CH2Br activate the carbonyl group of the aldehyde, making it liable to attack by indole. The nucleophilic attack of indole to the activated carbonyl compound leads to the formation of an intermediate, which undergoes elimination of water to form another intermediate. The second molecule of indole then reacts with this intermediate, which undergoes aromatization to form the BIM.

optimizations of a pyrene molecule and its mono bromomethyl derivatives 1-(bromomethyl)pyrene (1-BrCPy), 2(bromomethyl)pyrene (2-BrCPy), and 4-(bromomethyl)pyrene (4-BrCPy) show that the computed minimum energy is in the order of 2-BrCPy < 1-BrCPy < 4-BrCPy ≪ Py. As shown in Figure 4, both HOMO and LUMO are localized evenly on the entire pyrene and 1-BrCPy molecules. For 4BrCPy, the HOMO spreads mainly on the Py moiety, whereas the LUMO is evenly distributed to the entire molecule. For 2BrCPy, both HOMO and LUMO spread only on the Py moiety, not the bromomethyl group. ESP-fitted charges of benzylic carbons for 1-BrCPy and 4-BrCPy are 0.792 and 0.796, respectively, and that for 2-BrCPy is 0.767. In addition, ESPfitted charges of the two hydrogen atoms on benzylic carbons are 0.291 and 0.291 for 1-BrCPy and 0.290 and 0.296 for 4BrCPy, whereas they are 0.275 and 0.277 for 2-BrCPy. These results demonstrate that the electrophilic substitution of pyrene preferentially takes place at 1-, 3-, 6-, and 8-positions, as reported based on both experimental result43 and DFT calculation.44 Both HOMO and LUMO are localized evenly on the entire methylene-bridged pyrene dimer (di(pyren-1-yl)methane; dPy) molecule like pyrene. For dPy bearing a bromomethyl group, 1-(bromomethyl)-6-(pyren-1-ylmethyl)pyrene (BrC-dPy), the HOMO spreads on entire molecules except for bromomethyl group, whereas the distribution of the LUMO is about half of the BrCdPy molecule. For the dPy derivatives bearing two and three bromomethyl groups, 1,3bis(bromomethyl)-6-(pyren-1-ylmethyl)pyrene ((BrC)2dPy) and 1,3,6-tris(bromomethyl)-8-(pyren-1-ylmethyl)pyrene ((BrC)3dPy), respectively, HOMOs are mainly on the Py moieties bearing no bromomethyl groups, whereas LUMOs are predominantly distributed on the Py moieties bearing bromomethyl groups. In addition, the average ESP-fitted charges of hydrogen atoms in the benzylic position of the dPy derivatives are larger than those of monomeric BrCPy species, suggesting that the dimeric species are more reactive for electrophilic attack. The HOMO/LUMO band gap can be used as a measure of chemical reactivity parameter. For example, chemical hardness (η = (ELUMO − EHOMO)/2), electronic chemical potential (μ = −(ELUMO − EHOMO)/2), and electrophilicity parameter (ω = μ2/2η) are useful parameters to determine the relative stability and reactivity45,46 and are summarized in Table 4. For Py and

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CONCLUSIONS Highly stable and reusable heterogeneous organocatalysts were synthesized by Friedel−Crafts bromomethylation of Phn and Py, followed by self-polymerization of bromomethylated Phn and Py. The resultant microspheres were intrinsically decorated with unreacted bromomethyl groups on the surface. Using the electrophilicity of the benzylic hydride, they were used as 2248


