Thiophene derivatives have shown versatile pharmacological activities. The Suzuki reaction proved a convenient method for C–C bond formations in organic molecules. In the present research work novel derivatives of 2,5-dibromo3-methylthiophene (3a–k and 3l–p) has been synthesized, via Suzuki coupling reaction in low to moderate yields.
Rizwan et al Chemistry Central Journal (2018) 12:49 https://doi.org/10.1186/s13065-018-0404-7 Open Access RESEARCH ARTICLE Palladium(0) catalyzed Suzuki cross‑coupling reaction of 2,5‑dibromo‑3‑methylthiophene: selectivity, characterization, DFT studies and their biological evaluations Komal Rizwan1,2, Muhammad Zubair1*, Nasir Rasool1*, Tariq Mahmood3, Khurshid Ayub3, Noorjahan Banu Alitheen4*, Muhammad Nazirul Mubin Aziz4, Muhammad Nadeem Akhtar5, Faiz‑ul‑Hassan Nasim6, Snober Mona Bukhary6, Viqar Uddin Ahmad7 and Mubeen Rani7 Abstract Thiophene derivatives have shown versatile pharmacological activities The Suzuki reaction proved a convenient method for C–C bond formations in organic molecules In the present research work novel derivatives of 2,5-dibromo3-methylthiophene (3a–k and 3l–p) has been synthesized, via Suzuki coupling reaction in low to moderate yields A wide range of functional groups were well tolerated in reaction Density functional theory investigations on all synthesized derivatives (3a–3p) were performed in order to explore the structural properties The pharmaceutical potential of synthesized compounds was investigated through various bioassays (antioxidant, antibacterial, antiu‑ rease activities) The compounds 3l, 3g, 3j, showed excellent antioxidant activity (86.0, 82.0, 81.3%), respectively by scavenging DPPH Synthesized compounds showed promising antibacterial activity against tested strains 3b, 3k, 3a, 3d and 3j showed potential antiurease activity with 67.7, 64.2, 58.8, 54.7 and 52.1% inhibition at 50 µg/ml Results indicated that synthesized molecules could be a potential source of pharmaceutical agents Keywords: Density functional theory, Thiophene, Antioxidant, Antibacterial, Palladium Background Thiophene is found in central core of various compounds and is well known for its intrinsic electronic properties [1, 2] A number of thiophene based heterocycles have been reported for versatile pharmacological activities [3– 9] Biaryl thiophenes are pharmacologically important agents and widely used as anti-inflammatory [10], chemotherapeutic [11], antimicrobial [12] and antioxidant *Correspondence: zubairmkn@yahoo.com; nasirhej@yahoo.co.uk; noorjahan@upm.edu.my Department of Chemistry, Government College University, Faisalabad 38000, Pakistan Deparment of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Science, University Putra Malaysia, 43400 Serdang, Selangor Darul Ehsan, Malaysia Full list of author information is available at the end of the article agents [13] Several reports about regioselective Suzuki coupling of dibromothiophene are available in literature [14, 15] Palladium catalyzed coupling of 2,5-dibromothiophene has been reported and the yield of obtained product was low (29%) [16] Synthesis of 2,5-diheteroarylated thiophenes from 2,5-dibromo thiophene derivatives has been reported in good yield [17] Regioselective Suzuki coupling of 2,5-dibromo-3-hexylthiophene has been reported and preferably coupling occurred at C5 position [18] The more electron deficient carbon moiety is preferably reactive towards attacking nucleophiles, whereas other reactive carbons not show any response Different heterocycles undergo electrophilic substitutions and this regioselectivity can be applied to these substrates [19] In heterocycles substitution © The Author(s) 2018 This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated Rizwan et al Chemistry Central Journal (2018) 12:49 reactions, heteroatom (O, S and N) electron lone pair is being donated to the ring However, in halogenated thiophenes Suzuki reaction with high oxidative addition, the arylboronate anion preferably attacks the electron deficient carbon bonded with the halogen And it was observed that transmetallation step is faster due to negatively charged boronate anion then the neutral boronic acids [20] Extending the scope of Suzuki coupling reaction in regioselective domain a series of 2,5-dibromo3-methylthiophene derivatives has been synthesized specially with aim to explore their biological importance for the first time Results and discussion Chemistry A series of thiophene derivatives (3a–k) and (3l–p) has been synthesized by reaction of 2,5-dibromo-3-methylthiophene