untitled European Journal of Chemistry 5 (3) (2014) 513‐516 European Journal of Chemistry ISSN 2153‐2249 (Print) / ISSN 2153‐2257 (Online)  2014 Eurjchem Publishing ‐ Printed in the USA http://dx.doi.org/10.5155/eurjchem.5.3.513‐516.1086 European Journal of Chemistry Journal homepage: www.eurjchem.com A study of coupling reaction to synthesize diphenylmethane derivatives Huma Aslam Bhatti a,b,*, Qurat‐Ul‐Ain Zaheer a, Memoona Khatoon a, Mark Edward Light b, and Abdul Hameed a a Husein Ebrahim Jamal Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan b School of Chemistry, University of Southampton, Highfield, Southampton, SO17 1BJ, England *Corresponding author at: Husein Ebrahim Jamal Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan. Tel.: +92.111.222292. Fax: +92.213.4819018. E‐mail address: huma_aslam31@hotmail.com (H.A. Bhatti). ARTICLE INFORMATION ABSTRACT DOI: 10.5155/eurjchem.5.3.513‐516.1086 Received: 28 April 2014 Received in revised form: 26 May 2014 Accepted: 01 June 2014 Online: 30 September 2014 KEYWORDS The class of compounds having diphenylmethane framework occupy a distinct place in natural bioactive compounds and also serve as useful intermediates in various commercially important synthetic molecules. Conventionally, Friedel‐Craft type reactions were used to synthesize such diphenylmethane derivatives. However, herein we report a unique approach in which, two benzyl alcohol molecules were coupled in the presence of different halogenating agents (SOCl2, PBr3 and MeSO2Cl) to afford the desired diphenylmethane derivative, bis(2,4‐ bis(benzyloxy)‐5‐methoxyphenyl)methane. It has been found that the coupling reaction is strongly influenced by the electronic effects and number of the substituents on the phenyl ring. The resultant compound, bis(2,4‐bis(benzyloxy)‐5‐methoxyphenyl)methane, was obtained in excellent yield (83‐85%) and completely characterize with different spectroscopic techniques. Benzyl alcohol Thionyl chloride Coupling reaction Halogenating agents Phosphorus tribromide Diphenylmethane derivative 1. Introduction Diphenylmethane scaffold is found in various compounds of commercial importance in pharmaceutics [1] and fine chemical industries [2,3]. These compounds serve as important intermediates in the synthesis of new drug candidates [4,5], adhesives and epoxy resins [6,7], preserves in perfumes and as solvent in pressure sensitive reaction [8]. The diphenyl methane derivatives are also added to improve the thermal stability of polyesters [9] and lubricating properties of jet fuels [10]. However, there are some diphenylmethane derivatives, which have been isolated from natural sources and possess significant bioactivities. A class of brominated diphenyl methane derivatives 1 which has been isolated from green alga Avrainvillea nigrlcans and possessed antibiotic activity against several human pathogens [11] (Figure 1). While, recently a new diphenylmethane derivative 2 has been isolated from the bioactive mixture of Periploca sepium which, exhibited activity against autoimmune diseases, especially for the treatment of rheumatoid in traditional Chinese medicines [12] (Figure 1). The diverse applications of diphenylmethane derivatives make them interesting target for synthetic chemists. In literature, usually Friedel‐Craft reactions that including acyla‐ tion or alkylation were employed to prepare diphenylmethane derivatives. Figure 1. Naturally occurring diphenylmethane derivatives 1 and 2. However, in acylation the incorporation of formaldehyde group between two benzene rings is found tedious; while in alkylation the synthesis of benzyl chloride is sometime found inconvenient and low yielding [13,14]. 