- Research Article
- Open Access
Facile synthesis of N- (4-bromophenyl)-1- (3-bromothiophen-2-yl)methanimine derivatives via Suzuki cross-coupling reaction: their characterization and DFT studies
© The Author(s) 2018
- Received: 2 June 2018
- Accepted: 5 July 2018
- Published: 17 July 2018
- Suzuki coupling
- Density functional theory
Imines are an important class of organic compounds and these are synthesized by condensation of primary amines with carbonyl compounds (aldehyde or ketone). They are carrying a (–C=N–) functional group and also known as azomethine . These are pharmaceutically well known for broad spectrum biological activities including antimicrobial , analgesic , anticonvulsant , anticancer , antioxidant , antihelmintic  and many others. Imines are also key component of pigments, dyes, polymer stabilizers, corrosion inhibitors and also used as catalyst and intermediate of various organic reactions . Role of Imines for development of coordination chemistry, inorganic biochemistry is well known . These have been utilized for synthesis of biologically and industrially active compounds via ring closure, replacement and cycloaddition reactions . So, keeping in view the importance of imine functional group we synthesized a novel series of thiophene based imines via Suzuki cross coupling reaction and computational studies of synthesized derivatives was carried to determine their pharmaceutical potential.
In present studies the Suzuki cross coupling of N-(4-bromophenyl)-1-(3-bromothiophen-2-yl)methanimine (3) with various arylboronic acids has been investigated. According to best of our knowledge no such study about derivatization of imines via Suzuki cross coupling reaction has been reported before.
In additionally, we noted that regio selectivity, when reactions was carried out with 1 eq. boronic acids. Therefore during the transmetallation, bromide moiety of the phenyl ring eliminated rather than bromide mioty present of thiophene part of the substrate, the reason is that no steric hindrance was observed. It is also observed that hydrolysis of imine linkage was not occurred during oxidation, addition, transmetallation, even reductive elimination. While various research groups reported the imine bond cleavage during different Catalytic reaction pathway [10–12]. Herein fortunately, moderate to very good yield of the final products were observed without breaking the imine linkage. So we concluded that imine linkage of this substrate is stable and does not break during catalytic reaction conditions, PH, high temperature and even using the base.
Density functional theory (DFT) studies
To find the structural properties and reactivity’s of synthesized molecules the DFT studies were computed by using GAUSSIAN 09 software. First of all, molecules (3a–3i) were optimized by using B3LYP/6-31G(d,p) basis set along with the frequency analysis. After optimization the energy minimized structures were used further for the conceptual DFT reactivity descriptors [13, 14] and molecular electrostatic potential (MEP) analysis on the same basis set.
Molecular electrostatic potential analysis
MEP values of all compounds (3a–3i)
−ve potential (a. u.)
+ve potential (a. u.)
Ionization potential (I), electron affinity (A), chemical hardness (η), electronic chemical potential (µ), electrophilicity index (ω) nucleophilicity index (N), Fukui function (f k + and f k ¯ )
f k +
f k −
Conceptual DFT reactivity descriptors
The conceptual DFT reactivity descriptors such as ionization potential (I), electron affinity (A), chemical hardness (η), electronic chemical potential (µ), electrophilicity index (ω)  nucleophilicity index (N)  Fukui functions (f k + and f k ¯ ) as well as Parr functions [19, 20] are very helpful for the explanation of the reactivity of any molecule. The values of all important reactivity descriptors of all compounds are given in the Table 3. As per accordance with Koopmans’ theorem of closed-shell compounds, the energy values of the highest occupied molecular orbital (EHOMO) and the lowest unoccupied molecular orbital (ELUMO) correspond to the ionization potential (I) and electron affinity (A), respectively . With the help of these values chemical hardness (η), electronic chemical potential (µ), electrophilicity index (ω) and can be determined easily.
Tetracyanoethylene (TCE) is used as a reference standard because it has the lowest HOMO energy in a large series of organic molecules which are considered already. The nucleophilicity index of all synthesized compounds (3a–3i) is found in the range of 3.21–4.59 eV. Among all the lowest value of N is for 3c, i.e. of 3.21 eV, which is classified as soft nucleophile and highest value is 3i, i.e. of 4.59 eV (strongest nucleophile among all).
