Heterocyclic chemistry, the process of synthesizing aromatic rings with at least two distinct atoms in their primary ring, has long been acknowledged as one of the most important and appreciated disciplines of chemistry . Most pharmacological chemicals, as well as catalytic and photocatalytically active organic molecules, possess heterocyclic rings . In this regard, nitrogen-containing heterocyclic rings, known as quinolines, are of great interest due to their broad biological activities as antimalarial, antibacterial, antiasthmatic, antihypertensive, and anti-inflammatory . Researchers sought green, practical, and cost-effective catalytic methods to manufacture polyhydroquinolines due to their widespread use in Alzheimer's, hypertension, and cardiovascular disease therapy . Various catalytic systems have developed to promote the formation of polyhydroquinolines. Cooper (Cu)-based systems are particularly appealing owing to their availability, low cost, and the green and mild condition for the reaction's development in the presence of these catalysts .
In synthesizing natural and physiologically potent compounds, the Knoevenagel condensation process is routinely used as an essential step . This reaction was first introduced to the scientific community by German scientist Emil Albert Knoevenagel. When an aldehyde or ketone reacts with activated methylene in the presence of a basic catalyst, such as primary and secondary ammonia (but not third-tier ammonia), their salts, and ammonia, the reaction is known as a Knoevengel condensation . In particular, the amine may react with aldehyde or ketone to produce an iminium ion as an intermediate when utilized as a catalyst. The enolate simultaneously targets this iminium ion . Various solid-phase nanoparticles, including graphene oxide, perovskites, carbon nanotube, metal-organic frameworks, etc., have been utilized as supports and catalysts for organic reactions .
In recent years, metal-organic frameworks (MOFs) have gained increasing attention due to their fascinating capability to be designed, modified, and form composites with other materials to show enhanced features toward a specific application . High and permanent porosity, firm frameworks, tunable physical and chemical properties, and accessible compositions with other materials are just some of their unique properties, making them interesting to use as heterogeneous supports [11, 12]. IRMOF-3, as an isoreticular framework of MOF-5, demonstrates exceptional performance for various applications such as adsorption, separation, catalyst, photocatalyst, etc., due to its particular structure [13, 14]. The amine functionality of the organic linker increases its water stability compared with parent MOF-5 and improves its catalytic and photocatalytic performance. The amine pendant also provides the opportunity for post-synthesis modification of the MOF and helps to stabilize metal entities encapsulated by MOF .
Here, we managed to prepare an IRMOF-3 via a solvothermal method and use it to support the stabilization of Cu(II) ions. Characterizations showed that the amine functionality of the MOF helps the stabilization of the Cu(II) ions and boosts the catalytic performance of the proposed catalyst. The proposed catalyst was employed to promote the synthesis of polyhydroquinoline derivatives, which exhibited superior catalytic activity.
Materials and Methods
Chemicals and apparatus
Zinc(II) nitrate hexahydrate (Zn(NO3)2), amino-functionalized terephthalic acid (NH2-BDC), cooper(II) acetate (Cu(OAc)2), N,N-dimethyl formamide (DMF), Dimethyl sulfoxide DMSO, CHCl3, and CH2Cl2 were purchased from Merck.
Synthesis of IRMOF-3
IRMOF-3 was prepared by dissolving 12.5 mmol of Zn(NO3)2 (2.36 g) and 4.1 mmol NH2-BDC (0.075 g) in 100 mL dry DMF. After being agitated for 60 minutes at ambient temperature, the solution was sealed in a Teflon-lined autoclave and kept at 100 °C for 18 hours. IRMOF-3 was washed with DMF and CHCl3 and then vacuum-dried at 60 °C.
Synthesis of Cu@IRMOF-3
Loading of Cu(II) ions to the pores of IRMOF-3 has been performed by adding 0.025 g of Cu(OAc)2 to a 5 mL DMSO solution containing 0.12 g synthesized IRMOF-3. This solution was agitated for two h at room temperature. Afterward, the catalyst was removed from the solution and dried at 60 °C in a vacuum for storage. According to atomic absorption data, the adsorption rate of copper ions was 8 wt%.
