INTRODUCTION:

Environmental issues associated with chemical and pharmaceutical industries have become more and more pertinent in the recent era. The various synthetic methodologies need the utilization of high-priced and unsafe chemicals. Alternatives to the conventional synthetic methodologies^[1] would possibly increase the production efficiency or save the environment from the usage or generation of hazardous substances.^[2]A vast number of green metrics^[3]have been measured over recent years to increase the awareness among the chemist to change the methods and conditions to drive towards sustainable development.^[4]The whole world has great concern about the climate change due to the effects of human activity on environment. The main role of green chemistry is its environmental responsibility.

The real success of reducing the environmental impact of organic synthesis lies in measuring the greenness of the reaction. The metric such as environmental factor (E-factor) measures the environmentally benign nature of synthesis. ^[5]Another assessment is based on Eco-Scale which links both ecological and economical parameters of organic synthesis. ^[6]These two metrics have been assessed at the end of the process to evaluate the greenness.

Palladium chemistry was identified as a potential pathway for the synthesis of privileged molecules which have an affinity towards multiple receptors. ^[7]Various cross coupling reactions^[8]have been utilized for the construction of C-C bond formation. The biaryls formed through the coupling reactions have effective binding towards the receptor. The aromatic ring provides valuable interactions with the amino acid residues of the protein.^[9]Because of the significance of these interactions these molecules have gained attraction in the market. The role of transition metals such as nickel,^[10]copper^[11]and cobalt^[12]have proven to be a successful catalyst in cross couplings. However the palladium catalyzed coupling reactions have been mostly investigated in recent years.^[13]Palladium complexes with carbine and phosphine ligands,^[14]palladacycles ^[15] are employed in most protocols. However, these catalysts are expensive and they are also homogenous in nature. The heterogeneity and efficiency of the ligand free PdNPs have proved its superiority over the other forms of palladium. ^[16]The properties of nanoparticles are totally different from that of the bulk materials and this provides the way for the applications of these materials in numerous fields. Various nanomaterials based on proteins, ^[17]polysaccharides,^[18] silica^[19] and inorganic materials^[20] have been reported. The inorganic nanomaterials found application in water treatment,^[21] antibacterial activity,^[22]larvicidal activity,^[23]photo catalytic activity,^[24] cytotoxicity, ^[25]and so on. The importance of nanoparticles as catalyst in organic reactions can enhance the catalytic performance.^[26]Metallic nanoparticles such as TiO_2,^[27]SnO_2,^[28]ZnO,^[29]Fe,^[30] Pd ^[31]have been utilized in building up of the diverse heterocycles. Despite the growing pool of papers in the eco-friendly synthesis of PdNPs, the urge for the production of PdNPs from C. carandas has been figured out to examine the stability of the nanoparticles obtained from the same. The fruits of C. carandas are an edible one and are readily available in India. The usage of plant extract for the preparation of nanoparticles is mainly to focus on the role of biomolecules in the bioreduction of metal salts. ^[32]As per the literatures, phytochemical screening of C. carandas fruit extract has confirmed the presence of polyphenols, flavonoids, alkaloids, sterols, carbohydrates, tannins and glycosides. ^[33]These phytoconstituents acts as a reducing, stabilizing and capping agent for the preparation of stable nanoparticles (Figure 1). Since these nanoparticles can end up in the aquatic environment by various routes, there may be a chance for the contamination of aquatic organisms. ^[34]It is of prime importance to investigate the release of nanoparticles into the environment and its effect on the aquatic organisms. ^[35]In continuation of our earlier work, we herewith focused eco-friendly green synthesis ^[36]of PdNPs and its role in Suzuki Miyaura coupling. In addition, Artemia salina based bioassay^[37] was performed because of its rapidity, expediency and low cost to investigate the toxicology of the PdNPs. The most important goal of the chemists is to develop synthetic protocol for more sustainable and greener future generation. This can be achieved using the non-conventional energy resources, such as microwave^[38] photochemistry. ^[39]In short, we have decided to explore the methods that avoid drastic experimental conditions to protect the environment against hazardous chemicals.

