Molecularly Imprinted Polymer as an Eco-Compatible Nanoreactor

Research Article pubs.acs.org/journal/ascecg

Molecularly Imprinted Polymer as an Eco-Compatible Nanoreactor in Multicomponent Reactions: A Remarkable Synergy for Expedient Access to Highly Substituted Imidazoles Ahmad Shaabani,* Ronak Afshari, Seyyed Emad Hooshmand, and Mina Keramati Nejad Faculty of Chemistry, Shahid Beheshti University, Daneshjou Boulevard, Tehran 19396-4716, Iran S Supporting Information *

ABSTRACT: In this paper, an eco-compatible molecularly imprinted polymer (MIP) nanoreactor synthesized via miniemulsion polymerization was designed, and its catalytic activity was investigated in multicomponent reaction transformations for the first time. The synthesized MIP nanoreactor was characterized by means of Fourier transform infrared, thermogravimetric analysis, differential scanning calorimetry, scanning electron microscopy, transmission electron microscopy, and dynamic light scattering. The imidazole templatederived sites created within a polymeric matrix allow MIP nanoreactors to directly catalyze the reaction and conduct the target molecule. The results show the applicability of MIP nanoreactors in a one-pot expeditious synthesis of tri- and tetrasubstituted imidazole derivatives via pseudo-four- and fourcomponent reactions with excellent yields and purities. In addition, biocompatibility and cytotoxicity of MIP nanoparticles were examined, and no obvious adverse effects on the viability of human fibroblast cells were observed. This green and facile catalytic route has an easy setup, and the products are easily isolated without tedious purification such as aqueous workup or chromatography in high purity. Meanwhile, MIP nanoreactors showed admirable potential in reusable catalysis, being recycled for several runs without losing significant activities.The MIP nanoreactor utilization strategy can be extended to the other multicomponent reactions leading to manifold pharmaceutical and environmental applications. KEYWORDS: Molecularly imprinted polymer, Nanoreactor, Heterogeneous catalyst, Multicomponent reaction, Imidazole, Heterocyclic chemistry

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INTRODUCTION Nature, with no doubt, is the best creator, which inspires us to create the symphony of high performance biomimetic artificial constructions that are meant to overcome many human obstacles. One of these obstacles is irrecoverable “time”. Humans have always believed that time is a valuable factor in each activity, as the famous proverb says "time is money". Accordingly, an attitude to saving time has been the driving force for many inventions throughout the history of science.1 In this sense, in chemistry, the development of efficient catalysts for reducing the time of the principal reactions has been a hot field for the synthesis of organic and medicinal compounds in recent years.2 Besides conventional catalysts such as Lewis or Brønsted acids or bases, nowadays, nanocatalysts such as supported catalysts,3 metal organic frameworks4 or zeolite,5 ionic liquids,6 and polymer-based catalysts7 as well as enzymes8 have been used as a new class of catalysts for many of the organic and inorganic transformations. In the new generation of catalysts, besides basic and acidic functional groups, other factors play a key role for catalytic activity, such as hole theory or cavity effects, surface contact increase, deep hydrogen bonding, etc.9−11 © 2017 American Chemical Society

Molecular imprinting technology (MIT) is a considerable technique for polymer networks synthesis with highly specific memorized cavities for a given compound, and the retention mechanism involved is based on molecular recognition.12−14 The elegance of molecular imprinting and recognition is reminiscent of psychological phenomena in nature, spurring many organic scientists to mimic it as enzyme-mimetic catalytic systems.15 In the procedure, the target organic structure acts as the template, and then the monomers and cross-linker are arranged (covalently or noncovalently) around the template and polymerized to form a cast-like shell. After the polymerization process, the template is removed, and a snapshot of the network is taken so that the resultant molecular assembly specifically binds this template, and cavities are complementary with the shape and the functional group positions of the template. Subsequently, a molecular memory with the ability to rebinding with the template with high selectivity is created in the polymer matrixes.16−18 Similar to antibody catalysts, these Received: August 9, 2017 Revised: August 20, 2017 Published: September 4, 2017 9506

DOI: 10.1021/acssuschemeng.7b02741 ACS Sustainable Chem. Eng. 2017, 5, 9506−9516

Research Article

ACS Sustainable Chemistry & Engineering Scheme 1. Schematic Plan of MIP Preparation and Its Catalytic Application as a Nanoreactor in MCRs

