Chitosan decorated copper nanoparticles as efficient catalyst for synthesis of novel quinoline derivatives

Chitosan decorated copper nanoparticles (CS/CuNPs) catalysts were synthesized via reduction methods utilizing green protocol. The CS/CuNPs hybrid catalysts were tested for the synthesis of quinoline derivatives utilizing one-pot multicomponent reaction (MCR) under ultrasonic irradiation. The best catalyst (CS/CuNPs) that provided good conversion reaction yield and high turnover frequency (TOF) was characterized using Fourier transform infrared (FTIR), Thermogravimetric analyses (TGA), X-ray diffraction (XRD), , scanning electron microscopy (SEM), transmission electron microscope (TEM) and X-ray photoelectron spectroscopy (XPS) techniques. Generalization of the scope of the proposed catalytic process was studied using different aldehydes. Excellent products yield and high TOF in even shorter reaction time (~5 min) was attained. Recyclability performance of the catalyst over five times re-use without detectable loss in product yield was recorded. The current method is green process utilizing environmentally benign catalyst and considered to be promising sustainable protocol for the synthesis of fine chemicals.

The use of nanoparticles (NPs) in catalysis is considered to be one of the most significant principles of green chemistry that is owing to a number of different reasons; the reaction time is short, diminishes generation of hazardous materials, economically visible as high yields produced with low cost [15].Nanoparticles have been widely used as the catalyst support in organic transformation [16].Our previous achievements in the synthesis of different organic synthons of important biological activities utilizing different nanosized solid heterogeneous catalysts under green protocol [17][18][19][20][21][22] revealed that exploring efficient, sustainable and green catalyst is crucial to achieve green sustainable perspectives.To attain our goal, natural bio-polymer supported heterogeneous nano-catalysts that have been utilized in recent years [23,24], was selected to be a catalyst support.One of the promising catalyst's support candidate is chitosan, which is produced by the N-deacetylation of chitin.It is considered to be the second most abundant natural polymer after cellulose [25].Chitosan a chemically stable, non-toxic is an excellent candidate to be used as a support for copper and other transition metals due to its insolubility in organic solvents and the presence of functionalization of the free amine groups in the structure which is represented active sites for several of chemical modifications [26][27][28].
Nanoparticles have a special characteristic to aggregate and well clump together to form larger particles, thus nanoparticles lose their large surface area and other benefits [29] .Chitosan as a polymer-based stabilizes the nanoparticles to prevent their aggregation via coordination with metal nanoparticles through chelation mechanism, makes it a perfect support for metal nanoparticles [30] .
Gold, silver and transition metals nanoparticles such as palladium are available for the development of hybrid catalyst complexes and they can also be used in chemical transformation whereas a new glyoxal cross-linked chitosan Schiff base was prepared as a support material for palladium catalyzed Suzuki cross coupling reactions [31,32].In addition, chitosan was used as support of copper nanoparticles as catalyst for the C-S coupling of thiophenol with aryl halides [33] .The synthesis of Cu nanoparticles using chitosan as both reducing and capping agent have been reported [34,35] .This single step method is considered to be costeffective, convenient and eco-friendly relative to other method of preparation [34] .
In the present work, chitosan decorated copper nanoparticles catalysts were synthesized through green methods [34,35] and its application as an efficient catalyst in multicomponent reaction to the synthesis of novel quinolone derivatives under ultrasonic irradiation were extensively studied.The CS/CuNPscatalyst is a promising efficient sustainable green catalyst for the synthesis of quinolone derivatives in satisfactory yield in short reaction time under ultrasonication conditions.