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°C. Because the resultant sample bears unreacted bromo methylene groups on the surface, we define this sample as PPhn@CH2Br. The PPy@CH2Br sphere was also synthesized by a similar procedure. The bromine content of the unreacted part (−CH2Br) was determined by calorimetry.52 The PPy@ CH2OMe sphere bearing unreacted methoxy methyl groups instead of bromomethyl groups was synthesized also by a similar procedure using dimethoxymethane as a cross-linker and FeCl3 as a catalyst. General Procedure of Synthesis of BIMs. In a 10 mL reaction flask equipped with a magnetic stirring bar, 10 mg of PPhn@CH2Br or PPy@CH2Br spheres was added to a mixture of indole, 2-methylindole (1 mmol), and aldehyde (0.6 mmol). The resulting reaction mixture was stirred at 60 °C until the completion of the reaction was indicated by thin-layer chromatography. Subsequently, the product was dissolved with 10 mL of EA, and the insoluble HCP could be separated by centrifugation. The solvent was evaporated under reduced pressure, and the solid residue was washed with ether and recrystallized from methanol to afford the desired product. The separated HCP was washed twice with EA (5 mL) and then dried under vacuum before reuse. All previously known products afforded spectral and physical data consistent with those reported in the literature. The new products were characterized by their melting points and IR, 1H NMR, 13C NMR spectra and elemental analysis. The detailed descriptions of the reaction times, yields, melting points, and spectral data for the new compounds are given below, whereas those of the known compounds are given in the Supporting Information. 3,3′-((3,5-Dimethylphenyl)methylene)bis(1H-indole) (6). 96% yield in 40 min; solid, mp 94−96 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 7.86 (s, 2H, −NH), 7.40 (d, J = 8.0 Hz, 2H, Ar−H), 7.33 (d, J = 8.0 Hz, 2H, Ar−H), 7.16−7.12 (m, 2H, Ar−H), 7.01−6.95 (m, 4H, Ar−H), 6.83 (s, 1H, Ar− H), 6.65 (s, 2H, CH), 5.79 (s, 1H, Ar−CH), 2.23 (s, 6H, −CH3); 13C NMR (100 MHz, CDCl3): δ (ppm) 143.8, 137.4, 136.6, 127.7, 127.1, 126.4, 123.5, 121.7, 119.9, 119.1, 110.8, 40.0, 21.3; FTIR (KBr) ν (cm−1): 3349, 3316, 1572, 1482, 1285, 1145, 795. Anal. Calcd for C25H25N2: C, 85.68; H, 6.33; N, 7.99. Found: C, 85.76; H, 6.30; N, 7.94. 3,3′-((1-Phenyl-1H-pyrazol-4-yl)methylene)bis(1H-indole) (7). 85% yield in 60 min; solid, mp 118−120 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 7.91 (s, 2H, −NH), 7.41 (d, J = 5.6 Hz, 2H, Ar−H), 7.34 (d, J = 8.4 Hz, 2H, Ar−H), 7.24−7.16 (m, 6H, Ar−H), 7.06−6.97 (m, 5H, Ar−H), 6.70 (s, 2H,  CH), 5.83 (s, 1H, Ar−CH); 13C NMR (100 MHz, CDCl3): δ (ppm) 147.9, 138.5, 136.6, 129.4, 129.0, 127.0, 126.2, 124.1, 123.8, 123.4, 122.3, 121.8, 119.9, 119.1, 109.9, 39.5; FTIR (KBr) ν (cm−1): 3372, 3248, 1629, 1512, 1354, 1124, 812. Anal. Calcd for C26H20N4: C, 80.39; H, 5.19; N, 14.42. Found: C, 80.48; H, 5.15; N, 14.37. 2-Chloro-6-(di(1H-indol-3-yl)methyl)phenol (8). 92% yield in 50 min; solid, mp 202−204 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 7.90 (s, 2H, −NH), 7.40 (d, J = 7.6 Hz, 2H, Ar−H), 7.34 (d, J = 8.4 Hz, 2H, Ar−H), 7.18 (q, J = 8.6 Hz, 3H, Ar−H), 7.06−6.95 (m, 3H, Ar−H), 6.74 (d, J = 10.0 Hz, 1H, Ar−H), 6.70 (s, 2H, CH), 6.23 (s, 1H, −OH), 5.77 (s, 1H, Ar−CH); 13C NMR (100 MHz, CDCl3): δ (ppm) 149.1, 136.7, 131.4, 128.5, 127.0, 126.8, 123.5, 122.0, 120.6, 120.1, 119.8, 119.3, 118.0, 111.0, 34.0; FTIR (KBr) ν (cm−1): 3395, 3325, 3286, 1552, 1469, 1245, 1139, 805. Anal. Calcd for C23H17ClN2O: C, 74.09; H, 4.60; N, 7.51. Found: C, 74.11; H, 4.60; N, 7.48.