EXPERIMENTAL:

General remarks

Reagents which we have used for these experiments have been utilized without any recrystallization or purification. NMR of ¹H and ¹³Canalysis has been taken in Bruker Avance 400 MHz spectrometer using CDCl₃ and DMSO-D₆ with TMS as an internal standard. Chemical shift values (δ) were given in ppm. Melting point was observed using Elchem Microprocessor based DT apparatus and corrected with benzoic acid as standard. Exact mass measurements of the molecular ions were obtained on ESI-MS Thermo Fleet. The bio-mediated reduction of Pd(OAc)₂to PdNPs were monitored by UV-Vis spectroscopy (Shimadzu UV-spectrophotometer, model UV-1800) at regular intervals and the absorption maxima was scanned over the range of 200-800 nm. The presence of functional group was identified through Fourier Transform Infrared spectroscopy (FT-IR) with KBr pellets. X-ray powder diffraction (XRD) analysis to determine the phase identification of the crystalline material was done by Advance Powder X-ray diffractometer (Bruker, Germany, Model D8). TEM analysis was performed by Transmission electron microscopy-Hitachi H-7100 using an accelerating voltage of 120 kV and methanol as a solvent. The particle size distribution and the zeta potential value of the PdNPs were measured using the nanoparticle analyzer system (Nano Partica SZ-100, HORIBA Scientific). The non-conventional synthesis was carried out using UWave-1000 microwave (SINEO-china).

Preparation of C. carandas fruit extract

The collected fresh fruits of C. carandas were shade dried and powdered. The powdered sample material (500 g) was defatted with petroleum ether (1000 mL). Then the residue was extracted with methanol(1000mL) by maceration at room temperature for 48 h, stirring several times throughout the process. After filtering through the fluted paper, the methanol extract was concentrated in a rotary evaporator to yield a dark brown mass (10 g).

Synthesis of PdNPs using C. carandas fruit extract

To synthesize PdNPs, C. carandas fruit extract (20 mL) was carefully added to 80 mL of a previously prepared solution of palladium (II) acetate solution with constant stirring for 10 min at ambient temperature. Reduction occurred within a short time as indicated by a color change from light yellow to bright brown indicating the formation of PdNPs. The process was monitored by UV-Visible spectrometer for 24 h. The obtained PdNPs were puriﬁed by centrifugation in a Beckman Coulter's Avanti J-E Centrifuge (USA) at 10,000 rpm for 20 min.

General procedure for the synthesis of 6-substituted 2,3-dihydroquinazolin-4(1H)-ones, 3

A mixture of aryl halide, 1 (1 equiv), aryl boronic acid 2(1.1 equiv) and potassium carbonate (1.5 equiv) were dissolved in 1:1 ratio of water: 1,4-dioxane. Then the catalyst PdNPs, (0.3equiv) was added and then stirred at 80 ⁰C for appropriate time. The reaction mixture was filtered through the celite and the filtrate was extracted with chloroform. The chloroform layer was washed with water thrice, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The resulting product was then purified by column chromatography.

Scheme: Synthesis of 6-substituted 2,3-dihydroquinazolin-4(1H)-ones, 3

Recyclization of the catalyst

After completion of the reaction for the first run, the catalyst was removed from the reaction mixture for the second run. The reaction mixture was cooled to room temperature and centrifuged to settle down the nanoparticles. Then the nanoparticles were washed several times with chloroform and dried in oven for the further use.

Toxicity Study of PdNPs

Procedure of hatching for A. salina Cyst

The cysts were collected, cleaned and decapsulated (Removal of outer membrane of the cyst) in 200 ppm chlorine water for 15-20 min. Approximately 2 g of the precleaned cyst was incubated in 1 L of the sea water in a clean conical flask. Moderate aeration was maintained from the bottom of the container at the rate of 10 to 20 L of air per minute. The container was kept under illumination using a white lamp for 48 h for the eggs to hatch into shrimp larvae (nauplii).

