organic compounds
Methyl 3-[(1,1-dioxo-1λ6,2-benzothiazol-3-yl)amino]-5-nitrothiophene-2-carboxylate
aDepartment of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Ernst-Moritz-Arndt-University, Friedrich-Ludwig-Jahn-Str. 17, Greifswald, D-17489, Germany, bCouncil Scientific and Industrial Research (CSIR) Head Quarter, Anusandhan Bhavan, 2 Rafi Marg, Delhi-110001, India, and cChemical Faculty, Gdańsk University of Technology, G. Narutowicza 11/12, PL-80233 Gdańsk, Poland
*Correspondence e-mail: haridas.rode@csir.res.in
The title nitrothiophene compound, C13H9N3O6S2, crystallizes with two independent molecules in the the molecular structure of each is stabilized by an intramolecular N—H⋯O hydrogen bond. The two molecules adopt flattened but slightly different conformations, viz. the dihedral angle between the thiophene ring and the essentailly planar 1,2-benzisothiazole fragment (r.m.s. deviations = 0.0227 and 0.0108 Å, respectively) is 15.62 (11)° in one molecule and 5.46 (11)° in the other. In the crystal, molecules are arranged into layers parallel to (-111) with weak Car—H⋯O interactions formed within the layer. N—H⋯O hydrogen bonds also occur. There are π–π stacking interactions between the molecules in neighbouring layers, the distance between the centroids of the 1,2-benzisothiazole benzene rings being 3.8660 (16) Å. Moreover, dipolar S=O⋯C=O interactions with an O⋯C distance of 2.893 (3) Å are observed between the symmetry-independent molecules in different layers. The title compound showed weak inhibition of HLE (human leukocyte elastase).
Related literature
For general information on elastases, see: Bode et al. (1989); Edwards & Bernstein (1994). For biochemical assays of HLE inhibition, see: Rode et al. (2005, 2006). For information on the synthesis, see: Wade et al. (1979); Gupta et al. (1999).
Experimental
Crystal data
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Data collection
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Refinement
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Data collection: CrysAlis PRO (Oxford Diffraction, 2009); cell CrysAlis PRO; data reduction: CrysAlis PRO; program(s) used to solve structure: SUPERFLIP (Palatinus & Chapuis, 2007); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 (Farrugia, 1997); software used to prepare material for publication: publCIF (Westrip, 2010), PLATON (Spek, 2003), WinGX (Farrugia, 1999) and Mercury (Macrae et al., 2006).
Supporting information
https://doi.org/10.1107/S1600536812038378/gk2503sup1.cif
contains datablocks global, I. DOI:Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S1600536812038378/gk2503Isup2.hkl
Supporting information file. DOI: https://doi.org/10.1107/S1600536812038378/gk2503Isup3.cml
Synthesis of 2
3-Chlorobenzo[d]isothiazole 1,1-dioxide 1 (Figure 1) (3.00 g, 14.88 mmol) and 2.33 g of methyl 3-aminothiophene-2-carboxylate (14.88 mmol) were refluxed in 70 ml of dioxane. After cooling to room temperature, the solid was filtered off and washed with a little acetone. The solid was dried to give the analytically pure compound. Yield: 3.96 g (83%); M.p. 284–287°C, Rf = 0.87 (AcOEt/PE 8:2).
Synthesis of 3
To a cooled (-30 °C) and stirred solution of 2 (2.00 g, 6.20 mmol) in 95% H2SO4 (10 ml), 2 ml of concentrated HNO3 were added. The mixture was stirred at -30 °C for 45 minutes and allowed to warm to room temperature. The viscous liquid was poured on ice (10 g) and the resulting aq. phase extracted with dichloromethane (3 × 100 ml). The organic phase was separated, dried with sodium sulfate and evaporated in vacuo. The solid was crystallized from dichloromethane: methanol (9:1). Yield: 0.40 g (18%); M.p. 285–287°C (MeOH/CH2Cl2); Rf = 0.80 (AcOEt/PE 8:2).
See '_exptl_special_details' in the
file for more information.The positions of C-bound H atoms were calculated geometrically and refined in a riding model approximation with C-H bond lengths in the range 0.93–0.96 Å and Uiso(H) = 1.4Ueq(C). The amino hydrogen atoms H2A and H5A were found from difference Fourier maps and freely refined.