On the other hand, high pressure activation is presented as a potent organic synthetic strategy.44 Therefore, a coupling of high pressure with shape-memorized cavities in the MIP nanoreactor can accelerate the rate of the MCRs, which is inherently accompanied by entropy reduction in the transition state.45 Inspired by this enzyme-mimetic mechanism46 and encouraged by our continued interest in developing novel catalyst systems47−49 and MCRs methodology,50−54 we introduce MIP nanoreactors as applicable eco-compatible heterogeneous nanocatalysts in MCR. In recent years, development of imidazole derivatives via MCR protocols as one of the most significant categories of nitrogen-containing heterocyclic compounds has gained widespread attention because of high biological activity.55 Imidazole core structures have been presented in diverse biologically active systems such as histidine and the related hormone histamine. Noteworthy, imidazole scaffolds are present in many drugs such as clotrimazole, losartan, and eprosartan.56 For this purpose, one pot and step economic synthesis of pharmaceutically interesting diverse kind of imidazole derivatives via pseudo-four- and four-component reactions were investigated to expand the application scope of these tailor-made high-performance polymer networks (Scheme 1).

enzymatic active sites in the three-dimensional molecularly imprinted polymer (MIP) networks can act as a neoteric generation of task specific nanoreactors for catalyzing the reaction through the template molecule.19 These enzymemimic nanoreactors accelerate the reaction rates by their free cavities, which are capable of encapsulating reagents and creation of high local pressure through cavitation effects.20 In this case, the first priority is the imprinting of the cavity with the final product of the reaction. Next, precursors are entered into the shape-memorized cavities so that a reaction can convert it into the desired product.21 In addition, it is worth noting that MIPs synthesis is also relatively cheap with easy workup,22 making them an appropriate industrial alternative for traditional catalytic systems. In spite of numerous examples that have been reported for applications of molecular imprinting in drug and gene delivery systems,23 molecular recognition24,25 adsorption26,27 and extraction,28,29 the area of catalysis has been less exploited. The utilization of enzyme-mimetic MIPs as a catalyst was investigated previously in the reactions such as Diels− Alder,30,31 hydrolyses,32 dehydrofluorination,33 carbon−carbon bond formation,34 cross-aldol reaction,35 Huisgen 1,3-dipolar cycloaddition,36 concomitant reaction of hydrolysis along with reduction37 and control peptide disulfide bridge formation.38 On the basis of our literature survey, there is no report yet available on the synthesis of multicomponent reactions (MCRs) via MIP nanoreactors. MCRs are one-pot types of reactions made from three or more substrates which can lead to direct access to target products with inherent molecular diversity and atom economy. Nowadays, these efficient synthetic routes have been applied for rapid access to complex molecular architectures, especially for heterocycles,39 natural products,40 polymers,41 and macrocyclic compounds.42 Also, MCR approaches are being used for medicinal applications and drug discovery.43 Because the MCRs are highly convergent processes and MIP structures contain shape memorized cavity with high binding affinity for functional groups involved, it has been postulated that this virtually innocuous means of activation could efficiently catalyze MCRs.

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EXPERIMENTAL SECTION

Materials and Methods. Methacrylic acid (MAA) was purchased from Merck and distilled before use. AIBN was also obtained from Merck and recrystallized from methanol prior to usage. The other materials were purchased from Merck and Aldrich without the necessity for further purification. Synthesized products were analyzed using a Varian 3900 GC. Fourier transform infrared (FT-IR) spectra were recorded on a Shimadzu IR-470 spectrometer. Thermogravimetric analysis (TG/DTG) was carried out using PerkinElmer TGA, STA1640 with heating rate of 10 °C min−1 in a nitrogen atmosphere. The differential scanning calorimetric (DSC) analysis was performed on a METTLER TOLEDO DSC 1 with heating rate of 10 K/min in a nitrogen flow. Field emission scanning electron microscopy (FE-SEM) analyses were performed by Philips XL-30 ESEM. Transmission electron microscopy (TEM) was carried out using Philips CM30. 9507


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ACS Sustainable Chemistry & Engineering Scheme 2. General Mechanism for the Preparation of Molecularly Imprinted Nanoreactors for 4a

