Effect of Substrates on Catalytic Activity of Biogenic Palladium Nanoparticles in C-C Cross-Coupling Reactions.

This work describes a practical methodology for C-C bond formation reactions with the aid of biogenic palladium nanoparticles, which are synthesized by using phytochemicals extracted from two common plant species. Comparative studies have been done on the activity of two plant species (Ocimum sanctum and Aloe vera) in generation of palladium nanoparticles via ex situ and in situ methods. The structural and morphological characteristics of the nanoparticles are examined by UV/visible spectroscopy, powder X-ray diffraction, X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, and transmission electron microscopy analyses. We have observed a significant influence of the substrates on the catalytic activity of the palladium nanoparticles in Sonogashira and Suzuki cross-coupling reactions.

Introduction

In recent years, metal nanoparticles (NPs) have been widely applied in different areas ranging from catalysis to biomedical diagnostics on account of their unique size, shape, and composition. These materials are susceptible to various chemical and physical modifications and can conjugate with varying antibodies, ligands, and drugs providing a wide range of applications.[1−4] Various chemical, biological, and physical methods have been explored for synthesis of metal NPs.[5,6] The characteristic feature in the synthesis of NPs is that the nanosystems should be stable, biocompatible, and selective in their action. Catalytic activity of metal NPs finds wide application in organic synthesis and the “NP-catalyzed organic synthesis enhancement” (NOSE) approach is considered as an effective route for organic synthesis.[7,8] The catalytic activity of metal NPs is specifically related to their size and distribution. However, smaller NPs in some cases agglomerate to minimize their surface area due to their excess surface free energy, resulting in a remarkable decrease in their catalytic activities. As such there requires additional stabilizers or supports for the enhanced catalytic activity of the metal NPs. In situ-generated NPs (NPsin situ) on account of their one-pot condition does not demand additional stabilizers because it remains under the influence of the reactant species. Another advantage of NPsin situ is that it avoids the laborious preparative and isolation processes.

Considering the positive aspects of NPsin situ, researchers now tend to utilize transition-metal NPsin situ in different fields of catalysis and organic synthesis. Various approaches for generation of in situ NPs of Au, Ag, Cu, and Pd have been reported.[9−14] Chemical methods for generation of NPs are associated with toxic byproducts and uneconomical issues. From the green chemistry point of view, environmentally benevolent alternative reducing agents for the synthesis of NPs are in great demand. In this regard, the introduction of microorganisms and plant resources provides an environmentally benign and a cost-effective alternative route for the synthesis of metal NPs.[15−17] There are various methodologies in which the specific pure compound of plant origin is used in NP preparation, for example, ascorbic acid and gallic acid which are plant polyphenols and act as great stabilizing agents in synthesis of NPs.[18−20] Plant extracts possess various biologically active phytochemicals (e.g., alkaloids, terpenoids, and polyphenolic compounds) which themselves serve as a reducing/stabilizing agent for bulk transition metals to nanodimensional particles.[21] The plant-based approaches of synthesis of metal NPs not only provides a faster rate of reduction of metal ions to zero valent metal but nucleate/cap them into stable and controlled morphology. As such biogenic reduction of metal ions in the absence of chemical reagents is an interesting approach on account of the environmental sustainability.

The C–C framework in organic synthesis is an indispensable tool for synthesis of numerous structural functionalities which are indeed building blocks of natural products, agrochemicals, medicinally important compounds, and so forth. The simplest and of course the most imperative synthetic transformations are based on Csp2–Csp2 and Csp2–Csp bonds commonly known as Suzuki and Sonogashira cross-coupling reactions, respectively. These transformations turn up as a pioneer for synthesis of various biologically active compounds and construction of pharmaceuticals, fine chemicals, and smart engineering materials, including conducting polymers and molecular wires.[22−26] Of all transition metals, Pd contributes an impressive ability to construct C–C bonds between diversely functionalized substrates.[27] Very recently, we have reported the synthesis of Pd NPs using papaya peel extract and subsequently evaluated the catalytic efficiencies toward Suzuki and Sonogashira cross-coupling reactions.[28] Motivated by the remarkable results, we herein explore the tandem synthesis of Pd NPs and C–C cross-coupling reaction in a one-pot reaction process using two different plant extracts [Ocimum sanctum(OS) and Aloe vera(AV)]. Interestingly, we found a significant difference in the catalytic behavior of the two Pd NPs (PdAV NPs and PdOS NPs). PdAV NPs were found to be more effective for Suzuki coupling reaction, whereas PdOS NPs were more proficient for Sonogashira coupling reaction.

Results and Discussion

Characterization of Pd NPs

The Pd NPs were characterized by transmission electron microscopy (TEM), powder X-ray diffraction (XRD), UV/visible spectroscopy, X-ray photoelectron spectroscopy (XPS), and Fourier transform infrared spectroscopy (FTIR) spectroscopy and investigated the catalytic activity in C–C coupling reactions and annulation via C–X functionalization.