Elastases are endopeptidases (serine proteases) which by definition are able to solubilize elastin by proteolytic cleavage and are possibly the most destructive enzymes in the human body, having the ability to degrade virtually all connective tissue components (Bode et al. 1989). Uncontrolled proteolytic degradation by elastase has been implicated in a number of pathological conditions including ARDS (Adult Respiratory Distress Syndrome) and lung injury, cystic fibrosis, pulmonary emphysema, smoking related chronic bronchitis and rheumatoid arthritis (Edwards et al. 1994). Therefore considerable research has been focused on developing potent inhibitors or drugs against HLE (Human Leukocyte Elastase). Potent elastase inhibitors are based on peptidic, heterocyclic and non-heterocyclic scaffolds. Of interest are the heterocyclic inhibitors as these small molecules potentially offer advantages over the larger, peptide based inhibitors due to their increased proteinase stability, increased oral absorption and decreased structural complexity. In our earlier reports, we described peptidic and heterocyclic elastase inhibitors and illustrated that the pseudosaccharin amine derivatives are potential inhibitors of elastase (Rode et al. 2005, Rode et al. 2006). Pseudosaccharin α - position of thiophene to produce 3. Here we report the structural assignment of the thiophene derivative 3 using NMR spectroscopy and single crystal XRD. Compound 3 show weak inhibition of PPE (Porcine Pancreatic Elastase) and HLE.
were further explored to synthesize analogues containing thiophene and thiazole components. During the nitration of the thiophene analogue 2 (see Figure 1), we observed the electrophilic attack of a nitro group at theThe synthesis of pseudosaccharin chloride 1 (see Figure 1) was carried out according to the literature procedure (Wade et al., 1979). The reaction between 1 and methyl 3-aminothiophene-2-carboxylate resulted in a brown colored solid 2. This solid was treated in a nitrating mixture at -30 °C yielding C13H9N3O6S2, 3. The compound was further analysed as decribed below.
Compound 3 crystallizes with two independent molecules in the
(Z=4). An ORTEP view of the is shown in Figure 2. The molecules are chemically identical and the most significant differences are in dihedral angles between related NO2 groups and the aromatic ring and dihedral angle between thiophene and benzene mean planes. To be more specific: the torsion angles differ by ca. 14° [C9—C10—N3—O3 -9.3 (4) ° and C22—C23—N6—O9 4.9 (4)°] and the dihedral angles by ca. 10° [benzene C1-C6 and thiophene C8-C11-S2 form angle 15.50 (13)°, the related rings 5.41 (13)°]. Apart from that the molecules are very similar, overlay of the molecules by fitting all 24 non-hydrogen atoms gives mean r.m.s. deviation of 0.217 Å with maximum distance of 0.552 Å between O9 and O3 in nitro groups (Mercury 3.0, Macrae et al. 2006).The crystal packing is presented in Figure 3. Both molecules are placed in a layer parallel to the (-1 1 1) plane. Such planes spread throughout the crystal forming specific packing pattern. The only intramolecular hydrogen bonds are N2—H···O5 and N5—H···O11 in both molecules, respectively (Table 1). There are also weak C(aromatic)—H···O interactions between the molecules ( Table 1). One can also expect stacking interactions between the aromatic rings, but analysis with PLATON (Spek, 2003) reveals that most of the rings are too far away. The closest benzene rings C14–C19 are related by the symmetry center at 3/2, 0, 1 and their centroids are separated by the distance of 3.8660 (16) Å with perpendicular distance between the planes of 3.5883 (11) Å. Other ring centroids are separated by more than 4 Å. Noteworthy, short O1···C25i and O9ii···C12 contacts resemble transient states in early stages of the nucleophilic attack of negatively charged oxygen atoms on the partly positively loaded carbon atom in carbonyl groups.