The highest values of f k + and f k ¯ of all compounds are given in the Table 3. The Fukui functions results are in total agreement with the ESP results. In all compounds almost the all the hetro atoms (N and S) sites are favorable for the electrophilic attack (for detailed values see Table 3).
Electrophilic (P k + ) and nucleophilic (P k − ) Parr functions, local electrophilicity (ωk) and local nucleophilicity (Nk) of all compounds (3a–3i)
P k +
P k −
Frontier molecular orbitals analyses by using FERMO concept
FERMO concept is recently introduced in the literature where frontier orbitals other than HOMO and LUMO are taken into account to explain the reactivities of compounds under consideration [28–30]. In the FERMO concept, adequate orbital shape and composition are correlated with the reactivity indexes. It has been realized that a frontier molecular orbital other than HOMO and LUMO may have large contribution on atoms present at the active site. These frontier orbitals can fit the orbital choice criterion because they are present in all compounds under study and better correlate with the experimental observation rather than HOMO and LUMO.
Melting points were determined with help of (Buchi B-540) melting point apparatus (Buchi, New Castle, DE, USA). Proton (1H) NMR and Carbon (13C) NMR spectra were obtained in CDCl3 at 500/126 MHz (Bruker, Billercia, MA, USA), respectively. EI-MS spectra were obtained on JMS-HX-110 spectrometer (JEOL, Peabody, MA, USA). Silica gel (70–230 mesh) was used for purification of compounds in column chromatography. The reactions were monitored on TLC, using Merck silica gel 60 PF254 cards. Visualization of compounds was done by using UV lamp (254–365 nm).
General procedure for synthesis of Schiff base N-(4-bromophenyl)-1-(3-bromothiophen-2-yl)methanimine
First of all round bottom flask took and dried in an oven. 4-bromoaniline in ethanolic solution was condensed with 3-bromothiophene-2-carbaldehyde in the presence of few drops of glacial acetic acid. Then the mixture was refluxed for 6–10 h on water bath. After 6–10 h yellow coloured Schiff base was filtered, washed and purified by column chromatography .
General procedure for Suzuki coupling of Schiff base with arylboronic acids
The palladium catalyst Pd(PPh3)4 was added in N-(4-bromophenyl)-1-(3-bromothiophen-2-yl)methanimine (3), under nitrogen gas. The 1,4-dioxane was used as solvent and reaction mixture stirred for 30 min. After that arylboronic acid, K3PO4 and water were added [32, 33] and mixture was stirred for 12 h at 90 °C. After cooling to normal temperature, the mixture was diluted with ethyl acetate. After separation the organic layer was dried with MgSO4 and the solvent was removed under vacuum. The purification of crude residue was done by column chromatography by using ethyl-acetate and n-hexane, and further characterization was done by using different spectroscopic techniques.
Obtained as solid, mp = 114 °C, 1H NMR (500 MHz, CDCl3): δ 8.65 (s, 1H), 7.48 (d, J = 7.0, 2H), 7.15 (d, J = 6.8 Hz, 2H), 7.35 (d, J = 6.5 Hz, 1H), 6.75 (d, J = 5.8 Hz, 1H); 13C NMR (126 MHz, CDCl3): δ 150.1, 145.2, 132.9, 130.1, 125.7, 124.9, 124.5, 123.4, 122.1, 120.1, 109.1. EI/MS m/z (%): 346.0 [M+H]+; 347 [M+2]; 349 [M+4]; [M-Br] = 263.0, [M-2Br] = 186.1.
Obtained as solid, mp = 125 °C, 1H NMR (500 MHz, CDCl3): δ 9.75 (s, 1H), 7.78 (dd, J = 5.0, 1.5 Hz, 1H), 7.55(dd, J = 7.0, 2.5 Hz, 2H), 7.38–7.35 (m, 3H), 7.29–7.26 (m, 2H), 7.21 (d, J = 5.0 Hz, 1H); 13C NMR (126 MHz, CDCl3): δ 148.5, 138.9, 134.5, 132.2, 131.5, 131.1, 131.0, 130.4, 129.4, 129.3, 122.7, 121.9, 121.6, 117.1, 116.9, 116.4, 110.5. EI/MS m/z (%): 393.0 [M+H]+; 394.5 [M+2];396.5 [M+4]; [M-Br] = 314.0; [M-Cl, F] = 260.4.