During the preparation of Pd NPs, it was noticed that both the extract and the Pd(OAc)2 mixture undergoes reduction of Pd(II) to Pd(0) in different time intervals (Figure ).

Figure 1

Change in color of Pd(OAc)2 at different time intervals after addition of (a) Ext OS and (b) Ext AV.

The mixture of OS leaf extract (Ext OS) and Pd(OAc)2 shows a gradual change in color from light brown to black after 1 h (Figure a). The change in color of Pd(OAc)2 on addition of AV extract (Ext AV) was observed after 5 h (Figure b). This variation of reducing potential of the extracts with time may be due to the presence of different concentrations of phytochemicals present in the two plant species.

It was found from the existing literature that various quantitative analyses have been carried out to reveal the chemical compositions of OS and AV. From the comparative study of both the plant species, it was found that OS leaves possess a greater amount of reducing sugar and ascorbic acid, although different amounts were reported by Hassan et al. and Kashif et al. (Table ).[29−32] It is seen in various literature reports that ascorbic acid and different reducing sugars are used in generation of NPs.[33−35] As such these phytochemicals in the respective plant species helps in the reduction of the Pd(II) ion. However, the presence of a greater amount of these chemical constituents in OS as compared to AV reveals its greater reducing potential. Additionally, other phytochemicals such as flavanoids, essential oils, and phenolic contents are also present which may also assist in the reduction/stabilization of metal NPs.[36−41]

Table 1

Comparison of Basic Phytochemical Composition of OS[29,30] and AV[31,32]

parameters	A. vera	O. sanctum
ascorbic acid (mg/100 g)	1.90[31]	(65.41 ± 0.76)[29]	(02.41 ± 0.91)[30]
reducing sugar (%)	0.36[32]	(3.58 ± 0.14)[29]	(26.52 ± 1.54)[30]

Initially, we have performed powder XRD to understand the formation of the Pd NPs using both plant extracts. Figure a shows the powder XRD pattern of the PdOS NP, which matches well with standard JCPDS card no. 89-4897. The diffraction peaks at a 2θ value of 40.5°, 46.3°, and 67.8° corresponding to crystallographic planes (111), (200), and (220), respectively, suggest the formation of the face-centered cubic (fcc) lattice system of PdOS NPs. Again, Figure b shows the powder XRD pattern of PdAV NPs, which shows the formation of the fcc lattice system (JCPDS card no. 89-4897) with an additional tetragonal system for the PdO nanostructure (JCPDS card no. 75-0200). The observed peaks at a 2θ value of 39.9°, 46.1°, and 68.3° correspond to planes (111), (200), and (220), respectively, with two additional diffraction peaks of PdO at a 2θ value of 18.1 and 30.6 for (001) and (100) reflections, respectively. The formation of Pd/PdO in the case of PdAV NPs may be due to longer time requirement for reduction of Pd(II) which as a result leads to aerial oxidation of Pd(0).

Figure 2

Powder XRD pattern of (a) PdOS NPs and (b) PdAV NPs.

Further, we have characterized by X-ray photoelectron spectroscopy (XPS) analysis in order to confirm the oxidation state of Pd NPs in PdOS NPs and PdAV NPs. Figure a shows the survey scan spectrum of PdOS NPs, indicating the presence of Pd. The high-resolution peak fitting spectrum of PdOS NPs comprises two peaks at 335.05 and 340.20 eV attributed to the Pd 3d5/2 and Pd 3d3/2 spin-orbit peaks of Pd(0) as shown in Figure b. From the XPS analysis of PdOS NPs, it is evident that Pd NPs present in the zero (0) oxidation state.

Figure 3

(a) XPS survey spectrum of PdOS NPs, (b) high-resolution Pd 3d spectrum of PdOS NPs, (c) XPS survey spectrum of PdAV NPs, (d) high-resolution Pd 3d spectrum of PdAV NPs, and (e) high-resolution O 1s spectrum of PdAV NPs.

On the other hand, the survey scan XPS of PdAV NPs signifies the occurrence of Pd and O as shown in Figure c. The high-resolution peak fitting Pd 3d spectrum for PdAV NPs reveals the presence of four peaks at 334.66, 337, 338.93, and 342.30 eV, which belongs to Pd(0), Pd(II), Pd(0), and Pd(II), respectively (Figure d). Therefore, the formation of Pd/PdO NPs is confirmed from the high-resolution XPS spectrum. Further, the high-resolution O 1s spectrum as shown in Figure e also confirmed the presence of PdO in PdAV NPs.

FTIR of the PdOS NPs and PdAV NPs was recorded by comparing with the precursor Pd(OAc)2 as shown in Figure . The shifting/disappearance of characteristic peaks of Pd(OAc)2 reveals the formation of metallic Pd(0) particles. Figure a shows the vibrational peaks at 1604 and 1332 cm–1, which is due to the respective asymmetric and symmetric stretching of C=O.[42] The sharp peak at 1408 cm–1 is due to the ionized carboxylate group. The shifting of these vibrational modes after the addition of Ext OS and Ext AV to Pd(OAc)2 confirms the reduction of the Pd(II) ion (Figure b). Additionally, the disappearance of peak at 691 cm–1 due to Pd–O further validates the formation of the Pd(0) nanostructure using Ext OS.[43] Further, the peak in region 781 and 597 cm–1 signifies the presence of PdO along with Pd(0) particles.