Dynamic light scattering (DLS) was used for polydispersity index (PdI) measurement by Zetasizer Nano ZS90, Malvern Instruments. Melting points were measured on an Electrothermal 9100 apparatus. 1 H and 13C NMR spectra were obtained at 300.13 and 75.47 MHz in DMSO-d6 on a BRUKER DRX-300 AVANCE spectrometer. Synthesis of 2,4,5-Triphenyl-4,5-dihydro-1H-imidazole as a template (4a). This compound was synthesized according to the previously reported method.57 In a 50 mL flask, benzil (1.05 g, 5.00 mmol), benzaldehyde (0.53 g, 5.00 mmol), ammonium acetate (0.92 g, 12.00 mmol), and 10 mol % of InCl3.3H2O were mixed in methanol (15 mL) and stirred for 10 h at room temperature. After completion of the reaction as indicated by TLC, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 15 mL). The organic phase was dried with anhydrous Na2SO4 and recrystallized from ethanol for final purification. Synthesis of MIP Nanoreactors. The molecularly imprinted nanoreactors for the imidazole (4a) as a template were prepared via miniemulsion polymerization.58 In brief, MAA (0.34 g, 4.00 mmol) as a functional monomer, ethylene glycol dimethacrylate (EGDMA) (3.17 g, 16.00 mmol) as a cross-linker, and hexadecane (0.30 mL) as a hydrophobic agent were mixed in a three-neck round-bottom flask. Then, the imidazole (4a) (0.298 g, 1 mmol) and azobis(isobutyronitrile) (AIBN)(0.30 mmol) as an initiator were added to the mixture and sonicated for 30 min until the interaction of monomers and imidazole (4a) occurred. Afterward, 15 mg of the sodium dodecyl sulfate (SDS) were dissolved in 30 mL of deionized water and added dropwise to the mixture using a homogenizer at 24 000 rpm for 5 min. Then, the emulsion was degassed via dry N2, submerged in 70 °C water bath, and stirred for 24 h until the polymerization completed. After completion of the polymerization, the

synthesized nanoparticles were separated by centrifuging for 15 min at 21 000 rpm, washed 3 times with deionized water for removal of unreacted reagents, and dried overnight in an oven at 50 °C. The imidazole (4a) was removed by batch-mode solvent extraction upon 40 mL of ethanol, including 10% acetic acid (v/v) 5 times, and detected by thin layer chromatography (TLC). Finally, MIP nanoparticles (NPs) were washed with acetone and dried at 50 °C. Additionally, the nonimprinted polymers (NIPs) as a control polymer were synthesized through the same procedure but without the presence of the imidazole (4a). General Procedure for the Synthesis of Trisubstituted Imidazoles. In a pilot experiment, benzaldehyde (1.00 mmol), benzil, or benzoin (1.00 mmol), ammonium acetate (0.19 g, 2.50 mmol), and MIP NPs (0.04 g) were mixed and heated at 120 °C under solvent-free conditions for 20−50 min. TLC (hexane:ethyl acetate) was used for monitoring the process of the reaction. After completion of the reaction, 5 mL acetone was added, and the catalyst was separated by filtration. The synthesized compounds were further purified, if necessary, by recrystallization from acetone:water 9:1 (v/v) to give the desired trisubstituted imidazoles. General Procedure for the Synthesis of Tetrasubstituted Imidazoles. In brief, a mixture of benzil (1.00 mmol), anilines (1.00 mmol), benzaldehyde (1.00 mmol), and ammonium acetate (0.08 g, 1 mmol) in the presence of MIP NPs (0.04 g) was stirred at 110 °C under solvent-free conditions for 40−60 min. Completion of the reaction was monitored by TLC (hexane:ethyl acetate). Then, the reaction mixture was dissolved in ethanol (5 mL), and the MIP NPs were separated by filtration. If necessary, the obtained product was recrystallized from ethanol:water 7:1 (v/v) to produce the pure tetrasubstituted imidazoles. 9508