catalysts for the synthesis of a variety of BIM compounds including 12 new compounds. All compounds were obtained in 83−96% yield under neat conditions at 60 °C. The PPy@ CH2Br- or PPhn@CH2Br-catalyzed protocol provided clean reaction profiles based on readily available starting materials. The easy preparation route, low toxicity, and recyclability of PPy@CH2Br and PPhn@CH2Br catalysts coupled to an atomeconomic reaction, and the use of neat condition is a feature that makes this new HCP-based protocol a green alternative for the synthesis of BIMs.

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EXPERIMENTAL SECTION Materials. Anhydrous zinc bromide (ZnBr2, 98%, Acros), iron trichloride (FeCl3, 99%, Daejung Chemicals, Seoul, Korea), BMME (>95%, TCI), dimethoxymethane (>95%, TCI), and the aromatic hydrocarbons Phn (98%, SigmaAldrich) and Py (>98%, TCI) were used as received without further purification. DCE (>99%, Daejung Chem. Co., Seoul, Korea) was distilled before use. Indole, 2-methylindole, and various other aromatic aldehydes were obtained from SigmaAldrich. Instrumentation and Measurements. The FTIR spectra were recorded on a Shimadzu IRPrestige 21 spectrometer at rt. The samples were measured as KBr discs in the range of 4500− 500 cm−1. XRD was used to determine the crystallinity of the electrode materials on an automatic Philips powder diffractometer with nickel-filtered Cu Kα radiation. The XRD patterns were recorded from 10° to 80°. The morphology, size, and microstructure of the products were investigated by SEM (S-3000 and SU-70, Hitachi). The BET and the Barrett− Joyner−Halenda methods (NOVA 3200e system, Quantachrome Instrument, USA) were employed to investigate the BET specific surface area and pore size distribution of the samples. 1 H (400 MHz) and 13C (100 MHz) NMR spectra were recorded on a Varian INOVA 400 NMR spectrometer at rt. The chemical shifts of the protons were relative to tetramethylsilane (Me4Si). The data are presented as follows: chemical shift (ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet), and coupling constant J (Hz). The elemental analysis of the BIMs was performed with an Elementar Vario EL III element analyzer (Elementar Analysensysteme GmbH, Germany) for C, H, N, and S determination at Korea Basic Science Institute (Busan, Korea). Computational Details. The all-electron DFT calculations were carried out using the DMol3 code48 included in the Accelrys Materials Studio package.49 ESP-fitted charges were obtained from DFT calculations. A DNP basis set was employed in all calculations, and the PBE exchange−correlation functional was used.50 The DMol3 code uses the ESP method as proposed by Singh and Kollman.51 In the DMol3 code, the default grid spacing corresponds to 0.5 Å. Default settings were used in all calculations. Synthesis of Hyper-Cross-Linked PPhn and PPy Microspherical Particles. Anhydrous ZnBr2 (1.3 g, 5.7 mmol) and Phn (1 g, 5.6 mmol) were dissolved in 50 mL of DCE in a 100 mL flask, and BMME (1.4 g, 11.2 mmol) was added to the solution under a nitrogen atmosphere. The mixture was stirred for 18 h at 70 °C. Insoluble and spherical PPhn particles started to form after 10 min of reaction. The resulting microspherical polymer was washed thoroughly with water and methanol. Extraction was performed with methanol using a Soxhlet extractor for 24 h, and the sample was subsequently collected and dried overnight under vacuum at 60 2249