Figure 4

IR spectrum of (a) Pd(OAc)2, (b) PdOS NPs, and (c) PdAV NPs.

Next, the potential of Ext OS and Ext AV was examined in case of in situ generation of NPs considering C–C cross-coupling as the model reaction. The formation of Pd NPs was further confirmed by the UV/visible spectroscopic experiment and TEM analyses.

Figure a–c shows the UV/visible absorption spectra of the in situ-generated colloidal suspension of PdOS NPs. A weak band at 279 nm was observed in Figure a, which corresponds to Ext OS.[44,45] After the addition of Pd(OAc)2, an additional peak centered near 400 nm was observed which is a characteristic of the Pd(II) ion Figure b.[46] Subsequent bioreduction of the precursor Pd(OAc)2 solution results in the disappearance of the corresponding peak at 400 nm (Figure c), indicating the complete reduction of the Pd(II) salts to nanosized Pd(0). Figure d shows a distinctive UV absorption peak at 260 nm due to Pd(OAc)2 and Ext AV solutions. On addition of subsequent reactants of C–C coupling, the peak at 260 nm disappeared which signifies the complete reduction of Pd(II) (Figure e). However, a very broad UV absorption peak centered near 260 nm was observed for pre-prepared PdAV NPs (Figure f) which shows that the Pd(II) ion in this condition does not undergo complete reduction to Pd(0) even after prolonged stirring.

Figure 5

UV visible spectra of (a) Ext OS, (b) Pd(OAc)2 and Ext OS, (c) PdOS NPsin situ, (d) Pd(OAc)2 and Ext AV, (e) PdAV NPsin situ, and (f) PdAV NPsex situ.

The morphology of the in situ-generated PdOS NPs was studied by TEM analysis. It can be seen from the high-resolution TEM (HRTEM) image Figure a,c, and the interplaner distance of 0.22 and 0.19 nm corresponds to lattice planes (111) and (200), respectively. The TEM images also clearly reflect crystalline fringes with four well-resolved rings as indexed in the selected area electron diffraction pattern of the Pd NP inset in Figure c. The crystal lattice plane as depicted in the inset, namely, (111), (200), (220), and (222) agrees well with the XRD database for corresponding hkl planes which suggests the fcc crystal structure of the Pd NPs. Additionally, it is observed that the PdOS NPs are well dispersed and are spherical in shape (Figure b). The distribution of the in situ-generated PdOS NPs was analyzed using Gaussian fits (Figure d) and the resultant data were plotted in a histogram showing a majority of particles being in the range of 4–5 nm, with a mean diameter of about 4.41 nm.

Figure 6

HRTEM (a,c) images and TEM (b) and the particle size distribution (d) of PdOS NPsin situ. Inset in (c) is the selected area electron diffraction (SAED) pattern of PdOS NPin situ.

Again, the in situ-generated PdAV NPs show well-dispersed spherical NPs between 4 and 5 nm with an interplaner distance of 0.22, 0.19, and 0.29 nm, which corresponds to lattice planes (111) and (200) for Pd NPs and (100) for PdO, respectively, as presented in Figure a–c. The selected area electron diffraction pattern of PdAV NPsin situ shows polycrystalline fringes with four well-resolved rings corresponding to crystal lattice planes, namely, (111), (200), (220), and (311), which agrees well with the XRD database for the fcc crystal structure of the Pd NPs as shown in Figure d.

Figure 7

(a–c) are the TEM and HRTEM images and (d) is the SAED pattern of PdAV NPsin situ.