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ACS Sustainable Chemistry & Engineering Biocompatibility Tests. For biocompatibility tests, the cytotoxicity of MIP nanoparticles at different concentrations of 10, 20, and 50 μg mL−1 was determined by MTT assay following the same procedure as that in previous work.59,60 Initially, the human fibroblast (HDF) cells, obtained from Pasteur Institute of Iran, were seeded into 96-well plates (1 × 104 cells/well) using 100 mL of RPMI medium containing 10% fatal bovine serum (FBS) and 1% antibiotics and then incubated in a humidified 5% CO2 balanced air incubator at 37 °C for 24 h. In continuation, the medium was replaced with 100 mL of culture medium containing MIP nanoparticles with different concentrations, except for control cells. After incubation at 37 °C for 24 and 72 h, the medium was replaced with 100 mL of MTT solution with 0.5 mg mL−1 concentration. After continuous incubation for 4 h, the absorbance of the solutions was measured at a wavelength of 545 nm using an Elisa plate reader (STAT FAX 2100, United States). Each sample was analyzed in triplicate.

4a in size, shape, and arrangement of the complementary functional sites.21 The schematic representation of imprinting and removal of the 4a from the imprinted polymer is shown in Scheme 2. After the removal of 4a, polymers with tailored cavities were obtained, which structure and position of functional groups were predetermined by the chemical entity of 4a. FT-IR spectroscopy was performed to confirm the chemical structure of MIP after removal of template (Figure 1). The MIP shows

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RESULTS AND DISCUSSION Molecular imprinting, known as the key-to-lock process, provides a straightforward route to the synthesis of materials with molecular recognition sites comparable to those of natural enzymes but with improved properties due to their stable crosslinked structure.16 The fact that MIPs withstand more aggressive conditions and function in organic solvents under acidic or basic conditions at elevated temperature and pressure makes them promising catalysts.33 Generally, this system could serve as a great candidate for wide ranges of multicomponent reactions with various reaction conditions. Therefore, we investigated the catalytic ability of MIP in the MCR conducted to imidazole derivatives under solvent-free conditions. For this purpose, initially, the template must be chosen. As it is reported previously, for obtaining catalytically active imprinted materials, the template should be structurally in accordance with the substrate, the transition state (transition state analogue, TSA) of a reaction, or with the product.21 Meanwhile, the more studied approaches to catalysis by MIPs reaching out the TSA analogues. In this case, the recognition cavities of the 3-dimensional polymer networks can stabilize the formation of the transition state by conducting the transition energy requirement to the lower amount, which amplified the rate of the reaction.61 Because it is impossible to prepare and separate the TSA of imidazole scaffold in this reaction, we choose the product analogue of the reaction, imidazole (4a), as a template through noncovalent imprinting protocol. Noncovalent interactions show easiness of the preorganization and imprinting steps.62 Then, MAA and EGDMA as functional monomer and cross-linker were mixed with 4a and formed the in situ complex by noncovalent interactions. MAA is a good candidate for this polymerization due to the polar carboxylic acid group’s ability to interact with −NH segment of imidazole scaffold through hydrogen bonding and electrostatic forces, which increased efficient interaction of functional monomers with template molecules; also, better selectivity arose from the steric hindrance of the methyl group in MAA, which is a vital factor. Continuously, the miniemulsion polymerization process was performed for creating the molecularly imprinted nanoparticles. The most important reason for choosing this kind of polymerization is the ability of miniemulsion method to provide monodisperse nanosize reactors with an extended surface area for template uptake in a single-step procedure without need of hazardous organic solvents which open a sustainable gateway toward the green polymerization.63 Subsequent extraction of the 4a with ethanol then created the recognition sites in the polymer matrix that correspond to

Figure 1. FT-IR spectra of leached MIP nanoreactors.