514 Bhatti et al. / European Journal of Chemistry 5 (3) (2014) 513‐516 Table 1. Coupling reaction attempts with mono‐substituted benzyl alcohol. Entry Benzyl alcohol Reaction conditions Halogenated product Diphenylmethane derivative 1 (3) SOCl2, CH2Cl2, 0 °C to R.T., 24 hr (6) No product 2 (4) SOCl2, CH2Cl2, 0 °C to R.T., 24 hr (7) No product 3 (5) SOCl2, CH2Cl2, 0 °C to R.T., 24 hr O2N Cl (8) No product Also, both of the Friedel‐Crafts reaction necessarily required Lewis acids such as AlCl3, FeCl3, or ZnCl2, as pre‐ catalyst. These acid catalysts offer toxicity and various environ‐ mental hazardous effects [15,16]. So, in the loop of diphenyl methane analogues synthesis, we wish to report a unique cross‐coupling approach to synthesize the diphenyl methane derivatives from benzyl alcohol derivatives. 2. Experimental 2.1. Materials All the benzyl chlorides, halogenating agents and solvents were purchased from different available commercial sources. Silica gel column chromatography was performed with silica gel 60 as the stationary phase with different analytical grade solvents i.e. EtOAc, hexane, petroleum ether. Chromatograms were visualized by UV at 254 and 365 nm. 2.2. Instrumentation NMR spectra were obtained on Advance Bruker AM 300 and 400 MHz. Single crystal X‐ray diffraction data: Diffracto‐ meter: Nonius KappaCCD area detector ( scans and  scans to fill asymmetric unit). Cell determination: DirAx [17], Data collection: COLLECT data collection software [18]. Data reduction and cell refinement: Denzo [19]. Absorption correc‐ tion: Sheldrick, G. M. SADABS‐Bruker Nonius area detector scaling and absorption correction‐V2.10 Structure solution: SHELXS97 [20]. Structure refinement: SHELXL97 (G. M. Sheldrick (1997), University of Göttingen, Germany). Graphics: Cameron‐A Molecular Graphics Package [21]. Special details: All hydrogen atoms were placed in idealized positions and refined using a riding model. 2.3. Synthesis of diphenylmethane derivative, bis(2,4‐ bis(benzyloxy)‐5‐methoxyphenyl)methane (12) Method 1: The solution of thionylchloride (SOCl2) (0.01 mL, 0.21 mmole) in CH2Cl2 was added dropwise to the cold (0 °C) stirring solution of 2,4‐bis(benzyloxy)‐5‐methoxyphenyl) methanol 11 (100 mg, 0.28 mmoles) in CH2Cl2. The resulting mixture was stirred for 45 min at 0 °C, at which the solution was poured into ice water and extracted with dichloromethane (CH2Cl2). All the separated organic layers were combined, dried over MgSO4 and then subsequently evaporated dried the crude product by column chromatography to get the product 12 in 85 % yield. With phosphoroustribromide (PBr3), same protocol was used to afford the diphenylmethane derivative 12 in 83% yield. Method 2: Methane sulphonyl chloride (4.9 mL, 50.4 mmols) was added dropwise to a solution of 2,4‐bis(benzy loxy)‐5‐methoxyphenyl)methanol 11 (3.6 g, 12.6 mmoles) and Et3N (7 mL, 50.4 mmol) in THF (50 mL) at 0 °C. The resulting mixture was then stirred overnight at room temperature. The reaction was quenched with water and extracted with the Et2O and washed with brine, purified by column chromatography to get pure product 12 (3.9 g) in 83% yield. The structures of resultant compound 12 were confirmed with NMR spectros‐ copy, mass spectrometry and X‐ray crystallography. Bis(2,4‐bis(benzyloxy)‐5‐methoxyphenyl)methane (12): Color: White crystals. 1H NMR (300 MHz, CHCl3, δ, ppm): 7.49‐ 7.10 (m, 20H, ArH), 6.52 (s, 2H, ArH), 6.50 (s, 2H, ArH), 5.02 (s, 4H, 2(CH2)), 4.80 (s, 4H, 2(CH2)), 3.80 (s, 2H, CH2), 3.50 (s, 6H, (OCH3)2). 13C NMR (75 MHz, CDCl3, δ, ppm): 150.4 (C), 146.7 (C), 143.9 (C), 137.4 (C), 128.5 (CH), 127.7 (CH), 127.3 (CH), 122.6 (C), 115.5 (CH), 102.3 (CH), 71.7 (CH2 x 2), 71.0 (CH2 x 2), 56.5 (OCH3 x 2), 29.7 (CH2). MS‐EI (m/z, %): 652.2 (100), 653.29 (M+, 41). 3. Results and discussion The cross‐coupling reaction to prepare the diphenyl methane analogues from readily available benzyl alcohol derivatives were studied with various halogenating agents such SOCl2, PBr3 and MeSO2Cl. Initially, the benzyl alcohol was treated with thionyl chloride to produce the desired diphenyl methane. Unfortunately, the reaction proved to be unsuccessful and no desired product 6 was obtained. Further, the mono substituted benzyl alcohol derivatives 4 and 5, with electron denoting group (4′‐OMe) and electron withdrawing group (4′‐ NO2) were treated with thionyl chloride to see whether the electronic effect of substituents electronic affect the synthesis of corresponding diphenylmethane derivatives. However in both cases, only the corresponding halogenated products 7 and 8 were obtained (Table 1). Further in this study, a tri‐substituted brominated benzyl alcohol derivative 9 was then treated with thionyl chloride to get corresponding diphenylmethane derivative 10, which has close structural similarity with precursor of dibromo diphenyl methane derivative 2. We have observed that even in this case the reaction resulted in only the corresponding benzyl chloride product (Scheme 1). Though, we had obtained surprising results when we applied the above mentioned reaction conditions (SOCl2, CH2Cl2) with another tri‐substituted benzyl alcohol derivative 11 having all the substitutes of electron denoting nature. The cross coupling type reaction proceeded smoothly and region‐selectively to give the desired diphenyl methane derivative 12 in excellent yield (83‐85%). The resultant compound 12 has a close structural similarity with dimethoxydip henylmethane derivative 2. This suggested that a highly substituted phenyl ring with electro denoting groups is necessarily required for such type of cross coupling reactions. The chemical method was further elaborated with other halogenating reagents such as PBr3 and MeSO2Cl, which also afforded the same product 12 (Scheme 1). A plausible mechanism of this reaction has also been layout in the following Scheme 2. The first step in mechanism showed the chlorination of the benzyl alcohol derivative 11 to corres‐ ponding benzyl chloride 13 which then tautomerize with its more stable carbocation specie 14 due to the effect of different electron denoting substituents on the phenyl ring. Next the nucleophilic attack of the phenyl ring of benzyl alcohol 11 formed the diphenylmethane intermediate 15, which rapidly released a molecule of formaldehyde to retain the aromaticity. Bhatti et al. / European Journal of Chemistry 5 (3) (2014) 513‐516 515 Entry Reaction conditions % Yield 1 SOCl2, 0 °C, 45 min. 85 2 PBr3, DCM, 0 °C, 45 min. 83 3 MeSO2Cl, Et3N, DCM, 0 °C to R.T. overnight 83 Scheme 1 The resultant coupling product 12 was obtained in excellent yield (83‐85%). The structure of the diphenyl methane analogue 12 was characterized with different analytical techniques which are including 1H NMR, 13C NMR spectroscopy and mass spectrometry. The structure was further confirmed by X‐ray crystallography (Figure 2, Table 2‐ 4). Table 2. Crystal data and structure refinement for compound 12. Empirical formula C43H40O6 Formula weight 652.75 Temperature, K 120(2) Crystal system Monoclinic Wavelength, Å 0.71073 Space group P21/n a, Å 15.7508(2) b, Å 9.7835(2) c, Å 21.9581(4) α, ° 90.00 β, ° 92.4920(10) γ, ° 90.00 Volume/Å3 3380.50(10) Z 4 ρcalc , mg/mm3 1.283 m, mm‐1 0.085 F(000) 1384.0 Crystal size, mm3 0.3 × 0.03 × 0.03 Crystal Needle, Colourless 2Θ range for data collection 6.04 to 54.96° Index ranges ‐20 ≤ h ≤ 20, ‐12 ≤ k ≤ 11, ‐28 ≤ l ≤ 28 Reflections collected 41608 Completeness to  = 27.48° 99.8 % Absorption correction Semiempirical from