Catalytic Activity of Pd NPs

The catalytic activities of both PdAV and PdOS NPs were investigated for the Suzuki–Miyaura cross-coupling reaction. Initially, the catalytic activity was examined for the pre-prepared Pd NPs using 4-bromonitrobenzene and phenylboronic acid as the model substrate. The reaction affords only 30 and 10% of isolated yields of the cross-coupling product with both ex situ-generated PdAV and PdOS NPs. In the case of PdOS NPs, a significant amount of the homocoupling product of arylboronic acid was observed (Table , entries 1 & 2). We next opt to study the in situ catalytic effects of the aqueous plant extracts on the reaction progress. On using Ext AV, we were able to isolate 50% of the desired product using 1 mol % Pd(OAc)2 in biphasic solvent medium (Table , entry 3). On increasing the amount of Ext AV, a gradual increase in reaction yield was observed (Table , entries 4 & 5). Enhanced catalytic activity was observed using 2 mL of Ext AV (Table , entry 5). However, on performing the reaction using Ext OS, relatively lower yield of the cross-coupling product was obtained (Table , entries 6 & 7). Because the phytochemical constituents in both the plant extracts (Ext OS & Ext AV) vary in nature and composition (Table ),[29−32] the catalytic efficiency in the coupling reaction seems to differ. Interestingly, during the synthesis of Pd NPs using both the plant extracts, we have observed that Ext OS was more effective than Ext AV, and Pdos NPsex situ is formed quickly compared to PdAV NPsex situ (Figure ). On the contrary, during the in situ experiments, Ext OS was found to be less effective compared to Ext AV in Suzuki reaction. The cause of poorer conversion in case of Ext OS might be due to the presence of arylboronic acid. Liu et al. in 2008 described the role of arylboronic acid in the formation of NPs.[47] They had performed a controlled experiment for in situ generation of NPs, and established that arylboronic acid acts as an associate reducing agent in the formation of NPs. A similar case was observed in the present protocol in the generation of in situ PdAV NPs. As we have seen that in the synthesis of PdAV NPsex situ, it requires a longer time for the conversion of Pd(II) to Pd(0) nano without any chemical reducing agent. However, in the in situ catalytic approaches, after addition of arylboronic acid, the Pd(II) ions immediately changes to black color indicating the quickened formation of Pd NPs. UV/vis spectra have also revealed the difference in reduction of the Pd(II) ion. Moreover, arylboronic acids act as a stabilizer for NPs and serve as a capping agent to keep them constant in size. This may sometimes lead to limitation of catalytic activity of NPs,[48] which was observed in the case of PdOS NPsin situ. Because the Ext OS act a great reducing stabilizer in the generation of NPs, the additional stabilizing effect of arylboronic acid capped most of the free surface active site for catalysis resulting in the weaker catalytic activity of PdOS NPin situ. As such according to the adsorption theory, activation of 4-bromonitrobenzene was diminished because of adsorption/capping of arylboronic acid particulates in the catalyst surface, resulting in poor reaction yield. Again, it is seen that in the absence of either of the extracts, the reaction does not proceed efficiently, which reveal the significance of the plant extract in the reaction medium (Table , entry 8). Considering the higher activity of PdAV NPsin situ in this Suzuki–Miyaura coupling, further optimization was carried out using Ext AV. The catalytic activity of PdAV NPsin situ was examined by lowering the amount of Pd(OAc)2. However, a significant decrease in reaction yield was observed (Table , entry 9). The catalytic efficiency was checked using water as the reaction medium. However, no appreciable result was obtained (Table , entry 10). This may be due to insolubility of the reactant species in water resulting in weaker coordination with the catalyst. Next, we have performed the reaction considering 4-bromoanisole and phenylboronic acid as the coupling partners. In this case, the reaction seems to proceed efficiently in water as the reaction medium along with lower catalyst loading (Table , entries 11 & 12). This is evidence of the solubility and coordination issue of the reactant species with the reaction medium and the catalyst. Then, the effect of different bases such as NaOH, Na2CO3, and Na2PO4 has been studied, but superior catalytic activity was achieved only with K2CO3 (Table , entries 13–15 vs 12).

Table 2

Optimization of Reaction Conditions for Suzuki–Miyaura Reactiona

entry	R	Pd catalyst (mol %)	(Ext.) (mL)	solvent (mL)	base (mmol)	time (min)	yield (%)b
1	NO2	PdAVNPex situ (1)		EtOH/H2O (1:1)	K2CO3 (1.5)	6 h	30
2	NO2	PdOSNPex situ (1)		EtOH/H2O (1:1)	K2CO3 (1.5)	6 h	10
3	NO2	Pd(OAc)2 (1)	Ext AV(0.5)	EtOH/H2O (1:1)	K2CO3 (1.5)	1 h	50
4	NO2	Pd(OAc)2 (1)	Ext AV (1)	EtOH/H2O (1:1)	K2CO3 (1.5)	15	70
5	NO2	Pd(OAc)2 (1)	Ext AV (2)	EtOH/H2O (1:1)	K2CO3 (1.5)	15	90
6	NO2	Pd(OAc)2 (1)	Ext OS (0.5)	EtOH/H2O (1:1)	K2CO3 (1.5)	1 h	40
7	NO2	Pd(OAc)2 (1)	Ext OS (2)	EtOH/H2O (1:1)	K2CO3 (1.5)	1 h	40
8	NO2	Pd(OAc)2 (1)		EtOH/H2O (1:1)	K2CO3 (1.5)	1 h	50
9	NO2	Pd(OAc)2 (0.5)	Ext AV (2)	EtOH/H2O (1:1)	K2CO3 (1.5)	15	40
10	NO2	Pd(OAc)2 (1)	Ext AV (2)	H2O	K2CO3 (1.5)	15	60
11	OMe	Pd(OAc)2 (1)	Ext AV (2)	EtOH/H2O (1:1)	K2CO3 (1.5)	15	95
12	OMe	Pd(OAc)2 (0.5)	Ext AV (2)	H2O	K2CO3 (1.5)	15	92
13	OMe	Pd(OAc)2 (0.5)	Ext AV (2)	H2O	NaOH (1.5)	15	78
14	OMe	Pd(OAc)2 (0.5)	Ext AV (2)	H2O	Na2CO3 (1.5)	15	80
15	OMe	Pd(OAc)2 (0.5)	Ext AV (2)	H2O	Na2PO4 (1.5)	15	85

Reaction conditions: arylbromide (1 mmol), phenylboronic acid (1.2 mmol), solvent (2 mL).