clear stretching vibration at 3471 cm−1, corresponds to the −OH bond. The peak at 2977 cm−1 shows the asymmetric stretching vibration of the CH2 group, while CO stretching vibration and the bending vibrations are observed in 1730 and 1469 cm−1, respectively. Furthermore, the peaks at 1263 and 1159 cm−1 are attributed to the symmetric and asymmetric stretch bonds of C−O. Finally, the peak at 968 cm−1 is related to the presence of vinylic C−H bonds. One of the important factors for selecting a suitable catalyst for the reaction is thermal behavior and stability, especially in the solvent-free conditions that need heating. In this sense, TG/DTG experiment is carried out by heating MIP NPs up to 600 °C under N2 at a heating rate of 10 °C min−1 (Figure 2a). The TG/DTG thermogram showed the initial mass of approximately 7 wt % below 100 °C attributed to moisture and solvent evaporation from polymer structures. Obvious weight loss appeared in the temperature range of 350−480 °C, corresponding to the decomposition of polymeric matrix, and remained stable to about 490 °C with about 97% total weight loss. Overall, the result showed that the MIP nanoreactors can be remarkably stable at temperatures in excess of 340 °C. In a following investigation, to gain more insight about the thermal characterization of MIP networks, DSC analysis was performed from 30 to 200 °C (Figure 2b). In the first run, the MIP was heated to 180 °C, exhibited an endothermic peak for the evaporation of the solvent and moisture at about 100 °C, and was then cooled. As can be seen in the cooling curve, there is no evidence of any indexed endothermic peak at that temperature. Also, the glass transition temperature was determined to be 84.14 °C from the second heating run after the first run of heating to 180 °C and cooling to 25 °C. The DSC result of MIP nanoreactors confirmed that the initial weight loss that observed in TG/DTG curve was attributed to the remained solvent and moisture which was trapped in the 3D structure of the polymer networks. Also, these nanoparticles have a good thermal stability of more than 200 °C, which 9509


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ACS Sustainable Chemistry & Engineering

Figure 2. TG/DTG plot (a) and DSC thermogram (b) of MIP nanoreactors.

revealed that the average hydrodynamic particle diameter and PdI were 280 nm and 0.183, respectively. To assess the biocompatibility, the cytotoxicity of MIP nanoparticles (with a concentration of 10, 20, and 50 μg mL−1) in contact with HDF cells was measured within 24 and 72 h after incubation. On the basis of the protocols for biological evaluation of medical devices, the exposed materials are to be considered noncytotoxic and biocompatible if the percentage of a viable cell is equal to or greater than 70% of the untreated control (ISO 10993-5:2009). The viability of HDF cells in the presence of 10, 20, and 50 μg mL−1 of MIP nanoparticles is very close to the control sample, which was excluded from Figure 4. Even the sample at 50 μg mL−1concentration shows more than 85% of cell viability. On the basis of the abovementioned ISO standard this high cell viability confirms the biocompatibility of the synthesized nanoreactor, and according to the existing literature, there is no report yet available for the investigation of biocompatibility of the catalytic system in this progress. Most of the catalytic reports65−69 for the synthesis of these biologically active heterocycles are typically based on the presence of the wasting material supports, hazardous metals, and utilization of toxic organic solvents. According to the results, MIP nanoparticles did not have any toxic extract or

makes it a great candidate for catalyzing processes that need heating. In a follow-up investigation, the morphology of polymeric nanoreactors was investigated using SEM and TEM (Figure 3). As the SEM image reveals, the MIP NPs show high uniformly sized nanospheres with a narrow particle size distribution (Figure 3a). The TEM image exhibit that monodisperse spherical and uniform particles with an average mean diameter of 230 nm were formed (Figure 3b). Also, the TEM image represents the nanoparticles with an inner space that appear darker than the outer cortex. It can be concluded from the results that MIP scaffolds were accessed by the reactants, becoming nanoreactors. Because the main objective of nanocatalysis synthesis is to produce catalysts with extremely high selectivity and activity, low-energy consumption, and long lifetime, and since this can be achieved by controlling the size, shape, and spatial distribution of the nanoparticles;64 therefore, hydrodynamic diameter of the particles was measured with DLS analysis (Figure 3c). The sharp DLS measurement curve demonstrated the great efficiency of miniemulsion polymerization process for the synthesis of narrow nanosize MIP particles. The data 9510


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Figure 3. SEM image (a), TEM image (b), and particle size distribution (c) of MIP nanoreactors.

Figure 4. HDF cell viability at different MIP nanoparticle concentrations after 24 and 72 h.

complex molecular architectures with high atom economy.70 This type of procedure has been known as cascade synthesis. The main benefits of the cascade approach include high atom economy, reduction of solvent, and waste generated (byproducts, catalyst, etc.) caused by product isolation, and many workup procedures were developed among organic scientists by diminishing the number of synthetic steps. It has been postulated that synthesized MIP as a nanoreactor and task

degradation products in this concentration range and prove great biocompatibility of the nanoparticles even after 72 h. This finding demonstrates that the introduced nanoreactor could also be applied as an effective, safe, and sustainable catalyst for the synthesis of pharmaceutical and medicinal compounds. Ideal multicomponent syntheses involve the simultaneous addition of all reactants, reagents, and catalysts at the beginning of the reaction through a single-pot procedure, which causes 9511