Materials characterization
The reactions were monitored by TLC and all yields refer to isolated products.Melting points were obtained by the Barnstead international 1002 melting point apparatus.IR spectra of the catalyst and products were recorded for the compounds in PerkinElmer spectrum 100 FT-IR spectrophotometer. 1 H NMR and 13 C spectra of products were recorded on Burker WM 400 and 850 MHz spectrometer using TMS (0.00 ppm).Chemical shifts (δ) are given in ppm relative to the signal for TMS as standard, and coupling constants in Hz.Thermo-Microbalance TG 209 F3 (NETZSCH) was used to perform thermal gravimetric analysis for the prepared samples.The sample was first heated form room temperature up to 150ºC, 5ºC/min, and kept half an hour at 150ºC.Then the sample temperature was raised up to 550ºC, afterwards cooled down to 40ºC at the same rate of 10ºC / min.Mixture of 20 ml/min of dry air and 10 ml/min of helium was passed through during these processes.PXRD patterns catalyst sample were analyzed using a Powder XRD diffractometer (Model Equinox1000 -INEL (France) with Co K α (λ= 1.7890 Å) radiation at 30kV and 30mA.Catalyst morphology was investigated by means of field emission scanning electron microscopy (FEG-SEM, Quanta FEG450, FEI, the Netherlands) using an ETD Everhart Thornley detector (High Vacuum mode), a solid-state backscattering electron detector (VCD)and EDS detector (XFLASH6-30, Brucker) for elemental analysis.XPS measurements were carried out in an ultra-high vacuum multi-technique surface analysis system (SPECS GmbH, Germany) operating at a base pressure range of 1010 bar.HRTEM samples were prepared by sonication of the suspended powder in ethanol.A single drop of the sonicated suspension was deposited on TEM carbon grid 200 mesh and leaved for total evaporation at room temperature.Then the grid was mounted on a TEM single tilt holder, the residual solvent was removed by plasma cleaning process.The reactions that carried out by U.S irradiation was done using Daihan (Wiseclean, D-40 MHz) ultrasonic bath.Microanalysis was performed by Perkin Elmer elemental analyzer at the Faculty of Science, King Abdul Aziz University.

Synthesis of Chitosan decorated copper nanoparticles Catalyst
The synthesis of Chitosan decorated copper nanoparticles was carried out according to two methods: Firstly: (CS/CuNPs) have been prepared via one-step synthesis green protocol.In a typical method, 0.75 g chitosan dissolving in 100 ml 0.1% acetic acid (in distilled water) then 50 ml of the solution and 25 ml of 0.05 M copper solution were delivered under stirring at 70°C for 9 h till the reaction was completed.the colloid was centrifuged for 10min.to separate particles from suspension then washed with acetone (90%, v/v) and the centrifugation was repeated three times to remove unreacted reagents.The particles were dried under vacuum at the room temperature overnight and stored [34].Secondly: (CS/CuNPs/TPP) were prepared based on the ionotropic gelation between chitosan and sodium tripolyphosphate (TTP).Chitosan acted as a reducing/stabilizing agent.TPP was dissolved in water to a concentration of 0.25%.Under magnetic stirring at room temperature, 33 ml of TTP solution was added into 50 ml of chitosan solution 0.75% (in dil.acetic acid 0.1 %) and the mixture was stirred for 15min.Chitosan nanoparticles loaded Cu 2+ were obtained by adding metal ion solutions 16ml 0.05 M into the chitosan nanosuspensions and heated to 70 °C using a water bath, after a blue color appeared, stirring continued for another 90 min.before removing the heater.The resulting solution was cooled to room temperature for characterization [35] .

Synthesis of polyhydroquinolines in the presence of CS/CuNPs
A mixture of dimedone (3.6 mmol, 0.5 gm), aromatic aldehyde (3.6mmol, 0.5 gm), ethylcyanoacetoacetate (3.6 mmol, 0.38 ml), ammoniumacetate (28.8 mmol, 2.219 gm) and catalytic amounts of Cu-chitosan NPs (0.1 gm) in 10 ml absolute ethanol irradiate with ultrasonic waves at 80°C.After completion of the reaction (monitored by TLC, petroleum ether: EtOAc, 1:2), the reaction mixture was filtered to separate the catalyst, then cooled at room temperature and the solid product obtained and was filtered off, dried and recrystallized from ethanol.