Isolated yields.

The catalytic system was studied for electronically diverse arylbromides and arylboronic acid. The reaction efficiency for both the methods using Ext OS and Ext AV was shown in Table . As already discussed, method A (with Ext OS) does not show diverse substrate compatibility. Method B (Ext AV) delivers an excellent yield of the cross-coupling product with an electron donating substituent with lower catalyst loading in pure water as solvent (Table , 3a, 3e, 3k–o). The aryl halide-bearing hydroxyl group, on the other hand, demands greater catalyst loading with EtOH as cosolvent. The reaction was also compatible for electron withdrawing substituents affording excellent conversion in biphasic medium. However, a slightly greater amount of the catalyst was required in comparison to electron-donating arylbromides (Table , 3b–d, 3g–i). From Table , it is observed that electronically varied arylboronic acid does not affect the reaction yield. The t-Bu substituent on phenylboronic acid requires a biphasic condition for effective coupling. This may be due to a solubility issue of the substrate in water (Table , 3j). The effectiveness of method B was examined for heteroaryl halide, and moderate yield of the cross-coupling product was achieved although greater reaction time was required (Table , 3p).

Table 3

Substrate Scope for Suzuki–Miyaura Cross-Coupling Reactiona

Reaction conditions: arylbromides (0.5 mmol), arylboronic acid (0.6 mmol), Pd(OAc)2 (0.5 mol %), Ext (2 mL), and H2O (2 mL).

EtOH/H2O (2 mL, 1:1).

1 mol % Pd(OAc)2.

Because the recyclability of the catalyst is one of the most important factors in a reaction protocol, we have investigated the recyclability of the catalytic species using 4-bromoanisole and phenylboronic acid as the coupling partners. After the first catalytic cycle, the reaction mixture was extracted with ethyl acetate followed by centrifugation. The clearly separated organic fraction was removed and evaporated to get the crude product and purified to obtain 92% isolated yield. The residue catalyst was washed with ethanol and then directly reused for the next catalytic run with the addition of fresh reactants, base, and solvent. The reaction affords similar reactivity till the third cycle (Figure ). However, a slight decrease in catalytic activity was observed with 80% yield in the fourth cycle with a slight longer reaction time.

Figure 8

Reusability of PdAV NPsin situ in Suzuki–Miyaura Coupling.

The morphology of PdAV NPsin situ after the second catalytic cycle was studied by TEM and HRTEM analysis (Figure S57, Supporting Information). The TEM and HRTEM images show spherical NPs of Pd/PdO for PdAV NPsin situ. Most of the Pd/PdO NPs were agglomerated during the reaction course. Therefore, the size of the NPs after the second catalytic cycle is not clearly determinable. However, the lattice fringes are visible in the HRTEM image (Figure S57d). The lattice fringe distance was found to be 0.22 nm corresponding to the Pd(111) crystallographic plane.

Next, we have studied the catalytic activity of the ex situ- and in situ-generated Pd NPs in Sonogashira cross-coupling of arylhalides and terminal alkynes. Considering our previous work on Sonogashira coupling,[49] we have performed the reaction using 4-iodonitrobenzene and phenylacetylene as our screening substrates in EtOH and K2CO3 as a base at 40 °C. The results are summarized in Table .

Table 4

Screening the Catalytic Effect on Sonogashira Couplinga

entry	catalyst (mol %)	extract (mL)	solvent (mL)	base (mmol)	time (h)	yield (%)b
1	PdosNPex situ (1)		EtOH	K2CO3	3	95
2	PdAVNPex situ (1)		EtOH	K2CO3	10	78
3	Pd(OAc)2 (1)	Ext OS (0.5)	EtOH	K2CO3	2	97
4	Pd(OAc)2 (1)	Ext AV (2)	EtOH	K2CO3	8	88
5	Pd(OAc)2 (1)	Ext OS (0.5)	EtOH	K2CO3	3	82c
6	Pd(OAc)2 (1)	Ext OS (1)	EtOH	K2CO3	2	95
7	Pd(OAc)2 (1)		EtOH	K2CO3	4	60
8	Pd(OAc)2 (0.5)	Ext OS (0.5)	EtOH	K2CO3	6	50
9	Pd(OAc)2 (1)	Ext OS (0.5)	EtOH	Cs2CO3	2	97d
10	Pd(OAc)2 (1)	Ext OS (0.5)	EtOH	Na2CO3	6	60
11	Pd(OAc)2 (1)	Ext OS (0.5)	EtOH	NaHCO3	6	20
12	Pd(OAc)2 (1)	Ext OS (0.5)	EtOH	NaOAc	12	70
13	Pd(OAc)2 (1)	Ext OS (0.5)	EtOH	NaOH	3	80
14	Pd(OAc)2 (1)	Ext OS (0.5)	H2O	K2CO3	24	40
15	Pd(OAc)2 (1)	Ext OS (0.5)	EtOH/H2O	K2CO3	12	40
16	Pd(OAc)2 (1)	Ext OS (0.5)	2-MeTHF	K2CO3	24	nr
17	Pd(OAc)2 (1)	Ext OS (0.5)	2-MeTHF/H2O	K2CO3	24	20
18	Pd(OAc)2 (1)	Ext OS (0.5)	THF	K2CO3	12	30
19	PdCl2(1)	Ext OS (0.5)	EtOH	K2CO3	4	85
20	Pd(OAc)2 (1)	Ext OS (0.5)	EtOH	K2CO3	3	85e