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ACS Sustainable Chemistry & Engineering specific nanocatalyst could lead to rapid system for single-pot multicomponent cascade synthesis of imidazoles. For proving this hypothesis, the catalytic activities of MIP nanoreactors were evaluated, and the conditions were optimized. The model reaction of benzaldehyde (0.10 g, 1.00 mmol), benzil (0.21 g, 1.00 mmol), and ammonium acetate (0.16 g, 2.10 mmol) catalyzed by MIP nanoreactors was performed for the construction of4a. Likewise, the effects of reaction parameters such as temperature, solvent (exp., water, ethanol, acetonitrile, and toluene), solvent-free conditions, amount of catalyst, and reaction time on kinetics were investigated in detail. As shown in Table 1, the use of organic solvents or water

Table 2. Synthesis of 2,4,5-Trisubstituted Imidazoles via MIP Nanoreactors entry

entry

solvent

temperature (°C)

catalyst (g)

yield (%)c

1 2 3 4 5 6b 7 8 9

EtOH EtOH EtOH EtOH SF SF water toluene CH3CN

78 78 78 25 100 120 100 110 80

0.01 0.02 0.04 0.04 0.04 0.04 0.04 0.04 0.04

60 77 90 20 88 quant. trace 45 40

yields (%)a

benzaldehyde

H

4a

2

4-Cl-benzaldehyde

H

4b

3

4-NO2-benzaldehyde

H

4c

4

4-CH3-benzaldehyde

H

4d

5

1,3-benzodioxole-4carbaldehyde 2-formylphenoxyacetic acid 2-chlorobenzaldehyde 4-(benzyloxy) benzaldehyde 4-(dimethylamino) benzaldehyde

H

4e

benzil: quant. benzoin: 98 benzil: quant. benzoin: 96 benzil: quant. benzoin: 99 benzil: 97 benzoin: 94 benzil: 94

H

4f

benzil: 88

OMe OMe

4g 4h

benzil: 99 benzil: 93

F

4i

benzil: 94

7 8 9 a

product

1

6

Table 1. Optimization of the Reaction Conditions for Access to Trisubstituted Imidazole Derivatives via MIP Nanoreactorsa

R1

aldehyde

Isolated yields.

smart shapes caused increased yields of products and reduced the time of the MCRs. Subsequently, due to the importance of fully substituted heterocyclic rings in organic synthesis and medicinal chemistry, and also for the examination of selectivity ability of the MIP nanoreactors, this catalytic system was extended for the direct synthesis of tetrasubstituted imidazole derivatives. Initially, for straightforward access to tetrasubstituted imidazoles, optimization was made in the same fashion. The best conditions were found solvent-free at 110 °C and 0.04 g of MIP nanoreactors as the catalyst. To extend the scope of these nanoreactors, various anilines, benzaldehydes, and benzils containing electrondonating and electron-withdrawing substituents perform equally well as substrates for the direct synthesis of the corresponding imidazoles (Scheme 3, 5a−d). As can be seen, the reactions show good to excellent yields without preparation of any biproducts. Because the tetrasubstituted imidazole has a core skeleton similar to that of the template 4a (imidazole scaffold), under the influence of the MIP, nanoreactors were obtained with the same good yields as in the previous reaction. Although, due to small structure differences in comparison with compound 4a, the yield shows a negligible decrease, and time of the reaction takes longer. To gain more insight into the role of the binding sites and shape memorized cavities of polymer on the catalytic activity of MIP nanoreactors for the synthesis of 2,4,5-trisubstituted imidazoles, a comparison between imprinted and nonimprinted polymers for the model reaction was done. As is well-known, NIP was synthesized under the same reaction conditions but without participation of the template molecule. The catalytic activity of both MIP and NIP were investigated in the optimum conditions. Although NIP nanoparticles can relatively catalyze this MCR due to the presence of the created pressure, compared to MIP nanoreactors, the desired product was obtained with low yields and purity. However, the entity of shape-memorized cavities integrated with the imidazole template in the MIP scaffolds causes high selectivity of the MIP nanoreactors in comparison with NIP toward the synthesis of imidazole derivatives. Thus, the memorized sites have to be able to prepare the optimal spatial arrangement geometry, which causes appropriate conformation of the reactant and therefore cause the reaction to take place.21 The

a

Reaction conditions: benzaldehyde (0.10 g, 1.00 mmol), benzil (0.21 g, 1.00 mmol), and ammonium acetate (0.19 g, 2.50 mmol) in 30 min. SF = solvent-free. bThe reaction was performed under these conditions in 20 and 10 min with quantitative and 82% yields. c Isolated yields.