with variety of arylboronic acids in low to moderate yields (27–63%) (Scheme 1, Table 1) Under the developed Suzuki reaction conditions, when 1.1 eq of arylboronic acid was used the bromo group at position was selectively substituted and a variety of mono-substituted products was synthesized (3a–k) and double Suzuki cross coupling occurred by using 2.2 eq of arylboronic acids and diaryl derivatives of thiophene were synthesized (3l–p) (Table 1) To increase the substrate scope, the arylboronic acids with both electron donating and withdrawing groups were used The reaction conditions were tolerant of both electron donating and electron withdrawing arylboronic acids It was noted that some products were obtained in low yield as 3b, 3h, 3i, 3j, 3k, 3n, 3o which can be attributed to the presence of mixture of mono and di-arylated products in both Page of 12 single and double Suzuki cross coupling reaction and it has been very difficult to separate this reaction mixture and low yields were obtained This may be due to ineffective transmetallation and reductive elimination in overall reaction cycle [12] Density functional theory (DFT) studies DFT investigations were computed by using GAUSSIAN 09 software, in order to explore the structural properties and reactivity’s of synthesized derivatives First of all, compounds (3a–3p) were optimized by using B3LYP/631G(d,p) basis set along with the frequency analysis After optimization the energy minimized structures were used further for frontier molecular orbitals and molecular electrostatic potential (MEP) analysis on the same basis set Frontier molecular orbitals (FMOs) analysis Nowadays frontier molecular orbitals analysis is well known to explain the reactivity of compounds [21] by using different computational methods The HOMO/ LUMO band gap has direct correlation with the reactivity, e.g if the band is less the compound will be kinetically less stable (more reactive) and vice versa [22] The FMOs analysis of all derivatives (3a–3p) was carried out by using B3LYP/6-31G(d,p) basis set As observed from the HOMO/LUMO, the trend of dispersion of isodensity was almost similar in all compounds Therefore, as a model here we have given the HOMO/LUMO surfaces of compound 3a only (Fig. 1) (the rest are provided in Additional file 1: Figure S1) The corresponding HOMO and LUMO energies along with band gap are narrated in Table 2 Scheme 1 Synthesis of 2-bromo-3-methyl-5-arylthiophenes (3a–k) and 2,5-diaryl-3-methyl thiophenes (3l–p) Conditions: (i) (128 mg, 0.5 mmol, eq), (0.55 mmol, 1.1 eq), Pd(PPh3)4 (14.5 mg, 2.5 mol%), K3PO4 (212 mg, 1.0 mmol, eq), 1,4-dioxane (2.5 ml), H 2O (0.625 ml), 12 h, 90 °C under argon (ii) (128 mg, 0.5 mmol, eq), (1.25 mmol, 2.5 eq,), Pd(PPh3)4 (34.6 mg, 6 mol%), K3PO4 (424 mg, 2.0 mmol, eq), 1,4-dioxane (2.5 ml), H2O (0.625 ml), 12 h, 90 °C under argon Rizwan et al Chemistry Central Journal (2018) 12:49 Page of 12 Table 1 Substrate scope of Suzuki cross coupling reaction of 2,5-dibromo-3-methyl thiophene with variety of arylboronic acids 3a (HOMO) 3a (LUMO) Fig. 1 HOMO/LUMO surfaces of compounds (3a) The isodensity in HOMO of all compounds is dispersed on the benzene and thiophene moieties along with the groups attached to the main skeleton It is clearly reflected from Fig. 1, that in HOMO orbitals the methyl group attached to the thiophene ring and the groups attached to the para position are directly involved in electronic cloud and electronic transition Whereas isodensity in LUMO of all compounds reflected the similar Rizwan et al Chemistry Central Journal (2018) 12:49 Page of 12 Table 2 HOMO and LUMO energies, along with band gap Compounds no EHOMO (eV) ELUMO (eV) ΔE (eV) 3a − 5.93 − 1.39 4.54 − 5.83 − 1.38 4.45 − 1.69 4.15 − 1.77 4.31 − 1.05 4.55 − 1.40 4.50 − 0.86 4.12 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3m 3n 3o 3p − 5.39 − 5.99 − 5.84 − 5.39 − 6.08 − 5.60 − 5.60 − 6.04 − 5.91 − 5.81 − 4.98 − 5.06 − 5.24 6.05 − 0.92 4.47 − 1.50 4.49 − 1.12 4.26 − 1.06 4.52 − 1.43 4.61 − 1.59 4.21 − 1.16 3.89 − 1.38 4.67 − 1.04 4.19 trend, the methyl attached to thiophene ring and groups attached to the ortho position of benzene did not participate in electronic cloud The HOMO–LUMO band gap in all compounds found in the range 3.89–4.67 eV The smallest band gap observed for 3n i.e 3.89 eV and largest band gap observed for 3p i.e 4.67 eV HOMO–LUMO band gap is reflecting that 3n is most reactive and less stable among all, whereas 3p is most stable and less reactive This is might be that 3n has more planer structure, due