Reaction conditions: 4-iodonitrobenzene (0.5 mmol), phenylacetylene (0.6 mmol), base (1.5 mmol), solvent (4 mL) at 40 °C.

Isolated yield.

RT.

Cs2CO3 (1 mmol).

4-Iodonitrobenzene (0.5 mmol), phenylacetylene (0.5 mmol).

Initially, we have studied the catalytic activity of both Pd NPsex situ for Sonogashira coupling. We have noticed a significant difference in reactivity in comparison to the Suzuki–Miyaura cross-coupling reaction. Superior catalytic activity was observed using PdOS NPs with 95% of the cross-coupling product (Table , entry 1). A comparatively lower conversion was observed for PdAV NPs with extended reaction time (Table , entry 2). Similar observation was achieved in the case of the in situ approach with Ext OS (PdOS NPin situ) being more competent than Ext AV (PdAVNPin situ) (Table , entries 3 & 4). Moreover, PdOS NPin situ affords greater yield within shorter reaction time, which may be due to the greater reducing and stabilizing effect of the extract in the reaction medium (Table , entry 1 vs entry 3). Considering the enhanced catalytic activity of PdOS NPin situ, further screening of the reaction was performed using these conditions. At room temperature, the reaction delivers a lower yield of the cross-coupled product (Table , entry 5). On increasing the amount of Ext OS, the yield of the product slightly decreases (Table , entry 6). The difference in reaction yield on varying the amount of extract (Table entries 3 vs 6) may be due to greater capping of free Pd surface sites by the plant extract, which as a result lowers the accessibility of the Pd NP particle at the surface for catalysis.[50,51] Moreover, in the absence of Ext OS, the reaction bears very minimum conversion, which signifies their role and importance for the present cross-coupling reaction (Table , entry 7). On lowering the amount of Pd(OAc)2, the reaction efficiency decreases(Table , entry 8). Next, we have screened the Sonogashira cross-coupling for different bases. The activity of various inorganic bases such as Cs2CO3, Na2CO3, NaHCO3, NaOAc, and NaOH was studied (Table , entries 9–13). However, greater efficiency was achieved only in the case of K2CO3 and Cs2CO3 (Table , entries 3 & 9). However considering the cost and hygroscopic nature of Cs2CO3, we opt for the readily available and low-cost K2CO3 for our reaction protocol. Again, the efficiency of the catalyst was checked using varying solvent systems. Use of pure water or biphasic medium such as EtOH–H2O (1:1) significantly decreases the yield of the product (Table , entries 14 & 15). Other solvents such as 2-MeTHF, 2-MeTHF/H2O (1:1), and tetrahydrofuran (THF) do not meet to our expectation in terms of isolated yield (Table , entries 16–18). Later, considering the optimized reaction condition, the coupling reaction was also tested for different palladium sources such as PdCl2. But, lower conversion of the desired product was noticed (Table , entry 19). This lower activity of PdCl2 in the present reaction system may be due to difference in coordination of the anion (Cl– < OAc–) to the NP surface. Thus, lower efficacy of the Cl– anion toward stabilization of the nanostructure may hamper the catalytic performance.[52,53] We have carried out our reaction using 1:1 ratio of the substrates (Table , entry 20). However, a significant decrease in reaction efficiency was observed.

