A quick and low E-factor waste valorization procedure for CuCl-catalyzed oxidative self-coupling of (hetero)arylboronic acid in pomegranate peel ash extract

ABSTRACT The application of waste biomass-derived materials to synthetic chemistry is a remarkable achievement, and the use of aqueous media is further advancement. The switch towards earth's abundant metals like cobalt/copper/iron/nickel from precious palladium in C–C coupling reactions is also a high throughput in the global sustainability perspective. Herein, we describe a CuCl-catalyzed homocoupling of (hetero)arylboronic acids (HABAs) in water extract of pomegranate ash (WEPA) with low E-factor of 1.25 without including the column chromatographic separation of products, which helped in understanding the effectiveness of this method on comparison to reported protocols lacking amounts of silica gel and eluents, however, it was 171.64 by including column purification. The reactions are conducted at room temperature to deliver self-coupling products with 90–99% yields in 10–45 min under precious metal, ligand, non-renewable base, toxic/problematic organic solvent and added oxidant-free conditions. A wide range of substrates were screened with aryl and heteroaryl moieties containing diversified functional groups. The substitution of earth's rare metals-based catalysts by abundant copper, exploration of waste to state-of-the-art C–C coupling, use of biorenewable base, aqueous media, ambient conditions, operational simplicity, excellent yields of biaryls and quick reactions are the noteworthy advantages of this protocol. GRAPHICAL ABSTRACT


Introduction
The effective utilization/disposal of solid waste produced by the rapid urbanization and rise of living standards is an urgent and highly needed task for the sustainability of environment and human life (1). Further, the solid organic waste is the major contributor to the greenhouse gas (GHG) emission (1). In this connection recently the scientific community has been working on the utilization of solid waste ashderived aqueous medium for synthetic organic chemistry (1,2). Besides the effective use/disposal of solid organic waste, these processes are also associated with the application of nature's most preferred solvent such as water as the reaction medium (1,2). In several reports these biorenewable ash-derived aqueous extracts acts as catalysts/reagents or bases. Therefore, these procedures cover the most of the constituent principles of Green Chemistry. Inspired by our recent work on these extracts (1,(3)(4)(5) we report here a sustainable Cu-catalyzed self-coupling reaction of (hetero)arylboronic acids [(H)ABAs] using water extract of pomegranate ash (WEPA) as a biorenewable base and reaction medium.
A brief review of the existing strategies along with a comparative analysis of advantageous oxidative self-coupling reactions of organoboron compounds is displayed in Scheme 1 and Table 1. As can be seen, this protocol shows clear merits against the reported protocols like the use of non-precious CuCl as a catalyst, ambient conditions, application of biorenewable material, quick reactions, use of aqueous media, avoidance of non-renewable resources based solvents/promoters and wide substrate scope.
Moreover, the recently considered green metric, environmental factor (E-factor) indicates that the nonrecyclable substances in the development of a new process/method can be considered as waste (38)(39)(40). The water and other recyclable substances such as solvents, substrates, reagents and catalysts are not considered to be waste. Therefore, the estimation of the Efactor for a developed process can describe the effectiveness of the process toward environmental sustainability and the development of protocols with a low E-factor is highly favored (38)(39)(40). Hence, toward developing a low E-factor protocol for self-coupling of (H)ABAs, the Scheme 1. Brief overview on self-coupling reactions of organoboron compounds.
present CuCl-catalyzed procedure is found to be highly useful. Moreover, this method displayed a low E-factor over the other reported methods (Table 1).

General information
The (H)ABAs were procured from AVRA Synthesis, Sigma-Aldrich and Alfa Aesar and employed without any purification. Thin layer chromatography (TLC) has been used to know the progress of self-coupling reactions of (H)ABAs by employing varying ratios of ethyl acetate and n-hexane, and the improvements in reactions were visualized using UV light. 1 H NMR and 13 C NMR spectra have been obtained using JEOL, JNM ECS NMR instrument operating at 400/100 MHz employing the solvent, CDCl 3 and internal standard, tetramethylsilane (TMS). The chemical shift (δ) and coupling constant (J ) values were provided in ppm and hertz (Hz).