General procedure for the preparation of polyhydroquinolines
Preparation of the heterocyclic organic compounds was proceeded by adding 2 mmol of each of aldehyde, ketoester, dimedone, and ammonium acetate (NH4OAc) to a round-bottom flask containing 0.01 g of Cu@IRMOF-3 as a catalyst in ethanol and stirred at 80 °C for an appropriate time. Progress of the reaction was monitored by the thin-layer chromatography (TLC) technique. At the end of the reaction, the desired product was separated from the mixture by adding CH2Cl2 and purified by column chromatography. In this regard, an n-Hexane/ethyl acetate (9:1) solution was used as an eluent solution.
Results and discussion
Figure 1a represents a schematic illustration of the preparation steps of IRMOF-3 and Cu@IRMOF-3. The synthesis steps included solvothermal preparation of IRMOF-3 in a DMF solution at 100 °C and then deposition of Cu(II) ions into the pores of MOF. Figure 1b shows the cubic structure of synthesized bare IRMOF-3, and Figure 1c shows an aqueous solution containing Cu(II) ions embedded in IRMOF-3.
Figure 1: a) Schematic illustration of the preparation steps of IRMOF-3 and Cu@IRMOF-3. b) Optical photomicrograph  c) A solution containing Cu@IRMOF-3
The FT-IR spectra of IRMOF-3 and Cu@IRMOF-3 are presented in Figure 2, as mentioned in our previous report . For the FT-IR spectra of IRMOF-3, the amino group of the organic linker is responsible for the peaks at 3359 and 3470 cm-1 in IRMOF-3. Carboxylic acid's C-O group is shown by the peaks at 1385 and 1575 cm-1. The aromatic ring's C=C bonds are represented by the spectrum's three distinct peaks at 1421, 1496, and 1656 cm-1. The aromatic ring-amino group C-N bond is responsible for the peak at 1257 cm-1. In the case of Cu@IRMOF-3, there was a dramatic decrease in intensity of the -NH2 peak, proving that the amino group of organic linker helped the stabilization of Cu(II) ions.
Figure 2: The FT-IR of black) IRMOF-3 and red) Cu@IRMOF-3
We further hired X-ray diffraction analysis (XRD) to examine the crystallinity and phase purity of the synthesized IRMOF-3 and Cu@IRMOF-3 (Figure 3a). As we mentioned in our previous report , the IRMOF-3 XRD pattern displays firm peaks, indicating that the MOF was crystalline. Furthermore, the peak positions are in close agreement with previously reported cases, showing the successful formation of the structure . The XRD pattern of Cu@IRMOF-3 demonstrates that the crystallinity of IRMOF-3 was retained even after the encapsulation of Cu (II) ions. Compatible with the JCPDS-36-1451 data set, the ZnO lattice characteristics may be utilized to index a hexagonal wurtzite structure. As mentioned in our previous report , Figure 3b represents the Brunauer–Emmett–Teller (BET) of Cu@IRMOF-3. The BET plot is a type I, which proves its microporous structure. A hysteresis of type H4 is noticeable in the mentioned plot, which further emphasizes the microporous characteristics of the Cu@IRMOF-3. Hysteresis type H4 could further imply the blockage of the pores of the IRMOF-3, which proves the positioning of the Cu(II) ions into the pores of the MOF.
Figure 3: a) XRD patterns of IRMOF-3 (black) and Cu@IRMOF-3 (red). b) BET of Cu@IRMOF-3
Scanning electron microscope (SEM) images investigated the morphology of prepared Cu@IRMOF-3. Figure 4 exhibits the structural morphology of Cu@IRMOF-3. Noncovalent interactions between the Cu@IRMOF-3 layers, such as hydrogen bondings, π-π interactions, and aromatic-metal interactions, resulted in the aggregation of the MOF in this structure.