Catalytic Test
The synthesis of quinoline derivatives via four-component one-pot reaction of dimedone, pchlorobenzaldehyde, ethyl cyanoacetate and ammonium acetate is represented in scheme 1. Neat reaction (absence of catalyst) showed ~25% yield in 6 h using ethanol under refluxing condition.The neat reaction carried out under ultrasonic irradiation resulted in poor isolated yield of the product (~29%) in 15 (min).In order to find out suitable catalyst, for the synthesis of quinoline derivatives via MCR under ultrasound irradiation, two different catalysts (CS/CuNPs and CS/CuNPs/TPP) were synthesized and tested.The effect of mass of the two catalysts was studied and the results displayed in Figure 1.The results clearly showed that 0.1 g of CS/CuNPs provided high product's yield (~90 %) relative to the other catalyst under the same reaction conditions.The ultrasonic irradiation method was selected based on the advantages of this method in comparison to the conventional one in enhancing the product yield in shorter reaction time.Therefore, a variety of quinolines derivatives were also synthesized via this method by using the highly efficient catalyst (CS/CuNPs, 0.1 g).The optimal reaction conditions were determined to be catalyst loading: 0.1g CS/CuNPs; dimedone (3.6 mmol); aromatic aldehyde (3.6mmol); ethylcyanoacetoacetate (3.6 mmol); ammonium acetate (28.8 mmol) and 10 ml absolute ethanol under ultrasonic irradiation at 80°C for 15 min.Then, with the optimum reaction parameters, the catalytic performance of the catalyst was examined in MCR for quinoline derivatives and results are displayed in Table 1.As seen from the data in Table 1 catalyst provides an efficient synthesis of a new quinoline derivatives with high yield productivity, in short reaction time.In addition, the TON and TOF values were calculated and are existing in Table 1.A remarkably high TON and TOF values were found with small mass of catalyst.Considering such cyclocondensation reactions, chitosan decorated copper nanoparticles is considered to be a suitable efficient catalyst.Basically, catalytic activity of nanoparticles is related to the size of the particles and the good dispersion of active species on the catalyst's support.Therefore, extensive characterization of the most efficient CS/CuNPs catalyst was attained and presented in the next section.Many catalysts have been used for one pot-catalytic synthesis of organic precursors utilizing nanocrystalline and nanoparticle catalysts such as ClO /Zr-MCM-41 nanoparticles [37], Fe 3 O 4 @B-MCM-41 [38], and ZnO nanoparticles [39].All of these catalysts showed pronounced catalytic activity due to their nanosized and large surface area features.In contrary to that the produced % yield of products especially after re-use of catalysts for four time was not sufficient relative to our proposed catalyst in the present work.In order to study the sustainability of the present efficient catalyst towards four components one-pot catalytic synthesis of novel quinoline derivatives under ultrasound irradiation, the re-use test was carried out and the results are given in the following section.

Reusability Procedure
Reusability is crucial for supported catalysts [40].Therefore, the same catalytic particles were used after filtration from the reaction mixture for several reactions under the same conditions.Typically, after 15 min ultrasound irradiation, CS/CuNPs was filtered and washed 4-6 times with hot ethanol to remove all the unreacted educts then dried at room temperature for 24 h.The dried catalyst was used in the subsequent runs and the results are displayed in Figure 2. The results shown in Figure 2 depicted that there is no apparent decay of catalytic activity even after 5 runs, and the attained yields of the reusability test are within the experimental deviations.

Catalyst Characterization 3.3.1 FTIR
FT-IR spectra of chitosan and CS/CuNPs Figure 3 displayed a broad band for OH and NH stretching of amine groups located at 3250 cm −1 .The existence of band at 1553 cm −1 is due to the presence of the NH 2 groups.
Stretching vibrations due to C-OH and C-N appeared consequently in the absorption bands in the range 1016 and 1402 cm −1 .The absorption band placed at 2936 cm −1 is credited to the C−H stretching mode of methylene groups [41] .The decoration of chitosan by copper nanoparticles resulted in the formation of new intense peaks in the fingerprint region at low -frequency (600-500 cm -1 ) due to formation of Cu−N and Cu−O coordinate bonds.Furthermore, the peak at 612 cm -1 assigns for CuNPs-chitosan interaction, indication that NPs were capped by the biopolymer [34].