Procedure for the preparation of WEPA
The reported procedure of our previous publications (3-5,13) was employed for the preparation of WEPA.

Procedure for the CuCl-catalyzed selfcoupling of (H)ABAs using WEPA
To a solution of (H)ABA (1) (1 mmol) in 1 mL of WEPA and 0.5 mL of EtOH was added 5 mol% of CuCl and the reaction mixture was stirred at RT. After the completion of the reaction (Table 2), ethanol was evaporated. To the residue was added 5 mL of water. The crude biaryl was extracted from the aqueous mixture into ethyl acetate. The ethyl acetate mixture was then afforded the symmetrical biaryl, 2 using silica-gel packed column chromatography. In some cases, the products obtained during ethyl acetate extraction are sufficiently pure so that purification by column chromatography is not needed ( Table 3). The structures of symmetrical biaryls have been confirmed by 1 H NMR, 13 C NMR and mass spectrometric data; spectral data follow.   MnCl 2 (5) 1 0.5 720 a Reaction conditions: 1 mmol of phenylboronic acid (1a) at RT. b 1 mL of water extract of wood ash (WEWA) was employed. c 1 mL of water extract of banana peel ash (WEB) was used. Table 3. Self-coupling reactions of (H)ABAs using CuCl in WEPA. a a Reaction conditions: 5 mol% of CuCl and 1 mmol of (H)ABA (1) in 1 mL of WEPA and 0.5 mL of EtOH at RT. b Isolated yield. c Pure product was obtained after work-up and no column chromatography is performed.
comparison of the TLC retention factor (Rf) values with authentic samples of our recent reports (5,19).

E-factor calculation for the self-coupling of phenylboronic acid in WEPA without including the column chromatographic purification of product
The E-factor for the self-coupling of 1.0 mmol of phenylboronic acid (1a) using CuCl (5 mol%) and ethanol (0.5 mL) in WEPA to produce 99% yield of symmetrical biaryl, 2a ( Table 2,

E-factor calculation for the self-coupling of phenylboronic acid in WEPA by including the column chromatographic separation of product
The E-factor for the self-coupling of 1.0 mmol of phenylboronic acid (1a) to give 99% yield of 2a employing CuCl (5 mol%), and ethanol (0.5 mL) in WEPA followed by the column chromatographic purification of 2a using 9.10 g of silica-gel, 20 mL of n-hexane and 0.2 mL of ethyl acetate (the eluent, n-hexane and ethyl acetate was recovered @ 71% and reused for the column chromatography): E-factor = {[0.122 g of 1a + 0.007 g of CuCl + 0.39 g of ethanol + 0.002 g of WEPA + 9.10 g of silica-gel + 13.1 g of n-hexane + 0.180 g of ethyl acetate] -(0.35 g of recovered ethanol @ 90% + 0.076 g of biphenyl, 2a + 9.301 g of recovered n-hexane @ 71% + 0.129 g of recovered ethyl acetate @ 71%)}/0.076 g of biphenyl, 2a = 171.64.

Characterization of WEPA
Our previous characterization studies on WEPA using XRD, XPS, EDAX, XRF and FTIR displayed that the WEPA consists large quantities of K 2 O and KCl, reasonable quantities of SO 3 , Na 2 O, CaO, MgO, SiO 2 and Al 2 O 3 with some other metallic and non-metallic substances in a trace quantities (3)(4)(5)13) (please see the supporting information for XPS and XRF data).