General description and spectral properties
In the 1H NMR spectrum of 3, a sharp singlet appeared at δ 8.55 p.p.m. assignable to a proton of the thiophene ring. Information obtained from 1H NMR, 13C NMR, DEPT, HMQC and HMBC reveals that a carbon at δ 125.58 p.p.m. is assignable to a thiophene carbon bearing a proton, while carbons at δ 123.06, 133.65, 134.30, 121.74 p.p.m. are assignable to CH of the pseudosaccharin scaffold. A coupling is observed between a proton of the pseudosaccharin scaffold and a carbon at δ 157 p.p.m., allowing us to assign δ 157 p.p.m. for the carbon of C=N. Also a coupling between the methoxy group signal at δ 3.93 p.p.m. of thiophene scaffold and that of the carbonyl group at δ 161 p.p.m. was observed in HMBC. No coupling was observed between a proton at δ 8.55 p.p.m. (thiophene bearing proton) and any of the carbons of thiophene ring. If both the nitro-isomers i.e. 4-nitro analog (structure not shown) and 5-nitro analog (3) could have been isolated, that would have helped to solve the structure of 3 based on the relative chemical shifts. But only one isomer was obtained. Although the possibility of formation of the other isomer cannot be ruled out as in the 1H NMR spectrum of the crude product, more products were indicated but these products could easily be neglected in crystallization and only one isomer was obtained as a major product. Therefore the structure of the nitro thiophene analogue was determined by X-ray crystallography and in fact the product was found to be the 5'-nitro analogue 3. It is important to note that the thiophene undergoes electrophilic substitution reactions slowly and selectively at an α-position to sulfur rather than at β-position. The preferential electrophilic attack at an α-position in thiophene may be explained on the basis of stability of the transition state (Gupta et al., 1999).
Compound 3 was tested for its ability to inhibit PPE (Porcine Pancreatic Elastase) and HLE (Human Leukocyte Elastase) activity in the biochemical assay. More information on elastase can be found elsewhere (e.g. Bode et al. (1989); Edwards & Bernstein, 1994; Rode et al., 2005). The detailed description of these biochemical assays is reported in our earlier work (Rode et al., 2006). It is important to note that compound 3 inhibited 32% activity of PPE at 100 µM concentration and 15% activity of HLE at 200 µM concentrations. Although 3 has shown weak inhibition of HLE and PPE, it may serve as a starting point for developing potent HLE inhibitors.
For general information on elastases, see: Bode et al. (1989); Edwards & Bernstein (1994). For biochemical assays of HLE inhibition, see: Rode et al. (2005, 2006). For information on the synthesis, see: Wade et al. (1979); Gupta et al. (1999).
Data collection: CrysAlis PRO (Oxford Diffraction, 2009); cell
