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. 2016 Jun 28;17(7):912.
doi: 10.3390/ijms17070912.

One Pot Selective Arylation of 2-Bromo-5-Chloro Thiophene; Molecular Structure Investigation via Density Functional Theory (DFT), X-ray Analysis, and Their Biological Activities

Nasir Rasool  1 , Aqsa Kanwal  2 , Tehmina Rasheed  3 , Quratulain Ain  4 , Tariq Mahmood  5 , Khurshid Ayub  6 , Muhammad Zubair  7 , Khalid Mohammed Khan  8 , Muhammad Nadeem Arshad  9   10 , Abdullah M Asiri  11   12 , Muhammad Zia-Ul-Haq  13 , Hawa Z E Jaafar  14
Affiliations

One Pot Selective Arylation of 2-Bromo-5-Chloro Thiophene; Molecular Structure Investigation via Density Functional Theory (DFT), X-ray Analysis, and Their Biological Activities

Nasir Rasool et al. Int J Mol Sci. .

Abstract

Synthesis of 2,5-bisarylthiophenes was accomplished by sequential Suzuki cross coupling reaction of 2-bromo-5-chloro thiophenes. Density functional theory (DFT) studies were carried out at the B3LYP/6-31G(d, p) level of theory to compare the geometric parameters of 2,5-bisarylthiophenes with those from X-ray diffraction results. The synthesized compounds are screened for in vitro bacteria scavenging abilities. At the concentration of 50 and 100 μg/mL, compounds 2b, 2c, 2d, 3c, and 3f with IC50-values of 51.4, 52.10, 58.0, 56.2, and 56.5 μg/mL respectively, were found most potent against E. coli. Among all the synthesized compounds 2a, 2d, 3c, and 3e with the least values of IC50 77, 76.26, 79.13 μg/mL respectively showed significant antioxidant activities. Almost all of the compounds showed good antibacterial activity against Escherichia coli, whereas 2-chloro-5-(4-methoxyphenyl) thiophene (2b) was found most active among all synthesized compound with an IC50 value of 51.4 μg/mL. All of the synthesized compounds were screened for nitric oxide scavenging activity as well. Frontier molecular orbitals (FMOs) and molecular electrostatic potentials of the target compounds were also studied theoretically to account for their relative reactivity.

Keywords: 2-bromo-5-chloro thiophenes; Suzuki coupling; antibacterial; antioxidant; density functional theory (DFT).

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Figures

Scheme 1
Scheme 1
Synthesis of compounds 2a–f. R: 2a = 4-Me, 2b = 4-MeO, 2c = 4-Cl, 2d = 3-Cl,4-F, 2e = 3,5-dimethyl, and 2f = 3,4-dichloro.
Figure 1
Figure 1
Scope of the compounds 2a–f.
Scheme 2
Scheme 2
Scope of the compounds of compounds 3a–f. R: 3a = 4-Me, 3b = 4-MeO, 3c = 4-Chloro, 3d = 3-Chloro-4-fluoro, 3e = 3,5-dimethyl, and 3f = 3,4-dichloro.
Figure 2
Figure 2
Synthesis of compounds 3a–f.
Figure 3
Figure 3
ORTEP plots of 2d and 2f.
Figure 4
Figure 4
Unit cell diagrams of 2d and 2f. (Ball color: green, Cl; red, F; yellow, S; black and blue, C).
Figure 5
Figure 5
Optimized geometries of 2d and 2f at B3LYP/6-31G (d, p) level of DFT.
Figure 6
Figure 6
HO/LU orbitals of 2a–f and 3a–f.
Figure 7
Figure 7
Molecular electrostatic potential (MEP) graphics of mono substituted (2a–f) and di-substituted (3a–f) thiophenes (Red = Intense electron rich site, Yellow = Medium electron rich site site, Blue = Electron deficient site, Light green = Almost neutral site, Grey = White = Zero potential).
Figure 7
Figure 7
Molecular electrostatic potential (MEP) graphics of mono substituted (2a–f) and di-substituted (3a–f) thiophenes (Red = Intense electron rich site, Yellow = Medium electron rich site site, Blue = Electron deficient site, Light green = Almost neutral site, Grey = White = Zero potential).
Figure 8
Figure 8
IC50 values of antibacterial activity.
Figure 9
Figure 9
IC50 values of nitric oxide scavenging activity.
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