Optimization studies of self-coupling of (H)ABAs
The optimization experiments are shown in Table 2. Initially, 1 mmol of phenylboronic acid (1a) was analyzed for its self-coupling reaction using 0.5 mL of WEPA and 2 mol% of CuCl, and biphenyl (2a) was formed with 20% yield in 12 h at RT ( Table 2, entry 1). The addition of 0.5 mL of EtOH as the co-solvent at this stage provided 32% of 2a in 3 h (Table 2, entry 2). The use of 1 mL of WEPA delivered 39% of 2a in 1 h (Table 2, entry 3). The application of 3, 4, 5 and 6 mol% of CuCl gave 63%, 82%, 99% and 99% yields of 2a in 1 h, 40, 10 and 10 min at RT ( Table 2, entries 4-7) and these investigations indicate the necesscity of 5 mol% of CuCl and 0.5 mL of EtOH for this conversion. The use of 2 mL of WEPA did not show any improvement ( Table 2, entries 8), indicating the requirement of 1 mL of WEPA for this self-coupling reaction of 1a. The studies by avoiding WEPA or CuCl showed no reaction ( Table 2, entries 9 and 10) indicating the necessity of WEPA and CuCl for this conversion and also show that EtOH acts only as a co-solvent. The model reaction using 1 mL water extract of wood ash (WEWA) (43) and 1 mL water extract of banana ash (WEB) (44) showed 72% and 92% of 2a in 2.5 and 1 h ( Table 2, entries 11 and 12), indicating that WEPA is the best amongst them in light of its large amounts of K 2 O (Section 3.1) (44). The investigation of self-coupling reactions using other metal-based catalysts such as CuSO 4 , FeCl 3 , Ni (OAc) 2 , NiCl 2 and MnCl 2 showed no reaction ( Table 2, entries [13][14][15][16][17] and hence these cannot catalyze the present reaction under WEPA-assisted conditions.
The suitability of the CuCl-catalyzed conditions for a wide variety of ABAs and HABAs is an advantage of this development using waste-originated biorenewable extract, WEPA. The development of environmentally benign protocols or technology can obviously show a great influence on the sustainability of environment and human life (1,(45)(46)(47). To assist in understanding whether this protocol is better than other protocols where the amounts of silica-gel and eluents are not provided, we have calculated the E-factor of this protocol for the self-coupling reaction of 1a, and the value is found to be 1.25 without including the column chromatographic purification (Section 2.4). Thus, this method is more effective than those reported previously, which have E-factors between 3.3 and 79.3 (Table 1). However, by including the column chromatographic purification, this protocol shows an E-factor of 171.64 (Section 2.5).

Plausible mechanism of CuCl-catalyzed selfcoupling reaction of (H)ABAs
The advantage of copper in organic synthesis is that the copper can exist in a range of oxidation states from 0 to +3 in its catalytic cycles via a one or two electron process (48). The mechanism of the present method (Scheme 2) has been proposed based on the literature reports (37,49). Initially, Cu I Cl participates in oxidative addition (I) with the resultant species (a) formed by the reaction of ABA with the base of WEPA [the base is mostly KOH, since the large quantity of K 2 O (Section 3.1) of WEPA will be transformed readily to KOH in the presence of water (3)(4)(5)13)] to generate intermediatory Cu II species, A. The intermediate A reacts further with a (oxidative addition, II) to form Cu III intermediate, B, which undergoes reductive elimination (III) in WEPA to produce Cu I Cl and symmetrical biaryl, 2.

Conclusions
In summary, a CuCl-catalyzed, low E-factor protocol has been developed for the oxidative self-coupling reaction of (H)ABAs in WEPA at RT by avoiding non-renewable oxidants. WEPA is a waste-originated biorenewable basic media and hence the present strategy is a good example for waste valorisation to the C-C coupling reaction. The present method shows advantages like the use of biorenewable base and reaction media, ambient conditions, quick reaction times, high to nearly quantitative yields, elimination of volatile organic solvents and non-renewable oxidants and high substrate scope. The current CuCl-catalyzed method with mild conditions avoiding additional organics by using waste-derived media may become the most advantageous method for the Cu-assisted self-coupling reactions of (H)ABAs.

Disclosure statement
No potential conflict of interest was reported by the author(s).