CrysAlis PRO (Oxford Diffraction, 2009); data reduction: CrysAlis PRO (Oxford Diffraction, 2009); program(s) used to solve structure: SUPERFLIP (Palatinus & Chapuis, 2007); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 (Farrugia, 1997); software used to prepare material for publication: publCIF (Westrip, 2010), PLATON (Spek, 2003), WinGX (Farrugia, 1999) and Mercury (Macrae et al., 2006).Fig. 1. Reagents and conditions: (i) methyl 3-aminothiophene-2-carboxylate, dioxane, reflux, 2 h; (ii) conc. H2SO4, conc. HNO3, -30 °C, 45 min. | |
Fig. 2. Molecular structure and labeling scheme for 3. Displacement ellipsoids are drawn at the 50% probability level. | |
Fig. 3. Crystal packing of the title compound. The two symmetry independent molecules (coloured green and blue) bound by Car-H···O interactions form layers parallel to (-1 1 1). |
C13H9N3O6S2 | Z = 4 |
Mr = 367.35 | F(000) = 752 |
Triclinic, P1 | Dx = 1.619 Mg m−3 |
Hall symbol: -P 1 | Melting point = 558–560 K |
a = 8.4462 (7) Å | Mo Kα radiation, λ = 0.71073 Å |
b = 12.5495 (11) Å | Cell parameters from 4406 reflections |
c = 15.2557 (14) Å | θ = 2–30° |
α = 100.754 (7)° | µ = 0.39 mm−1 |
β = 96.956 (7)° | T = 293 K |
γ = 105.287 (7)° | Plate, light yellow |
V = 1507.5 (2) Å3 | 0.44 × 0.29 × 0.12 mm |
Kuma Diffraction KM4CCD Sapphire2 diffractometer | 7242 reflections with I > 2σ(I) |
Graphite monochromator | Rint = 0.033 |
Detector resolution: 8.1883 pixels mm-1 | θmax = 30°, θmin = 2.6° |
ω scans | h = −11→11 |
14750 measured reflections | k = −17→17 |
8613 independent reflections | l = −21→20 |
Refinement on F2 | Primary atom site location: structure-invariant direct methods |
Least-squares matrix: full | Secondary atom site location: difference Fourier map |
R[F2 > 2σ(F2)] = 0.060 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.165 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.09 | w = 1/[σ2(Fo2) + (0.0822P)2 + 0.8507P] where P = (Fo2 + 2Fc2)/3 |
8613 reflections | (Δ/σ)max = 0.006 |
443 parameters | Δρmax = 0.71 e Å−3 |
0 restraints | Δρmin = −0.32 e Å−3 |
C13H9N3O6S2 | γ = 105.287 (7)° |
Mr = 367.35 | V = 1507.5 (2) Å3 |
Triclinic, P1 | Z = 4 |
a = 8.4462 (7) Å | Mo Kα radiation |
b = 12.5495 (11) Å | µ = 0.39 mm−1 |
c = 15.2557 (14) Å | T = 293 K |
α = 100.754 (7)° | 0.44 × 0.29 × 0.12 mm |
β = 96.956 (7)° |
Kuma Diffraction KM4CCD Sapphire2 diffractometer | 7242 reflections with I > 2σ(I) |
14750 measured reflections | Rint = 0.033 |
8613 independent reflections |
R[F2 > 2σ(F2)] = 0.060 | 0 restraints |
wR(F2) = 0.165 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.09 | Δρmax = 0.71 e Å−3 |
8613 reflections | Δρmin = −0.32 e Å−3 |
443 parameters |