Obtained as solid, mp = 131 °C, 1H NMR (500 MHz, CDCl3): δ 9.91 (s, 1H), 8.52 (d, J = 5.0 Hz, 1H), 7.73 (d, J = 2.0 Hz, 2H), 7.52–7.46 (m, 3H), 7.28–7.04 (m, 3H), 2.41 (s, 6H); 13C NMR (126 MHz, CDCl3): δ 153.7, 145.1, 142.1, 138.4, 137.6, 133.9, 132.1, 131.1, 130.6, 130.1, 129.0, 128.0, 127.4, 126.5, 122.8, 121.7, 120.1, 21.9, 21.5. EI/MS m/z (%): 371.0 [M+H]+; 372.1[M+2]; [M-Br] = 290.0; [M-2CH3] = 339.0.
Obtained as solid, mp = 128 °C, 1H NMR (500 MHz, CDCl3): δ 8.62 (s, 1H), 7.80–7.79 (m, 3H), 7.60–7.58 (m, 3H), 7.52–7.50 (m, 2H), 6.57 (d, J = 9.0 Hz, 1H), 13C NMR (126 MHz, CDCl3): δ 152.9, 146.4, 141.8, 137.8, 133.0, 132.0, 130.9, 130.1, 129.0, 128.9, 128.0, 127.5, 127.1, 124.8, 122.8, 122.1, 114.4. EI/MS m/z (%): 409.0 [M+H]+; 410.1[M+2]; 412.1 [M+4]; 414.1 [M+6], [M-2Cl] = 337.9.
Obtained as solid, mp = 135 °C, 1H NMR (500 MHz, CDCl3): δ 8.82 (s, 1H), 7.96 (d, J = 3.0 Hz, 2H), 7.48 (d, J = 7.0 Hz, 2H), 7.35 (m, 4H), 6.90 (m, 2H), 13C NMR (126 MHz, CDCl3): δ 150.1, 146.7, 141.2, 140.1, 134.9, 130.1, 129.9, 129.3, 127.8, 126.9, 125.6, 123.9, 123.4, 122, 121.1, 120.2, 112.1. EI/MS m/z (%): 377.0 [M+H]+; 378.1 [M+2]; 380.4 [M+4], [M-Cl] = 339.9, [M-aryl, Cl fragments] = 264.0.
Obtained as solid, mp = 142 °C, 1H NMR (500 MHz, CDCl3): δ 8.72 (s, 1H), 7.86 (m, 4H), 7.44 (d, J = 6.98 Hz, 2H), 7.00 (m, 2H), 6.97 (m, 2H), 3.65 (s, 3H). 13C NMR (126 MHz, CDCl3): δ 160.2, 154.1, 148.2, 140.1, 134.1, 132.1, 131.3, 130.2, 129.1, 125.1, 124.1, 123.1, 122.1, 120.1, 115.6, 113.1, 109.1, 56.1. EI/MS m/z (%): 373.0 [M+H]+; 374.1 [M+2], [M-OMe] = 340.1 [M-Br, OMe] = 261.1.
Obtained as solid, mp = 128 °C, 1H NMR (500 MHz, CDCl3): δ 8.72 (s, 1H), 7.90 (d, J = 5.0 Hz, 2H), 7.82 (d, J = 7.0 Hz, 2H), 7.31 (m, 4H), 6.90 (m, 2H), 13C NMR (126 MHz, CDCl3): δ 151.1, 146.2, 140.2, 139.1, 137.9, 132.1, 129.9, 129.2, 128.1, 127.0, 124.6, 123.5, 123.1, 122.0, 121.1, 120.1, 111.1. EI/MS m/z (%): 377.0 [M+H]+; 378.1 [M+2]; 380.4 [M+4], [M-Cl] = 339.9.