gave inferior results in both yield and reaction time, even though the using of ethanol was relatively satisfactory in both cases. At last but not least, MIP nanoreactor (0.04 g) under solvent free conditions at 120 °C in 20 min provided the best results quantitative yield, in accordance with the hypothesis. After optimization of the reaction conditions, we subsequently extended the scope of the present system through MIP as an eco-compatible nanoreactor with a variety of aldehydes as well as diketone compound derivatives to conveniently access to a small library of 2,4,5-trisubstituted imidazoles. Various aldehydes containing electron-deficient and electron-rich functional groups were found to react efficiently. Also, diketone compounds such as benzoin and various benzils were applied to obtain the desired products with excellent yield (Table 2). According to the results in Table 2, it is clear the MIP that polymerized around 4a, as a task specific template, can play a robust catalyst role for the synthesis of the other imidazole scaffolds. In this case, the chemical structure of 4a was particularly designed to possibly simulate the chemical geometry of the transition state or an intermediate of this reaction and perform the high binding between the general cavities of product analogue to a transition state of the reaction. On the basis of the concept of transition state stabilization, catalytically active antibodies were raised against the stable transition state of the reactions known from enzyme catalysis.71,72 Similarly, the 3-dimensional polymer network of MIP was used to direct the reaction through decreasing the energy of the transition state. Also, acoustic cavitation of MIP and increasing the interaction of trapped reagent molecules in 9512


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ACS Sustainable Chemistry & Engineering Scheme 3. Structures and Isolated Yields of Tetrasubstituted Imidazoles

total amount of product (4a) obtained with MIP was 1.47 times that with NIP. On the other hand, these cavities lead to a local high pressure that has a clear effect on the reaction rate because this MCR is accompanied by an entropy decrease in the transition state.44,73 To wrap up the discussion, when pressure and selectivity are intermixed, a perfect synergy is created for imidazole derivatives synthesis. Quick access to imidazole derivatives via pseudo-four- and four-component reactions with MIP nanoreactors obtained not only lower production costs resulting from atom economy and high convergence but also increases the eco-compatibility, which is the main principle of green chemistry. In addition, the reaction was carried out in a single-pot and step process with excellent yield and short reaction time. Above all, using MIP as a robust nanoreactor caused 100% conversion and quiet product isolation without using particular purification such as chromatography. Because this MCR catalyzed with reusable MIP nanoreactors was carried out under solvent-free conditions, it could improve E-factor and mass intensity as important green chemistry metrics. The comparison between our reaction conditions with previous reports for the synthesis of multisubstituted imidazoles was established with respect to their yields, temperatures, solvent, and the time of the reaction. As shown in Tables 3 and 4, in comparison with previous works, the reaction yields in nanoreactors increased significantly in short reaction times without need of alternate input energy such as microwave or ultrasonic. This effect can be explained via the cavity effect of the nanoreactor, which could enhance the preorganization of precursors by creating strain inside its cavity. This nanoreactor as heterogeneous catalyst can have chemical transformations take place in its high pressure cavities, which have ability to encapsulate reactants. It is therefore not too surprising that the integration of the mentioned effects could overcome the energy barrier of MCRs. In addition, compared to other activation modes, high pressure coupled with shape-memorized cavities are very mild and nondestructive preparation methods.45,74 Also, it has been shown that, when catalysts are not used, these reactions gave very poor yield or no product at all. Consequently, it can be inferred from all of above that

Table 3. Catalyst Performance Comparison between the Literature and the MIP Nanoreactors for the Synthesis of 2,4,5-Trisubstituted Imidazoles entry

catalyst

1 2

InCl3·3H2O nanosilica phosphoric acid montmorilonite K10 zeolite L-proline [Hbim]BF4 Fe3O4-PEG-Cu