Brine Shrimp Lethality Bioassay

About 10 mg of the sample was weighed and dissolved in 20 ml of water to get a final concentration of 500 µg/ml. Around 11 test tubes were taken, 5 ml of sea water and 10 nauplii were transferred to each test tube using Pasteur pipette. The test tubes were marked from 1 to 10 for sample and 11^th test tube was marked as control. In test tube 1, 2.5 ml of the sample was added to get the concentration of 1250 µg/ml. Similarly 2 ml, 1.75 ml, 1.50 ml, 1.25 ml, 1 ml, 0.75 ml, 0.5 ml and 0.25 ml were added to each test tube to get the concentration of 1000, 875, 750, 625, 500, 375, 250 and 125 µg/ml. For control, 5 ml of sea water containing only 10 nauplii was taken. Each concentration was tested in triplicate. The test tubes were kept under illumination for 24 h. After the incubation period, survivors were counted with the aid of 3X magnifying glass. LC₅₀value and percentage of mortality for various concentrations of PdNPs were determined and compared with the control. Percentage mortality was calculated by using the following formula, ^[40]

% Mortality = Number of dead Artemia nauplii x 100

Initial number of live Artemia nauplii

Green Metrics Evaluation

E-factor that focuses attention on the problem of waste generation is expressed as the ratio of total waste generated in the reaction to the weight of the end product. The following formula can be used for the calculation:^[41]

E-factor= Mass of total waste

Mass of product

Higher calculated E-factor value indicates the more negative impact of the organic reaction over the environment. Eco-Scale value for an ideal organic reaction is 100. The value decreases based on the parameters of the reactions and each parameter has some specific penalty points.

Eco-Scale = 100 - Sum of individual penalties.

Spectral data for the synthesized 6-Substituted 2, 3-dihydroquinazolin-4(1H)-ones: (Figure 2,3 & 4)

2,2,3-trimethyl-6-phenyl-2,3-dihydroquinazolin-4(1H)-one,3: Off-White Solid. MP: 172-174 °C.FT-IR (KBr pellet) ν_max/cm^-1: 3292(-NH), 2972 (Ar C-H), 1629 (-C=O), 1508 (Ar C=C). ¹H NMR (400 MHz, CDCl₃): δ (ppm), 1.56 (s, 6H), 3.08 (s, 3H), 4.30 (brs, 1H), 6.68 (d, J=8.2 Hz, 1H), 7.27 (t, J=7.3 Hz, 1H), 7.39 (t, J=7.4 Hz, 2H), 7.52-7.58 (m, 3H), 8.18 (d, J=2.1 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃): δ (ppm), 2 X 26.8, 27.3, 71.3, 114.9, 115.9, 2 X 126.4, 126.6, 126.9, 2 X 128.7, 2 X 131.9, 140.3, 144.0, 163.4.GC-MS m/z 266.29 [M⁺].

RESULTS:

Characterization of PdNPs

The formation of the PdNPs was monitored over a period of 2 h by drawing out the aliquot of sample from the reaction vessel and measured the absorbance of the solution in 1 mm optical path length quartz cuvette after appropriate dilutions. The results of FTIR spectroscopy revealed the presence of various functional groups and their role in the biosynthesis of nanoparticles. The C. carandas fruit extract showed absorptions at 3406 (OH), 2927 (C-H), 1633 (C=O), 1392 (C-C stretch) and 1068 (C-H bending). These are the functional groups present in the bio-constituents of fruit extract. Dynamic light scattering (DLS) technique was used to determine the size distribution of the PdNPs. DLS is modeled on the basis of small molecules undergoing Brownian movement. The zeta potential of the nanoparticle measures the charge on the surface of the particles. The motion of the particle is measured using electrophoretic light scattering. The charge on the particle determines the direction of motion and magnitude of the particle is determined by its speed. Zeta potential of the sample is used as an indicator of dispersion stability. The reports of SEM and TEM studies were carried out to understand the size and shape of the PdNPs. The XRD pattern of PdNPs was studied and the results were matched with the JCPDS data.