Obtained as solid, mp = 125 °C, 1H NMR (500 MHz, CDCl3): δ 8.61 (s, 1H), 7.92 (m, 6H), 7.61 (d, J = 6.58 Hz, 2H), 7.75 (d, J = 7.25 Hz, 2H), 7.20 (m, 2H), 13C NMR (126 MHz, CDCl3): δ 160.1, 156.7, 150.1, 145.1, 139.0, 137.9, 136.8, 134.5, 131.9, 130.8, 130.1, 129.9, 129.1, 128.3, 127.1, 123.8, 122.9, 122.1, 121.1, 120.1, 119.7, 118.1, 116.1. EI/MS m/z (%): 445.4 [M+H]+; 446.1 [M+2]; 448.1 [M+4]; [M-2Cl] = 375.0; [M-2Cl, F] = 357.4.
Obtained as solid, mp = 127 °C, 1H NMR (500 MHz, CDCl3): δ 8.51 (s, 1H), 7.82 (m, 4H), 7.61 (d, J = 5.58 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H), 7.10 (m, 4H), 2.50 (s, 12H). 13C NMR (126 MHz, CDCl3): δ 153.1, 148.1, 141.1, 1401.1, 139.8, 139.1, 138.1, 137.1, 136.1, 135.1, 131.1, 130.9. 130.1, 129.9, 129.1, 128.4, 128.1, 127.1, 126.8, 126.1, 125.1, 121.4, 120.1, 21.8, 21.0, 20.1, 19.8. EI/MS m/z (%): 396.1 [M+H]+; [M-CH3] = 382.0; [M-4CH3] = 338.1.
Obtained as solid, mp = 140 °C, 1H NMR (500 MHz, CDCl3): δ 8.72 (s, 1H), 7.71 (m, 6H), 7.61 (m 2H), 7.52 (m, 2H), 7.10 (m, 4H), 3.50 (s, 6H). 13C NMR (126 MHz, CDCl3): δ 160.1, 158.1, 152.5, 147.1, 139.1, 136.1, 131.1, 133.2, 130.9, 130.2, 129.9, 129.2, 128.2, 127.9, 127.0, 122.9, 122.1, 121.4, 120.9, 114.9, 114.2, 113.1, 112.1, 55.8, 55.0. EI/MS m/z (%): 400.3 [M+H]+; [M-CH3] = 3368.0 [M-2CH3] = 338.0.
Calculations were performed with the help of GAUSSIAN 09 software , visualization of results and graphics were executed by using GaussView 05 program . The geometries of all compounds (3a–3i) were optimized at B3LYP/6-31G(d,p) level of DFT and confirmed with the help of vibrational analysis (no single imaginary frequency). The optimized geometries further used for conceptual DFT reactivity descriptors including the Fukui as well as Parr functions and molecular electrostatic potential (MEP) analyses at the same level of theory.
In present study we have synthesized a variety of thiophene based imine derivatives (3a–3i) via Palladium catalyzed Suzuki reaction in moderate to good yields (58–72%). Both electron donating and withdrawing groups were well tolerated in reaction conditions. DFT studies reflect that all molecules (3a–3i) are relatively less stable and more reactive. The reactivity descriptors revealed that 3i is most reactive among all the synthesized derivatives. The MEP analysis reelects that negative potential lies on the N=CH moiety in all derivatives (3a–3i). The local electrophilicity results shows that among all the 3i is most electrophilic in whereas 3c is most nucleophilic among all synthesized compounds. In light of this research, synthesized Imine derivatives might be a potential source of therapeutic agents. Future investigations in this dimension will provide new visions towards development of novel pharmaceutically important drugs.
KR, NR, RR, GA, AM significantly contributed to experimental work of this research, analysis and drafting of manuscript. SAK, MNA, NBA and MNA contributed for analysis and interpretation of data. TM, KA and TR contributed towards computational studies. All authors read and approved the final manuscript.
This work was supported by the research Projects RDU150349 and 150109 from Universiti Malaysia Pahang, Malaysia. The authors also gratefully acknowledge the financial support by HEC (HEC Project No. 20-1465/R&D/09/5458).
All authors declare that they have no competing interests.
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