Experimental. Column chromatography (CC) was performed by using Merck silica gel 60, Nr. 7734. Melting points (M.p.) were determined by MEL-TEMP (Mel-Temp laboratories Inc, USA) melting point apparatus and are uncorrected. Analytical TLC was performed on Merck TLC plates (Aluminium plates coated with silica gel 60 F254, No. 5554). Visualization of spots was carried out by using ultraviolet illumination (λ = 254 nm) and analytical data are reported as "ratio of front"-values (Rf -value). Infrared spectra were obtained by using an IR spectrophotometer, Perkin-Elmer 1600 series FTIR. Absorption is reported in relation to wavenumber (¯ν). 1H NMR spectra were measured with a Bruker DPX 200 (200 MHz) spectrometer, and 13C NMR spectra were measured with a Bruker DPX 200 (50 MHz), both at 25° C with tetramethylsilane (TMS) as an internal standard. Chemical shifts are reported as parts per million (p.p.m., δ units). Coupling constants are reported in Hz. The spectra were analysed by MESTREC NMR software. The following abbreviations were used -s: singlet, bs: broad singlet, d: doublet, m: multiplet. Analytical purity was assessed at 30° C by RP-HPLC using LaChrom apparatus series 7000, Merck Hitachi (Pump: L-7100, Diode-Array-Detector L-7450, Auto sampler L-7200, thermostat column L-7350, Solvent degasser L-7612, Interface D-7000). Column used was LiChrospher 250–4, RP-18, 5 µm. The measurement was carried out at λ max 220 nm unless otherwise stated. All solvents were used without further purification. 3-Aminothiophene-2-carboxylic acid methyl ester was purchased from Aldrich. PPE (EC 3.4.21.36, ≈200 U/mg) and HLE (EC 3.4.21.37, ≈34 U/mg) were purchased from Serva. Suc-(Ala)3-pNA, and N-methoxysuccinyl-(Ala)2 –Pro-Val-pNA were obtained from Bachem. compound 2 IR: ¯ν = 3446 (NH), 3090, 2990, 2944 (CH), 1683 (ester with intramolecular hydrogen bonds), 1616 (C=N), 1320, 1161 (SO2); 1H NMR [D6]DMSO: δ = 11.07 (bs, 1H, NH), 8.19–8.10, 8.04–7.90 (2 m, 4H, ar), 8.09 (d, J = 5.40 Hz, 1H, 5'-Hthiophene), 7.85 (d, J = 5.40 Hz, 1H, 4'-Hthiophene), 3.89 (s, 3H, OMe); 13C NMR [D6]DMSO: δ = 162.84, 156.30, 140.94, 140.83, 134.18, 133.72, 133.08, 127.12, 124.15, 122.63, 121.81, 116.71, 52.46; HPLC: k' = 4.57, t0 = 1.85 (RP-18, ACN/ H2O 1:1). compound 3 IR: ¯ν = 2958 (CH), 1707 (C=O), 1610 (C=N), 1344, 1174 (SO2); 1H NMR [D6]DMSO: δ = 11.20 (bs, 1H, NH), 8.55 (s, 1H, 4'-Hthiophene), 8.28–8.19, 8.18–8.10, 8.01–7.92 (3 m, 4H, ar), 3.93 (s, 3H, OMe); 13C NMR [D6]DMSO: δ = 160.98, 157.37, 152.00, 141.04, 137.58, 134.42, 133.79, 126.72, 125.50, 123.50, 123.11, 121.89, 53.37; HPLC: k' = 4.60, t0 = 1.77 (RP-18, ACN/ H2O 1:1). |
Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes. |
Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger. |
x | y | z | Uiso*/Ueq | ||
S1 | 0.78764 (6) | 0.38838 (4) | 0.14560 (4) | 0.03408 (13) | |
S2 | 0.82812 (8) | 0.09330 (5) | 0.48592 (4) | 0.04228 (15) | |
N1 | 0.7960 (2) | 0.32182 (15) | 0.22894 (13) | 0.0378 (4) | |
N2 | 0.9528 (2) | 0.35411 (15) | 0.37411 (12) | 0.0355 (4) | |