Figure 4: SEM image of Cu@IRMOF-3 in various scale bars 
In this report, according to our previous reports on multi-component reactions and porous materials [15, 17–21], a reaction between benzaldehyde, dimedone, ammonium acetate, and ethyl acetoacetate was chosen as the model reaction to test the efficiency of Cu@IRMOF-3 as a porous catalyst (Scheme 1). The substrates were stirred at 80 °C for 2 h in an ethanol solution in this proposed method. The TLC technique was employed to study the progress of the reaction. Finally, the products were extracted by CH2Cl2 and purified by column chromatography.
Scheme 1: The model reaction for preparation of polyhydroquinolines
The optimization of this reaction proceeded by investigating the effect of various parameters, including dosage of the catalyst, solvent, and temperature, on the progress of the reaction. First, to obtain the best solvent, we monitored the progress of the reaction in EtOH, MeOH, H2O, CH3CN, and DMF (Table 1). According to the findings of this investigation, protonic solvents are the best at promoting the progression of the reaction. Because of the higher yield of the reaction in EtOH and the environmentally friendly quality of this solvent, we selected ethanol as the optimum solvent. Then, the progress of the reaction was investigated at various temperatures, including room temperature, 70, 80, and 100 °C, to obtain the best temperature. The reaction yield was almost 100% at 80 °C in ethanol, chosen as the optimum condition.
We investigated the generality of the proposed method by synthesizing a series of polyhydroquinolines. This study shows that using aromatic aldehydes with electron-donating groups in the para position of the aromatic ring as substrate results in more yield. However, the existence of an electron-donating or withdrawing group in the ortho position of the aromatic ring lowers the yield of the reaction due to the steric hindrance of such groups. Table 2 provides an overview of the structure and the yield of synthesized polyhydroquinolines
Scheme 2 exhibits the proposed mechanisms for preparing polyhydroquinolines in the presence of Cu@IRMOF-3 catalyst. The Knoevenagel reaction (the proposed reaction for the synthesis of polyhydroquinolines) involving ethyl acetoacetate, benzaldehyde, and ammonia, yields ester enamine. Dimedone may also be Knoevenagel condensed with ammonia and benzaldehyde to produce ester enamine and cyclic benzaldehyde derivatives of dimedone. The intermediates thus formed further undergo condensation to yield polyhydroquinolines.
Scheme 2: The proposed mechanism for preparing polyhydroquinolines using Cu@IRMOF-3 as the catalyst
Finally, to test the reusability of the proposed catalyst, ethanol and CH2Cl2 were used as eluents to recover the catalyst (Figure 5). The recovered catalyst was used for the synthesis of polyhydroquinolines derivatives several times. The results showed that even after five cycles, Cu@IRMOF-3 exhibited no significant loss in its catalytic performance. However, by the 6th cycle, the catalytic performance dropped dramatically due to the loss of crystallinity.
Table 3 provides the necessary information to compare the result of the model reaction in this work with previously reported outcomes. Based on the results, the Cu@IRMOF-3 shows superior catalytic performance compared with many others.
Figure 5: Recycling ability of the proposed catalyst
We were able to construct an IRMOF-3 using a solvothermal approach and utilize it to aid in the stabilization of Cu(II) ions in this study. Characterizations revealed that the MOF's amine functionality aids in stabilizing Cu(II) ions and improves the catalytic performance of the proposed catalyst. The suggested catalyst was used to enhance the production of polyhydroquinoline derivatives, which showed high catalytic activity.
This research did not receive any specific grant from fundig agencies in the public, commercial, or not-for-profit sectors.
All authors contributed toward data analysis, drafting and revising the paper and agreed to responsible for all the aspects of this work.
Conflict of Interest
We have no conflicts of interest to disclose.
HOW TO CITE THIS ARTICLE
Reza Taghavi, Sadegh Rostamnia. Four-Component Synthesis of Polyhydroquinolines via Unsymmetrical Hantzsch Reaction Employing Cu-IRMOF-3 as a Robust Heterogeneous Catalyst. Chem. Methodol., 2022, 6(9) 639-648