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ACS Omega 2-(tert-Butyl)-6-(di(1H-indol-3-yl)methyl)phenol (9). 84% yield in 60; solid, mp 188−190 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 8.00 (s, 2H, −NH), 7.37 (t, J = 7.6 Hz, 4H, Ar−H), 7.18 (t, J = 7.2 Hz, 4H, Ar−H), 7.03−6.97 (m, 4H, Ar−H), 6.77 (s, 2H, CH), 5.94 (s, 1H, −OH), 5.56 (s, 1H, Ar−CH), 1.34 (s, 9H, −CH3); 13C NMR (100 MHz, CDCl3): δ (ppm) 153.4, 136.8, 129.4, 127.6, 126.8, 125.3, 123.7, 122.3, 121.4, 119.9, 119.5, 118.8, 116.9, 111.1, 36.2, 34.6, 29.7; FTIR (KBr) ν (cm−1): 3386, 3336, 3278, 1549, 1394, 1261, 1132, 729. Anal. Calcd for C27H26N2O: C, 82.20; H, 6.64; N, 7.10. Found: C, 82.28; H, 6.60; N, 7.06. 2-(Di(1H-indol-3-yl)methyl)-6-methoxy-4-nitrophenol (10). 88% yield in 55 min; solid, mp 228−230 °C; 1H NMR (400 MHz, DMSO-d6): δ (ppm) 10.81 (s, 2H, −NH), 10.34 (s, 1H, −OH), 7.63 (s, 2H, Ar−H), 7.34 (d, J = 8.0 Hz, 2H, Ar− H), 7.23 (d, J = 7.6 Hz, 2H, Ar−H), 7.02 (t, J = 7.4 Hz, 2H, Ar−H), 6.86 (t, J = 7.2 Hz, 2H, Ar−H), 6.79 (s, 2H, CH), 6.23 (s, 1H, Ar−CH), 3.91 (s, 3H, −OCH3); 13C NMR (100 MHz, DMSO-d6): δ (ppm) 150.9, 147.5, 139.4, 137.0, 132.1, 126.9, 124.1, 121.4, 119.0, 118.7, 118.1, 117.0, 112.0, 105.0, 56.7, 32.2; FTIR (KBr) ν (cm−1): 3401, 3371, 3294, 1562, 1438, 1249, 824. Anal Calcd for C24H19N3O4: C, 69.72; H, 4.63; N, 10.16. Found: C, 69.61; H, 4.65; N, 10.25. 1-(Di(1H-indol-3-yl)methyl)naphthalen-2-ol (11). 96% yield in 60 min; solid, mp 245−248 °C; 1H NMR (400 MHz, DMSO-d6): δ (ppm) 8.13 (d, J = 8.4 Hz, 1H, Ar−H), 7.98 (s, 2H, −NH), 7.82 (d, J = 8.0 Hz, 1H, Ar−H), 7.40 (d, J = 8.8 Hz, 2H, Ar−H), 7.36 (d, J = 8.0 Hz, 2H, Ar−H), 7.30 (d, J = 8.0 Hz, 2H, Ar−H), 7.19 (t, J = 7.4 Hz, 3H, Ar−H), 6.98 (q, J = 5.0 Hz, 3H, Ar−H), 6.78 (s, 2H, CH), 6.74 (s, 1H, −OH), 6.48 (s, 1H, Ar−CH); 13C NMR (100 MHz, DMSOd6): δ (ppm) 153.9, 137.0, 132.8, 129.4, 129.0, 128.7, 126.7, 123.8, 123.0, 122.6, 122.4, 119.7, 119.4, 116.4, 111.3, 109.9, 32.2; FTIR (KBr) ν (cm−1): 3409, 3327, 3283, 1605, 1513, 1312, 1132, 755. Anal. Calcd for C27H20N2O: C, 83.48; H, 5.19; N, 7.21. Found: C, 83.39; H, 5.18; N, 7.31. 3,3′-((3,5-Dimethylphenyl)methylene)bis(2-methyl-1H-indole) (23). 90% yield in 50 min; solid, mp 230−232 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 7.64 (s, 2H, −NH), 7.23 (d, J = 8.0 Hz, 2H, Ar−H), 7.03−6.98 (m, 4H, Ar−H), 6.88 (s, 2H, Ar−H), 6.86−6.82 (m, 3H, Ar−H), 5.91 (s, 1H, Ar−CH), 2.20 (s, 6H, −CH3), 2.01 (s, 6H, −CH3); 13C NMR (100 MHz, CDCl3): δ (ppm) 143.4, 137.3, 134.9, 131.6, 129.0, 127.5, 126.8, 120.4, 119.3, 118.9, 113.6, 109.8, 39.1, 21.4, 12.4; FTIR (KBr) ν (cm−1): 3332, 3294, 1571, 1461, 1252, 1095, 820. Anal. Calcd for C27H26N2: C, 85.68; H, 6.92; N, 7.40. Found: C, 85.65; H, 6.90; N, 7.45. 3,3′-((1-Phenyl-1H-pyrazol-4-yl)methylene)bis(2-methyl1H-indole) (24). 83% yield in 120 min; solid, mp 130−132 °C; 1 H NMR (400 MHz, CDCl3): δ (ppm) 7.70 (s, 2H, −NH), 7.22−7.18 (m, 4H, Ar−H), 7.08−7.04 (m, 2H, Ar−H), 7.01 (d, J = 7.2 Hz, 3H, Ar−H), 6.97 (d, J = 8.8 Hz, 4H, Ar−H), 6.94 (s, 1H, Ar−H), 6.89−6.85 (m, 2H, Ar−H), 5.94 (s, 1H, Ar− CH), 2.08 (s, 6H, −CH3); 13C NMR (100 MHz, CDCl3): δ (ppm) 147.9, 145.5, 138.5, 135.0, 131.6, 129.9, 129.0, 128.9, 124.5, 123.6, 122.1, 120.5, 119.2, 118.9, 113.5, 109.9, 38.7, 12.4; FTIR (KBr) ν (cm−1): 3316, 3259, 1605, 1523, 1252, 1134, 798. Anal. Calcd for C28H24N4: C, 80.74; H, 5.81; N, 13.45. Found: C, 80.67; H, 5.82; N, 13.51. 2-(Bis(2-methyl-1H-indol-3-yl)methyl)-6-chlorophenol (25). 88% yield in 45 min; solid, mp 265−268 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 10.68 (s, 2H, −NH), 8.96 (s, 1H, −OH), 7.24 (s, 1H, Ar−H), 7.20 (d, J = 8.0 Hz, 2H, Ar−H),