N3 | 0.5301 (3) | −0.00535 (17) | 0.37232 (14) | 0.0422 (4) | |
O1 | 0.6285 (2) | 0.40847 (18) | 0.12949 (14) | 0.0516 (4) | |
O2 | 0.8372 (2) | 0.32854 (15) | 0.06896 (12) | 0.0482 (4) | |
O3 | 0.4174 (2) | −0.00021 (18) | 0.31698 (13) | 0.0553 (5) | |
O4 | 0.5245 (3) | −0.08320 (18) | 0.41086 (16) | 0.0677 (6) | |
O5 | 1.1821 (2) | 0.38075 (15) | 0.52810 (12) | 0.0465 (4) | |
O6 | 1.1375 (2) | 0.23414 (16) | 0.59779 (12) | 0.0475 (4) | |
C1 | 0.9457 (3) | 0.51416 (17) | 0.20129 (15) | 0.0328 (4) | |
C2 | 1.0033 (3) | 0.6138 (2) | 0.17343 (19) | 0.0463 (5) | |
H2 | 0.9595 | 0.6231 | 0.1174 | 0.065* | |
C3 | 1.1305 (4) | 0.6994 (2) | 0.2336 (2) | 0.0574 (7) | |
H3 | 1.1714 | 0.7683 | 0.2179 | 0.080* | |
C4 | 1.1979 (4) | 0.6846 (2) | 0.3168 (2) | 0.0528 (6) | |
H4 | 1.2854 | 0.7426 | 0.3546 | 0.074* | |
C5 | 1.1361 (3) | 0.58433 (19) | 0.34400 (16) | 0.0399 (5) | |
H5 | 1.1799 | 0.5748 | 0.4000 | 0.056* | |
C6 | 1.0071 (2) | 0.49860 (16) | 0.28539 (14) | 0.0314 (4) | |
C7 | 0.9133 (2) | 0.38550 (17) | 0.29652 (14) | 0.0310 (4) | |
C8 | 0.8755 (3) | 0.25233 (17) | 0.39677 (14) | 0.0319 (4) | |
C9 | 0.7199 (3) | 0.17426 (18) | 0.35328 (15) | 0.0361 (4) | |
H9 | 0.6530 | 0.1811 | 0.3028 | 0.050* | |
C10 | 0.6826 (3) | 0.08730 (18) | 0.39657 (15) | 0.0369 (4) | |
C11 | 0.9476 (3) | 0.21983 (18) | 0.47066 (14) | 0.0350 (4) | |
C12 | 1.1014 (3) | 0.2871 (2) | 0.53436 (15) | 0.0375 (4) | |
C13 | 1.2858 (3) | 0.2927 (3) | 0.66588 (18) | 0.0529 (6) | |
H13A | 1.3808 | 0.3111 | 0.6367 | 0.074* | |
H13B | 1.3026 | 0.2446 | 0.7060 | 0.074* | |
H13C | 1.2723 | 0.3612 | 0.7000 | 0.074* | |
H2A | 1.036 (4) | 0.401 (3) | 0.416 (2) | 0.057 (9)* | |
S3 | 1.19939 (7) | 0.08057 (5) | 0.84081 (4) | 0.03976 (14) | |
S4 | 0.55736 (7) | −0.42292 (5) | 0.68575 (4) | 0.03977 (14) | |
N4 | 1.0485 (2) | −0.04004 (16) | 0.80561 (13) | 0.0387 (4) | |
N5 | 0.9233 (2) | −0.19586 (15) | 0.86273 (12) | 0.0332 (3) | |
N6 | 0.5555 (3) | −0.2926 (2) | 0.56298 (13) | 0.0463 (5) | |
O7 | 1.3266 (3) | 0.08190 (17) | 0.78639 (13) | 0.0556 (5) | |
O8 | 1.1299 (3) | 0.17360 (16) | 0.84891 (16) | 0.0604 (5) | |
O9 | 0.6148 (3) | −0.2076 (2) | 0.53579 (13) | 0.0627 (6) | |
O10 | 0.4332 (3) | −0.3710 (2) | 0.52161 (15) | 0.0746 (7) | |
O11 | 0.7795 (2) | −0.38408 (16) | 0.93357 (12) | 0.0487 (4) | |
O12 | 0.6092 (2) | −0.53493 (14) | 0.82870 (12) | 0.0441 (4) | |
C14 | 1.2651 (3) | 0.05876 (18) | 0.94846 (14) | 0.0352 (4) | |
C15 | 1.3942 (3) | 0.1271 (2) | 1.01748 (18) | 0.0474 (6) | |
H15 | 1.4612 | 0.1963 | 1.0117 | 0.066* | |
C16 | 1.4187 (3) | 0.0876 (3) | 1.09528 (18) | 0.0541 (7) | |
H16 | 1.5047 | 0.1307 | 1.1428 | 0.076* | |
C17 | 1.3169 (4) | −0.0153 (2) | 1.10338 (17) | 0.0516 (6) | |
H17 | 1.3359 | −0.0397 | 1.1565 | 0.072* | |
C18 | 1.1866 (3) | −0.0831 (2) | 1.03386 (15) | 0.0394 (5) | |
H18 | 1.1185 | −0.1519 | 1.0398 | 0.055* | |