TGA analyses
Thermograms of CS and CS/CuNPs samples are shown in Figure 4.The TGA study is used to illuminate the thermal stability and approach of decomposition of the pristine chitosan and copper decorated chitosan.The TGA thermogram of investigated samples display three mass loss stages.The preliminary mass loss (8%) for CS and (21%) for CS/CuNPs in the temperature range 25-200 o C, could be to attributed to the hygroscopic nature of the chitosan and dehydration of copper decorated chitosan sample [42].The second thermal stage in the temperature range 200-400 o C displayed 48 and 40% mass loss for CS and CS/CuNPs, respectively is mainly assigned to de-polymerization along with breakdown of acetylated and deacetylated unit of chitosan.The third thermal decomposition stage (400-550 o C) was accompanied by about 30% mass loss for both investigated samples.The total mass loss of copper nanoparticles decorated chitosan is higher than that of pristine chitosan (~10% higher) as the introduction of a metal nanoparticles into the biopolymer matrix, affect the chain packing and causes releasing of the packed assembly [43,44].

XRD analyses
X-ray diffraction patterns of pure chitosan (CS) and chitosan decorated copper nanoparticles (CS/CuNPs) are displayed in Figure 5.Some characteristic peaks for chitosan at 2θ = 11.5 o and 22.5 o were observed [45,46].A slight right shift with wider peak at 2θ=23 o recommends the decrease in crystallinity after anchoring copper nanoparticles in the chitosan structure.The main structure of chitosan was not disturbed with the absence of any characteristic peaks for copper nanoparticles.This observation suggests the dispersion of copper nanoparticles over the surface of chitosan and the structure of chitosan was not changed during the preparation method.

SEM-EDX
The morphology of chitosan decorated copper nanoparticles sample (CuNPs) described by SEM image Figure 6 displayed asymmetrical deposits of chitosan.The nonattendance of copper nanoparticles could be ascribed to the good scattering of copper nanoparticles over chitosan.EDX spectra Figure 7 showed copper in addition to carbon, nitrogen and oxygen elements.The atomic % of copper should be complemented by XPS analysis in order to give accurate turnover number of copper relative to the total atomic percentage derived from ICP-AES analysis.

Tentative Mechanism
A tentative mechanism for multicomponent reaction of quinolines derivatives over CS/CuNPs has been proposed to occur via three different reaction steps (Scheme 2).Firstly, the well dispersed copper nanoparticles facilitate the electrophilicity of carbonyl group of the aldehyde via reduction of Cu 2+ ions into Cu o , which resulted in ease of attack on the active methylene carbon of ethylcyanoacetate and elimination of water.Secondly, the reaction proceeded via Michael addition assisted by basic sites of the catalyst then followed by the last step in ionic mechanism.Scheme 2: proposed mechanism for the synthesis of quinolone derivatives.

Conclusions
A series of chitosan decorated copper nanoparticles were successfully synthesized using green methods.All the investigated catalysts showed high catalytic performance towards the synthesis, in acceptable yield, of novel quinoline derivatives at very short time under ultrasonic irradiation.CS/CuNPs catalyst showed superior TOF for the synthesis of novel quinoline derivatives of expected biological activity.Thanks to the well dispersion of nanoparticles over natural inactive good support the pronounced superior catalytic efficacy was attained.The re-use of this particular catalyst for five times without appreciable change in its catalytic efficacy open the gate towards promising noble metal free catalysts for fine chemical products utilizing green protocol.

Figure 2 .
Figure 2. Robust feature of CS/CuNPs catalyst after five times r-use.

Table 1 :
Effect of CS/CuNPs catalyst on the synthesis of polyhydroquinolines 2 a-j using various aromatic