Catalytic efficiency of PdNPs and its application

The catalytic efficiency of the PdNPs were experimented on the Suzuki Miyaura coupling of 2, 3-dihydroquinazolin-4(1H)-ones and the plausible mechanism for the same is proposed (Figure 5). This reaction was carried out by both conventional and non-conventional method. The initial stage of investigation was performed to optimize the amount of catalyst (Table 1). The recyclability of the catalyst was also investigated. The reaction was conducted several times using the recycled catalyst under similar reaction conditions. The conventional and non conventional synthesis of 6- substituted 2, 3-dihydroquinazolin-4(1H)-ones was carried out using the optimized concentration (3 mol %) of PdNPs.

Table 1 Mole percentage optimization of PdNPs in Suzuki Miyaura coupling for the synthesis of compound, 3

S. No	PdNPs (mol %)	Time (min)	Yield (%)
1	1	75	33
2	2	75	41
3	3	60	95
4	4	75	51

Figure 5: Mechanism of Suzuki Miyaura coupling reaction

Brine Shrimp Lethality Bioassay

A. salina exposed to PdNPs displayed concentration dependent toxicity effect after exposure for 24 h. The results of the toxicity tests with A. salina are given in Table 2.

Table 2. Mortality Rate for the Brine Shrimp of A. salina at different concentrations of PdNPs after 24 h

S.No	Concentration (µg/ml)	Initial no. of *A. salina*	*No. of A. salina* dead after 24 hours**	% Mortality after 24 hours
1	Control	10	0	0
2	0.125	10	1	10
3	0.25	10	1	10
4	0.375	10	1	10
5	0.5	10	2	20
6	0.625	10	2	20
7	0.75	10	2	20
8	0.875	10	3	30
9	1	10	3	30
10	1.125	10	4	40
11	1.25	10	5	50

Green Metrics Evaluation

The comparison of E-factor value between the conventional and non-conventional methodology indicates that the conventional methodology gave comparatively less value (12.45). The non-conventional methodology displayed E-factor value in the range of 13-20.

DISCUSSION:

The UV-Vis spectrum showed a broad peak at 260 nm and at various time intervals there is a shift in the absorbance peak (Figure 6). The reduction of metal ions may be the reason for the shift in the peak. After 90 min, there was a sudden increase in peak which indicates that the optimized time for the formation of PdNPs is 2 h. From the results of IR spectroscopy, it was found that functional group peaks in the extract got disappeared after treatment with palladium acetate solution which indicates that they are involved in the reduction of metal ion solutions (Figure 7).The average particle size of PdNPs was found to be 74.9 nm from Dynamic light scattering (DLS) technique (Figure 8).The zeta potential of the PdNPs was found to be -22.3 mV (Figure 9). This indicates that the PdNPs are highly stable and the stability is due to the electrostatic repulsion between the particles. The morphology of PdNPs were observed to be spherical in shape (Figure 10). In TEM study, it was identified that PdNPs are spherical in shape and size (Figure 11) was found to be in the range of 65 nm in diameter with relatively good monodispersity (Figure 12).Figure 13 shows two intense peaks 2θ= 40.02˚ and 46.32˚ corresponding to PdNPs which was found to be matched with the JCPDS data (File no. 88-2335). The main peak of θ= 40.02° matches the (111) crystallographic plane of PdNPs. Unidentified crystalline peak at 34.25° may be due to the organic component which is present in the extract. This entrapping may leads PdNPs to be environmently and non-toxic in nature.

While testing the catalytic efficiency of palladium nanoparticles, 3 mol % was found to be the optimized one and increasing the amount of catalyst to 4 mol % does not have an impact on percentage of yield. In the process of recyclability, there is only little discrepancy in product conversion. In 4^th cycle, there was a significant change in percentage conversion of the product (Figure 14). In conventional synthesis, the time required for conversion of product was found to be 60 min. Further optimization of the reaction condition was carried out using microwave coupled photochemistry. The attempts to carry out the reaction in ultraviolet radiation displayed negative result. Unfortunately, no conversion was observed after 60 min of exposure to ultraviolet radiation. Alternatively, the effect of microwave radiation on Suzuki coupling was experimented. The microwave irradiation has considerably reduced the reaction time from 60 min to few min. This quick acceleration in reaction time may be due to superheating, hot-spot formation and polarization of the reactant molecules. In addition the synergistic effect of the microwave and ultraviolet radiation was observed on Suzuki Miyaura coupling. There was no alteration in the reaction time whereas the synergism has caused significant change in percentage of the yield. In addition to that optimization of power and time was performed (Table 3).