6.95 (d, J = 7.6 Hz, 1H, Ar−H), 6.87 (t, J = 7.4 Hz, 2H, Ar−H), 6.79 (d, J = 8.0 Hz, 2H, Ar−H), 6.72−6.65 (m, 3H, Ar−H), 6.13 (s, 1H, Ar−CH), 2.02 (s, 6H, −CH3); 13C NMR (100 MHz, CDCl3): δ (ppm) 150.9, 135.4, 134.2, 132.3, 128.9, 129.0, 128.9, 127.6, 128.9, 127.6, 120.8, 120.0, 119.8, 118.5, 118.3, 111.8, 110.7, 33.9, 12.2; FTIR (KBr) ν (cm−1): 3421, 3366, 3276, 1526, 1482, 1271, 1140, 782. Anal. Calcd for C25H21ClN2O: C, 74.90; H, 5.28; N, 6.99. Found: C, 74.79; H, 5.32; N, 6.96. 2-(Bis(2-methyl-1H-indol-3-yl)methyl)-6-(tert-butyl)phenol (26). 89% yield in 60 min; solid, mp 204−206 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 7.76 (s, 2H, −NH), 7.22 (q, J = 4.0 Hz, 3H, Ar−H), 7.04 (t, J = 7.2 Hz, 2H, Ar−H), 6.86 (t, J = 7.4 Hz, 2H, Ar−H), 6.78 (d, J = 7.2 Hz, 3H, Ar−H), 6.72 (t, J = 7.6 Hz, 1H, Ar−H), 5.94 (s, 1H, −OH), 5.46 (s, 1H, Ar−CH), 2.08 (s, 6H, −CH3), 1.35 (s, 9H, −CH3); 13C NMR (100 MHz, CDCl3): δ (ppm) 153.5, 136.5, 135.1, 132.7, 129.1, 128.6, 126.9, 125.1, 121.0, 119.8, 119.4, 118.9, 110.2, 110.0, 34.6, 29.6, 12.2; FTIR (KBr) ν (cm−1): 3409, 3319, 3285, 1627, 1512, 1248, 1131, 812. Anal. Calcd for C29H30N2O: C, 82.43; H, 7.16; N, 6.63. Found: C, 82.51; H, 7.14; N, 6.57. 2-(Bis(2-methyl-1H-indol-3-yl)methyl)-6-methoxy-4-nitrophenol (27). 90% yield in 55 min; solid, mp 219−221 °C; 1H NMR (400 MHz, DMSO-d6): δ (ppm) 10.72 (s, 2H, −NH), 10.15 (s, 1H, −OH), 7.67 (d, J = 2.4 Hz, 1H, Ar−H), 7.61 (d, J = 2.4 Hz, 1H, Ar−H), 7.19 (d, J = 8.0 Hz, 2H, Ar−H), 6.86 (t, J = 7.4 Hz, 2H, Ar−H), 6.76 (d, J = 8.0 Hz, 2H, Ar−H), 6.66 (t, J = 7.4 Hz, 2H, Ar−H), 6.06 (s, 1H, Ar−CH), 3.89 (s, 3H, −OCH3), 2.00 (s, 6H, −CH3); 13C NMR (100 MHz, DMSOd6): δ (ppm) 151.5, 147.3, 139.0, 135.4, 132.4, 131.6, 128.6, 120.04, 120.0, 118.8, 118.5, 118.2, 111.0, 110.8, 56.8, 33.4, 12.2; FTIR (KBr) ν (cm−1): 3412, 3326, 3294, 1585, 1459, 1215, 1131, 745. Anal. Calcd for C26H23N3O4: C, 70.73; H, 5.25; N, 9.52. Found: C, 70.82; H, 5.22; N, 9.46. 1-(Bis(2-methyl-1H-indol-3-yl)methyl)naphthalen-2-ol (28). 94% yield in 60 min; solid, mp 254−256 °C; 1H NMR (400 MHz, DMSO-d6): δ (ppm) 10.61 (s, 2H, −NH), 9.06 (s, 1H, −OH), 8.00 (d, J = 2.8 Hz, 1H, Ar−H), 7.71 (d, J = 6.4 Hz, 1H, Ar−H), 7.65 (d, J = 8.4 Hz, 1H, Ar−H), 7.18 (d, J = 8.0 Hz, 3H, Ar−H), 7.12 (s, 3H, Ar−H), 6.84 (t, J = 7.2 Hz, 2H, Ar−H), 6.74 (d, J = 9.6 Hz, 3H, Ar−H), 6.59 (s, 1H, Ar−CH), 1.85 (s, 6H, −CH3); 13C NMR (100 MHz, DMSO-d6): δ (ppm) 153.3, 135.2, 134.4, 132.5, 129.1, 128.9, 125.8, 122.3, 120.9, 119.8, 119.0, 118.7, 118.2, 111.9, 110.5, 32.2, 12.3; FTIR (KBr) ν (cm−1): 3431, 3340, 3273, 1550, 1485, 1267, 1128, 815. Anal. Calcd for C29H24N2O: C, 83.63; H, 5.81; N, 6.73. Found: C, 83.73; H, 5.79; N, 6.65.

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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/acsomega.7b01925. Typical procedure and characterization data for BIMs and 1H and 13C NMR spectra of all synthesized compounds (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: Hong:[email protected] (S.C.H.). *E-mail: [email protected] (I.K.). ORCID

Sung Chul Hong: 0000-0003-0961-7245 2250


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Il Kim: 0000-0001-8047-7543 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Basic Science Research Program of the National Research Foundation of Korea (2015R1D1A1A09057372). The authors are also grateful to the BK21 PLUS Program for partial financial support.

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Synthesis of Bis(indolyl)methanes Using Hyper-Cross-Linked

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