Electronically different substrates were examined to verify the catalytic activity of method A and method B for Sonogashira coupling (Table ). Method B, as already discussed provides lower efficiency in terms of yield and time (Table , 6a, b & c). Method A provides efficient cross-coupling for diverse range of substrates (Table , 6d–6u). It is compatible for aliphatic alkynes which in general is low reactive in nature (Table , 6q–6u).[54,55] Aryl iodides-bearing electron withdrawing groups in p- and m-positions proceed to completion of reaction with excellent yield of the cross-coupling product (Table , 6d, 6f, 6g, 6l–p). However, electron-donating aryl iodides are less competent in comparison to the later (Table , entry 6h & 6i). The variation in reaction efficiency may be due to the electronic effect of the substituents. Because the presence of the electron-donating group increases, the electron density over sp2 carbon and halide bond causes difficulty in C–X bond breaking for the oxidative addition step.[56,57] Again, the steric effect as in case of 2-iodonitrobenzene results in low yield of the product (Table , 6j). Next, the effect of different aromatic and aliphatic alkynes was investigated. The catalytic system delivers similar conversion in the case of different substituted aromatic alkynes (Table , 6k–6p). A slightly longer reaction time is required for aliphatic alkynes; nevertheless, in all cases, modest to good yield of the desired product was achieved (Table , 6q–6u). However, a difference in reactivity of 1-hexyne was observed with 4-iodonitrobenzene and 4-iodotoluene (Table , 6t and 6u). Iodobenzene in all cases offers comparable catalytic performance in terms of both reaction yield and time (Table , 6e, 6k, and 6q–6s). Next, we have tried to extend our catalytic system for arylbromides. Because C–Br activation is difficult in comparison to C–I, coupling of substituted arylbromides was found to be difficult. Only 50–65% of isolated yield was achieved for p-NO2 and p-CH3 substituents of arylbromide (Table , 6d and6h). Bromobenzene, on the other hand, delivers a good yield of the desired cross-coupled product within shorter reaction time (Table , 6e). However, the reaction did not proceed with aryl chlorides. Moreover, we have tried to investigate the catalytic activity of the present protocol in the synthesis of indole derivatives via intermolecular cyclization of 2-iodoaniline and arylalkynes. The catalytic activity of both the ex situ- and in situ-generated Pd NPs was examined. The results are shown in Table . However, the yield of the desired product was not satisfactory. A comparatively better activity was observed in the case of PdAV NPsex situ, which may be attributed to the presence of PdO, thereby favoring the interaction between the amine lone pair and the Pd(II) center.[58]

Table 5

Substrate Scope for Sonogashira Cross-Coupling Reaction

Reaction conditions: aryl halide (0.5 mmol), acetylene (0.6 mmol), Pd(OAc)2 (1 mol %), Ext OS (0.5 mL), Ext AV (2 mL), K2CO3 (1.5 mmol), EtOH (4 mL) at 40 °C.

Isolated yield.

Table 6

Annulation of 2-Iodoaniline with Phenyacetlyenea

entry	Pd catalyst (mol %)	extract (mL)	yield (%)b
1	PdosNPex situ (5)		20 (50)c
2	PdAVNPex situ (5)		40 (10)c
3	Pd(OAc)2 (5)	Ext OS (0.5)	30 (50)c
4	Pd(OAc)2 (5)	Ext AV (2)	(10)c

Reaction conditions: 2-iodoaniline (0.5 mmol), phenylacetylene (0.6 mmol), Pd(OAc)2 (1 mol %), Ext OS (0.5 mL), Ext AV (2 mL), K2CO3 (1.5 mmol), dimethylformamide (DMF) (4 mL) at 90 °C, 24 h.

Isolated yield.

Sonogashira cross-coupling yield.

As an additional assessment, to identify the catalytic nature of both the Pd NPs (PdAV NPsin situ and PdOS NPsin situ), in the reaction medium, we have performed the hot filtration test for both the cross-coupling reactions.[59] Leaching of Pd particles was not observed because the reaction did not proceed further after the filtration of the catalytic species from the reaction mixture. Hence, the in situ-generated Pd NPs are heterogeneous in nature. As per the recyclability of PdOS NPsin situ in Sonogashira coupling reaction, the catalyst could not be recovered after the workup, which may be due to smaller particle sizes of PdOS NPsin situ. However, in Suzuki coupling, boronic acid stabilized and capped the Pd NPs and as such prevents the Pd NPs to dissociate into smaller aggregates.

Conclusions

The present system highlights the different reducing characteristics of two naturally abundant herbs found over worldwide. This protocol provides a platform for the study of different catalytic influences of Pd NPs in C–C cross-coupling reactions with a wide range of substrate scope under mild reaction conditions. The significant influence of the substrates on the catalytic activity of the biogenic palladium NPs has been observed in Sonogashira and Suzuki cross-coupling reactions. Moreover, the present work focuses on one-pot biogenic generation of Pd NPs under aerobic conditions without the use of any additional chemical reducing agent. The process appears as an excellent alternative for many ligand-assisted systems for C–C coupling and elegantly follows the green chemistry principles of a safer reaction strategy.

Experimental Section

General Information and Characterization Techniques

In this work, the chemicals were used without further drying or purification. Plant species were collected from the Tezpur University Campus, India. The UV/visible spectra were recorded in a UV/visible spectrophotometer (Shimadzu Corporation, UV-2550). Infrared spectra were recorded using an FTIR spectrophotometer (PerkinElmer Frontier MIR FIR). Measurements are performed by pelletizing the samples with KBr in the midinfrared region. The X-ray diffraction study of the samples was carried out in a Rigaku MultiFlex instrument using a nickel-filtered Cu Kα (0.15418 nm) as the radiation source. The morphology and particle size distribution were studied by TEM analysis with JEOL JEM 2100 (200 kV). 1H and 13C spectra were recorded in CDCl3 using tetramethylsilane as an internal standard on a JEOL, JNM ECS NMR spectrometer operating at 400 MHz. X-ray photoelectron spectroscopy (XPS) measurements were performed by the ESCALAB Xi+ spectrometer (Thermo Fisher Scientific Pvt. Ltd. UK) having a monochromatic Al Kα X-ray source (1486.6 eV).