In brine shrimp lethality bioassay, mortality rate was found to be 10 % for the concentration of 0.125, 0.25, 0.375 µg/ml. Gradually the toxicity increases to 20 % at the concentration of 0.5, 0.625 and 0.75 µg/ml and 30 % at the concentration of 0.875 and 1 µg/ml. The LC₅₀value was found to be 1.39 µg/ml concentrations (Figure 15). The mechanism of action for the mortality of the organism may be due to the increased concentration that causes accumulation of PdNPs in the gut which prevents them from the food intake.

Green metric evaluation indicates that more waste has been generated during the non-conventional synthesis. In case of Eco-Scale value, the results above 75 in the scale indicate that the reaction conditions are excellent. The value 50 to 75 in the scale indicates that the reaction conditions are acceptable. As shown in table 4, the Eco-Scale value for both the methodology is greater than 60. In short, the results indicate that the conventional methodology is superior to non-conventional methodology and the results of non-conventional methodology also lie within the limit.

Figure 12. Size distribution histogram of PdNPs

Figure 13. Recyclability of PdNPs in the synthesis of Compound, 3

Figure 14. XRD pattern of Carissa carandas fruit extract mediated palladium nanoparticles

Figure 15. Mortality rate (24 h) of A. salina treated with various concentrations of PdNPs

Table 3. Optimization of the reaction condition for the synthesis of compound, 3

Condition	Time (Min)	Area %	Temperature	Power
MW	2	80.49	80	200
MW	3	83.18	80	300
MW	1	52.37	80	400
MW	2	62.28	80	400
MW	3	75.10	80	400
MW+UV	1	67.99	80	400
MW+UV	2	75.00	80	400
MW+UV	3	86.24	80	400

Table 4. Determination of E-factor and Eco-Scale for the synthesis of compound, 3

Condition	E-factor Value	EcoScale Value
Conventional	12.45	77.50
MW	14.81	70.44
MW	13.88	72.97
MW	20.88	60.33
MW	17.60	64.38
MW	15.64	68.43
MW+UV	19.07	61.85
MW+UV	17.06	65.39
MW+UV	14.23	71.96

CONCLUSION:

In conclusion, successful reduction of palladium acetate to PdNPs using the readily available source of C. carandas fruit extract was carried out. The biosynthesized PdNPs found catalytic application in the metal catalyzed Suzuki Miyaura coupling reaction. The organic component peak confirmed through the XRD graph forms a sheath around the PdNPs and stabilizes it in catalysing the reaction. The difficulty in handling the oxygen sensitive phosphine ligand catalyst can be overcome by the eco-friendly PdNPs. The impact of nonconventional methodology on the Suzuki Miyaura coupling reduced the reaction time and percentage of yield. The toxicity assessment of PdNPs was tested against A. salina bioassay and it was found to be non-lethal. Therefore the release of eco-friendly synthesis of PdNPs into the environment does not arise any issue. All the reaction conditions are considered to be ‘green’ based on E-factor and Eco-Scale value. The applicability of the microwave photochemistry in the synthesis of biologically relevant small molecules may help the scientists of interdisciplinary chemistry.

ACKNOWLEDGEMENTS:

Author Dr. G. Madhumitha thank to DST-FTYS (No. SB/FT/CS-113/2013), Government of India, New Delhi for providing the research grants. We thank the management of VIT University for providing all the facilities to carry out this work. The author’s acknowledge the VIT University Management for providing the Seed fund to carry out the research. The authors gratefully acknowledge DST-FIST for providing NMR facilities to the school. We acknowledge the support extended by VIT-SIF for GC-MS, NMR and UV-analysis.

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Received on 03.11.2015 Modified on 18.11.2015

Research J. Pharm. and Tech. 8(12): Dec., 2015; Page 1691-1700

DOI: 10.5958/0974-360X.2015.00305.4