3 4 5 6 7 8 9 10 11 a

diethyl bromophosphate Fe3O4@SiO2Imid-PMAn boehmite nanoparticles MIP nanoreactors

condition MeOH, rt solvent-free, 140 °C EtOH, reflux

time (min)

yields (%)a

ref

500 180

82 90

57 75

90

70

76

EtOH, reflux MeOH, 60 °C RTIL, 100 °C solvent-free, 110 °C US, CH3CN, rt

60 540 60 30

80 90 95 98

76 77 78 79

40

95

67

MW (100W), solvent-free solvent-free, 120 °C solvent-free, 120 °C

10

95

80

40

98

81

20

quant.

this work

Isolated yields.

synthesized MIP nanoreactors could be versatile catalysts for the other MCRs that need high pressure for performing the reaction. Easy catalyst recycling is one of the advantages for heterogeneous catalysts from the view of green chemistry and industrial interest. The recyclability of the nanoreactor was investigated during the synthesis of 4a (Figure 5). After reaction completion, the catalyst can be easily reused for the next run. For this purpose, nanoreactors were washed with ethanol and distilled water and then dried under an oven at 60 °C. It was observed that MIP nanoreactors are reusable at least four times without significant loss in the isolated yield of 4a. As shown in the TEM image, after the fourth run, MIP nanoreactors morphologically remained stable and still had semispherical morphology, and there was also no sign of any particle agglomeration or deformation (Figure 5b). However, 9513


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reactors. Also, the catalyst was reusable even for four runs without obvious loss of catalytic activity. Because in these enzyme-mimetic nanoreactors two or more reactants could encapsulate in the same cavity and directly orient to complex organic structures, it seemed that MIP nanoreactors could be a great candidate for catalyzing the other MCRs, especially those that have known transition states. In addition, it is important to point out that, due to the high biocompatibility of this nanoreactor, it could be a great candidate for drug design and industrial production.

Table 4. Catalysts Performance Comparison between the Literature and the MIP Nanoreactors for the Synthesis of 1,2,4,5-Tetrasubstituted Imidazoles entry 1 2 3 4 5 6 7 8

catalyst SbCl5/SiO2 L-proline

Fe3O4@ chitosan n-CTW-SAb Fe3O4-PEGCu WD/SiO2c DABCO MIP nanoreactors

condition

time (min)

yields (%)a

solvent-free, 140 °C MeOH, 60 °C EtOH, reflux

120 510 120

90 86 95

66 77 82

solvent-free, 120 °C solvent-free, 110 °C

40 55

94 96

83 79

solvent-free, 140 °C t-BuOH, 60−65 °C solvent-free, 110 °C

120 720 40

85 92 97

84 85 this work

ref

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acssuschemeng.7b02741. Spectral data and copies of 1H NMR and 13C NMR of new compounds (PDF)

a Isolated yields. bNano-ceramic tile waste-SO3H. cWells−Dawson heteropolyacid supported on silica.

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AUTHOR INFORMATION

Corresponding Author

*Tel.: +982129902800; E-mail: [email protected]. ORCID

Ahmad Shaabani: 0000-0002-0304-4434 Ronak Afshari: 0000-0003-4688-4406 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge financial support from the Iran National Science Foundation (INSF), the Research Council of Shahid Beheshti University, and Catalyst Center of Excellence (CCE) at Shahid Beheshti University.

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REFERENCES

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Figure 5. (a) Reusability of MIP nanoreactors and (b) TEM image of recovered nanoreactors after four runs.

its catalytic activity gradually decreased with consecutive runs (100, 98, 90, and 84%, respectively), and hence the longer reaction times are probably due to occupation or chemical damage of the holes in the polymeric matrixes of catalysts.

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CONCLUSION In conclusion, for the first time, it was shown that molecularly imprinted polymer nanoreactors can be directly applied in multicomponent reactions through a one-pot and step economic procedure. The MIP nanoreactors were demonstrated to possess an excellent yield and high degree of purification toward the synthesis of multisubstituted imidazole derivatives under solvent-free conditions. The results obtained from characterizations show that the miniemulsion polymerization can efficiently provide monodisperse nanosize reactors with free inner space that are stable in high temperatures. Short reaction times, eco-compatibility, low cost, and simple manufacture are the best advantages of using MIP nano9514


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Molecularly Imprinted Polymer as an Eco-Compatible Nanoreactor

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