Isolation of Plant Extracts

Preparation of Ext OS

Fresh leaves of OS (1 g) were collected and washed thoroughly with distilled water and grounded in a mortar. The pastes so obtained were boiled in 10 mL distilled water for 5 min. The mixture was then centrifuged, and the filtrate was collected for further use.[60]

Preparation of Ext AV

Healthy leaves of AV (10 g) were collected and washed thoroughly with distilled water. The leaves were squeezed to extract the gel and collected in a beaker. The mixture was sonicated for 30 min to obtain the uniform gel type extract and then stored in the refrigerator for further use.[60]

General Method of Preparation of Pd NPs by Ex Situ Method

In a 10 mL round-bottom flask, 2 mL 0.05 N alcoholic Pd(OAc)2 [0.01 g of Pd(OAc)2] was stirred with 4 mL of the aqueous extract at room temperature. The mixture of Pd(OAc)2 and Ext OS show a gradual change in color from brown to dark brown within 15 min and to complete black after 1 h, indicating the reduction of the Pd(II) ion (Figure a). However, the mixture of Pd(OAc)2 and Ext AV shows a gradual change in color from brown to dark brown in 5 h and subsequently to black after 12 h (Figure b). The resulting Pd NPs were separated through centrifugation, and the pastes were dried under vacuum for further analysis.

General Information about Catalytic Experiments

Cross-coupling and annulation reactions were carried out under aerobic conditions. The progress of the reactions was monitored by aluminum-coated TLC plates (Merck silica gel 60F254) and visualized under a UV lamp. The desired products were purified and isolated by the column chromatographic technique using a silica gel (60–120 mesh) and n-hexane. The desired isolated products were identified by comparing their 1H and 13C NMR spectra as presented in the Supporting Information.

Experimental Procedure for the Catalytic Reactions

Typical Procedure for in Situ-Catalyzed Suzuki–Miyaura Reaction

A mixture of aryl halide (0.5 mmol), arylboronic acid (0.6 mmol), K2CO3 (1.5 mmol), Pd(OAc)2 (1 mol %), required amount of extract, and (1:1) EtOH/H2O was taken in a 25 mL round-bottom flask. The reactants were allowed to stir at room temperature. After completion (vide TLC), the catalyst was separated from the reaction mixture by centrifugation, and the crude reaction mixture was extracted with ethyl acetate (3 × 10 mL). The resultant organic fraction was separated and washed with brine (2 × 10 mL) and dried over anhydrous Na2SO4 and evaporated under reduced pressure. The desired product was isolated by column chromatography using ethyl acetate and hexane as an eluant and purity was confirmed by 1H and 13C NMR spectroscopy analyses.

Typical Procedure for in Situ-Catalyzed Sonogashira Coupling Reaction

In a 50 mL round-bottom flask, 1 mol % (0.001 g) Pd(OAc)2 and the required amount of extract was mixed. To the resulting mixture, 0.5 mmol (1 equiv) aryl halide and 0.6 mmol (1.2 equiv) terminal alkyne were added followed by addition of 4 mL EtOH and K2CO3 (1.5 mmol). The mixture was then stirred at 40 °C, and the progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with H2O and extracted with ethyl acetate (3 × 10 mL), dried over Na2SO4, and concentrated in vacuum. The residue was purified by column chromatography on silica gel using hexane as an eluent to obtain the pure product (functionalized alkyne). Purity of isolated products was confirmed by 1H and 13C NMR spectra.

Catalytic Procedure Using Pd NPsex situ Prepared from Respective Ext OS (PdOS NP) and Ext AV (PdAV NP)

Pd NPs (1 mol %) were mixed with 0.5 mmol aryl halide, 0.6 mmol of arylboronic acid, and phenylacetylene with 1.5 mmol K2CO3 with the required amount of solvent. The progress of both the Suzuki–Miyaura and Sonogashira coupling reactions was monitored via TLC, and the desired product was isolated by the column chromatographic technique.

Typical Procedure for Annulation Reaction of 2-Iodoaniline and Phenylacetylene

Pd(OAc)2 (5 mol %), a specific amount of extract, 0.5 mmol 2-iodoaniline, 0.6 mmol phenylacetylene, and 1.5 mmol K2CO3 in DMF were mixed in a 50 mL round-bottom flask. The mixture was then allowed to stir at 90 °C, and the progress was monitored via TLC. The reaction mixture was then extracted with ethyl acetate and water, and the organic fraction was dried over Na2SO4 and concentrated in vacuum. The desired product was isolated by column chromatography and characterized by 1H and 13C NMR spectroscopy. Again considering the same substrate ratio, the reaction was performed using 5 mol % of both the ex situ Pd NPs, and the comparative conversion of each reaction was monitored via TLC. Later, the reaction mixture was extracted with ethyl acetate, dried over Na2SO4, and concentrated in vacuum. The desired product was then isolated by the column chromatographic technique and analyzed by NMR spectroscopy.