equivalents Max. and min. transmission 0.9975 and 0.9651 Refinement method Full‐matrix least‐squares on F2 Independent reflections 7748[R(int) = 0.0720] Data/restraints/parameters 7748/0/444 Goodness‐of‐fit on F2 1.054 Final R indexes [I≥2σ (I)] R1 = 0.0820, wR2 = 0.1560 Final R indexes [all data] R1 = 0.1246, wR2 = 0.1796 Largest diff. peak/hole , e Å‐3 0.413/‐0.290 4. Conclusion We have prepared a highly substituted diphenylmethane derivative 12, which has close structural similarity with the nature product 2, via a simple coupling reaction. The reaction with substituted benzyl alcohol 11 was optimized with three different types of halogenated reagents. The percentage yield of the desired diphenylmethane derivative 12 with each reaction condition was found excellent (83‐85%). Altogether, the chemical method is rapid and useful to excess the substituted diphenylmethane derivative 12 of biological importance and intermediates as well in the chemical industry. Figure 2. Crystal structure of compound 12. Table 3. Bond lengths for compound 12. Atom‐Atom Length, Å Atom‐Atom Length, Å C1‐C2 1.386(4) C22‐C23 1.522(4) C1‐C6 1.382(4) C23‐C24 1.394(4) C2‐C3 1.380(5) C23‐C28 1.388(4) C3‐C4 1.393(4) C24‐C25 1.388(4) C4‐C5 1.386(4) C25‐C26 1.400(4) C5‐C6 1.393(4) C25‐O6 1.373(3) C6‐C7 1.506(4) C26‐C27 1.388(4) C7‐O1 1.429(3) C26‐O5 1.368(3) C8‐C9 1.392(4) C27‐C28 1.395(4) C8‐C13 1.395(4) C28‐O4 1.384(3) C8‐O1 1.381(3) C29‐C30 1.502(4) C9‐C10 1.392(4) C29‐O4 1.439(3) C10‐C11 1.400(4) C30‐C31 1.384(4) C10‐O2 1.376(3) C30‐C35 1.387(4) C11‐C12 1.376(4) C31‐C32 1.384(5) C11‐O3 1.382(3) C32‐C33 1.372(5) C12‐C13 1.391(4) C33‐C34 1.384(5) C13‐C22 1.515(4) C34‐C35 1.402(5) C14‐C15 1.503(4) C36‐O6 1.423(4) C14‐O2 1.441(3) C37‐C38 1.500(4) C15‐C16 1.387(4) C37‐O5 1.437(3) C15‐C20 1.378(4) C38‐C39 1.395(4) C16‐C17 1.384(4) C38‐C43 1.388(4) C17‐C18 1.383(5) C39‐C40 1.387(4) C18‐C19 1.376(5) C40‐C41 1.388(4) C19‐C20 1.388(4) C41‐C42 1.386(4) C21‐O3 1.425(3) C42‐C43 1.386(4) 516 Bhatti et al. / European Journal of Chemistry 5 (3) (2014) 513‐516 Scheme 2 Table 4. Bond angles for compound 12. Atom‐Atom‐Atom Angle, ˚ Atom‐Atom‐Atom Angle, ˚ C6‐C1‐C2 120.6(3) C25‐C24‐C23 122.0(3) C3‐C2‐C1 120.5(3) C24‐C25‐C26 119.2(2) C2‐C3‐C4 119.5(3) O6‐C25‐C24 125.3(2) C5‐C4‐C3 119.9(3) O6‐C25‐C26 115.5(2) C4‐C5‐C6 120.6(3) C27‐C26‐C25 119.5(3) C1‐C6‐C5 119.0(3) O5‐C26‐C25 115.7(2) C1‐C6‐C7 120.9(3) O5‐C26‐C27 124.8(2) C5‐C6‐C7 120.1(3) C26‐C27‐C28 120.2(3) O1‐C7‐C6 108.2(2) C23‐C28‐C27 121.1(3) C9‐C8‐C13 121.2(2) O4‐C28‐C23 116.7(2) O1‐C8‐C9 123.5(2) O4‐C28‐C27 122.2(2) O1‐C8‐C13 115.4(2) O4‐C29‐C30 107.6(2) C8‐C9‐C10 119.8(3) C31‐C30‐C29 121.0(3) C9‐C10‐C11 119.5(3) C35‐C30‐C29 120.0(3) O2‐C10‐C9 124.5(2) C35‐C30‐C31 119.0(3) O2‐C10‐C11 116.0(2) C32‐C31C30 120.8(3) C12‐C11‐C10 119.5(2) C33‐C32‐C31 120.3(3) C12‐C11‐O3 124.7(2) C32‐C33‐C34 120.0(3) O3‐C11‐C10 115.7(2) C33‐C34‐C35 119.8(3) C11‐C12‐C13 122.1(3) C30‐C35‐C34 120.1(3) C8‐C13‐C22 121.2(2) O5‐C37‐C38 107.4(2) C12‐C13‐C8 117.8(2) C39‐C38‐C37 121.0(2) C12‐C13‐C22 121.1(2) C43‐C38‐C37 120.1(3) O2‐C14‐C15 108.5(2) C43‐C38‐C39 118.9(3) C16‐C15‐C14 120.1(3) C40‐C39‐C38 120.3(3) C20‐C15‐C14 121.3(3) C41‐C40‐C39 120.4(3) C20‐C15‐C16 118.6(3) C42‐C41‐C40 119.5(3) C17‐C16‐C15 120.6(3) C41‐C42‐C43 120.2(3) C18‐C17‐C16 120.2(3) C38‐C43‐C42 120.8(3) C19‐C18‐C17 119.5(3) C8‐O1‐C7 117.7(2) C18‐C19‐C20 120.1(3) C10‐O2‐C14 116.2(2) C15‐C20‐C19 121.0(3) C11‐O3‐C21 116.2(2) C13‐C22‐C23 115.2(2) C28‐O4‐C29 116.5(2) C24‐C23‐C22 119.5(2) C26‐O5‐C37 118.2(2) C28‐C23‐C22 122.6(2) C25‐O6‐C36 116.2(2) C28‐C23‐C24 117.9(2) Acknowledgement We are thankful to Higher Education Commission of Pakistan for providing financial support of this project. 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