to which transition of electrons is more feasible, whereas in 3p the structure is non-planer and does not facilitating the promotion of electrons to higher orbitals easily Molecular electrostatic potential (MEP) Molecular electrostatic potential study by using quantum chemical tools is useful to explain reactivity, charge separations and monovalent interactions of molecules [23] ESP analysis of compounds 3a–3p was computed by using DFT/B3LYP/6-31G(d,p) basis and graphics (Fig. 2) The range of MEP values of all compounds are given in Additional file 1: Table S1 In ESP analysis, the dispersion of electronic density is explained on the basis of different colors e.g the red color indicates the –ve potential and blue color is indicative of +ve potential [24] It is cleared from ESP analysis that the electronic density in every compound is dispersed with respect to the electronic effect of group attached to the benzene moiety The groups attached to the para position of benzene ring have direct effect on the electronic cloud of whole molecule In 3a, the electron withdrawing group (fluoro) is attached to the benzene ring, due to which the –ve potential is dispersed bromo, chloro and fluoro groups instead of concentrating on benzene ring Whereas in 3b the –ve potential is concentrated on benzene and thiophene ring due to electron donating effect of –OCH3 attached to the para position on benzene ring Almost similar kind of effect is observed in ESP analysis of all other synthesized derivatives If electron donating group is attached to the ortho or para position of benzene moiety the electronic density is concentrated on the benzene and thiophene rings (rather the electronic density also depends on the electron donating ability of group as well), such as in compounds 3c, 3f, 3g, 3h, 3i, 3k, 3m, 3n, 3o and 3p In all these molecules the –ve potential is concentrated on the benzene and thiophen rings, whereas in the rest of molecules the –ve potential is concentrated on the different groups attached at the different positions of scaffolds (Fig. 2) Antioxidant activity by DPPH radical scavenging assay Antioxidants have been broadly studied for their capability to protect cells and organisms from the harm induced by reactive oxidative species (ROS) [25, 26] So, scientists are more interested to find sources for antioxidants which may be either natural or synthetic The DPPH radical has been widely used for determining antioxidant activity of various systems [27] DPPH radical is purple in colour and antioxidants decay that purple colour of DPPH by capturing free radicals The potential of DPPH scavenging can be quantified by noting absorbance at 517 nm A study was designed to determine the antioxidant potential of some novel thiophene derivatives (3a–k and 3l–p), by DPPH radical scavenging assay (Table 3) Ascorbic acid was used as control which exhibited 100% DPPH scavenging at 50 µg/ml The compounds 3l, 3g, 3j, showed excellent antioxidant activity (86.0, 82.0, and 81.3%), respectively by scavenging DPPH It is noted that some compounds (3d, 3n) showed mild antioxidant activity with 48.2, 40.9% DPPH radical scavenging at 50 µg/ml However other compounds showed significant antioxidant activity by scavenging DPPH while some compounds exhibited low activity (Table 3) Mabkhot and coworkers found some thiophene moiety containing compounds inactive towards scavenging DPPH and proved them poor antioxidants [28] The substituents on ring system have pronounced effect on DPPH radical scavenging [29] So, in light of this reference, this may be cause of variability in DPPH radical scavenging of thiophene based compounds Antibacterial activity Thiophene and its various derivatives have been reported for potential anti-microbial activity [30–32] To overcome the drug resistance issues it is very important to Rizwan et al Chemistry Central Journal (2018) 12:49 Fig. 2 ESP maps of compounds 3a–3p, calculated at DFT/B3LYP/6-31G(d,p) level Page of 12 Rizwan et al Chemistry Central Journal (2018) 12:49 Page of 12 Table 3 Antioxidant potential of compounds (3a–k and 3l– p) by DPPH radical scavenging activity Entry Compounds no Percentage inhibition at 50 µg/ml 3a 33.4 ± 0.29 3b 23.9 ± 0.31 3c 37.5 ± 0.42 3d 48.2 ± 0.42 3e 38.5 ± 0.42 3f 39.2 ± 0.42 3g 82.0 ± 0.78 3h *** 3i 28.9 ± 0.45 10 3j 81.3 ± 0.72 11 3k 21.9 ± 0.32 12 3l 86.0 ± 0.73 13 3m 1.19 ± 0.02 14 3n 40.9 ± 0.21 15 3o 15.1 ± 0.21 16 3p 30.9 ± 0.29 17 Ascorbic acid 100 ± 0.99 *** Showed no activity The results are average ± SD of triplicate experiments p