C19 | 1.1628 (2) | −0.04395 (16) | 0.95559 (13) | 0.0302 (4) | |
C20 | 1.0386 (2) | −0.09623 (16) | 0.86997 (13) | 0.0302 (4) | |
C21 | 0.7995 (2) | −0.25694 (17) | 0.78739 (13) | 0.0301 (4) | |
C22 | 0.7594 (3) | −0.21886 (18) | 0.70763 (14) | 0.0337 (4) | |
H22 | 0.8117 | −0.1487 | 0.6967 | 0.047* | |
C23 | 0.6318 (3) | −0.30199 (19) | 0.64987 (14) | 0.0355 (4) | |
C24 | 0.7004 (2) | −0.36494 (17) | 0.78475 (13) | 0.0317 (4) | |
C25 | 0.7026 (3) | −0.42710 (18) | 0.85771 (15) | 0.0351 (4) | |
C26 | 0.5853 (5) | −0.6019 (3) | 0.8964 (2) | 0.0609 (8) | |
H26A | 0.6918 | −0.5963 | 0.9303 | 0.085* | |
H26B | 0.5291 | −0.6797 | 0.8671 | 0.085* | |
H26C | 0.5191 | −0.5739 | 0.9368 | 0.085* | |
H5A | 0.936 (4) | −0.233 (3) | 0.902 (2) | 0.052 (8)* |
U11 | U22 | U33 | U12 | U13 | U23 | |
S1 | 0.0325 (2) | 0.0321 (2) | 0.0353 (2) | 0.00579 (18) | −0.00127 (19) | 0.01206 (19) |
S2 | 0.0439 (3) | 0.0377 (3) | 0.0409 (3) | 0.0013 (2) | −0.0005 (2) | 0.0190 (2) |
N1 | 0.0393 (9) | 0.0300 (8) | 0.0371 (9) | −0.0008 (7) | −0.0044 (7) | 0.0136 (7) |
N2 | 0.0383 (9) | 0.0300 (8) | 0.0320 (8) | 0.0002 (7) | −0.0011 (7) | 0.0111 (7) |
N3 | 0.0435 (10) | 0.0370 (9) | 0.0382 (9) | −0.0006 (8) | 0.0040 (8) | 0.0093 (8) |
O1 | 0.0346 (8) | 0.0658 (12) | 0.0582 (11) | 0.0152 (8) | 0.0018 (8) | 0.0270 (9) |
O2 | 0.0598 (11) | 0.0430 (9) | 0.0405 (9) | 0.0169 (8) | 0.0036 (8) | 0.0071 (7) |
O3 | 0.0434 (10) | 0.0597 (11) | 0.0490 (10) | −0.0026 (8) | −0.0065 (8) | 0.0141 (9) |
O4 | 0.0666 (13) | 0.0477 (11) | 0.0740 (14) | −0.0122 (9) | −0.0064 (11) | 0.0319 (10) |
O5 | 0.0420 (9) | 0.0400 (8) | 0.0485 (9) | −0.0029 (7) | −0.0049 (7) | 0.0181 (7) |
O6 | 0.0429 (9) | 0.0492 (9) | 0.0435 (9) | −0.0013 (7) | −0.0057 (7) | 0.0241 (8) |
C1 | 0.0320 (9) | 0.0275 (9) | 0.0392 (10) | 0.0077 (7) | 0.0046 (8) | 0.0111 (7) |
C2 | 0.0520 (14) | 0.0355 (11) | 0.0557 (14) | 0.0125 (10) | 0.0100 (11) | 0.0210 (10) |
C3 | 0.0613 (16) | 0.0294 (11) | 0.0760 (19) | 0.0017 (11) | 0.0118 (14) | 0.0160 (12) |
C4 | 0.0490 (14) | 0.0309 (11) | 0.0650 (16) | −0.0022 (10) | 0.0071 (12) | 0.0001 (11) |
C5 | 0.0362 (10) | 0.0322 (10) | 0.0421 (11) | 0.0025 (8) | 0.0002 (9) | 0.0008 (8) |
C6 | 0.0313 (9) | 0.0246 (8) | 0.0370 (10) | 0.0069 (7) | 0.0047 (7) | 0.0066 (7) |
C7 | 0.0313 (9) | 0.0276 (9) | 0.0336 (9) | 0.0067 (7) | 0.0039 (7) | 0.0098 (7) |
C8 | 0.0326 (9) | 0.0311 (9) | 0.0312 (9) | 0.0056 (7) | 0.0045 (7) | 0.0111 (7) |
C9 | 0.0360 (10) | 0.0347 (10) | 0.0349 (10) | 0.0059 (8) | 0.0023 (8) | 0.0108 (8) |
C10 | 0.0375 (10) | 0.0322 (10) | 0.0350 (10) | 0.0012 (8) | 0.0023 (8) | 0.0091 (8) |
C11 | 0.0352 (10) | 0.0326 (9) | 0.0346 (10) | 0.0036 (8) | 0.0026 (8) | 0.0127 (8) |
C12 | 0.0363 (10) | 0.0397 (11) | 0.0328 (10) | 0.0042 (8) | 0.0019 (8) | 0.0121 (8) |
C13 | 0.0490 (14) | 0.0580 (15) | 0.0436 (13) | 0.0027 (11) | −0.0078 (11) | 0.0210 (11) |
S3 | 0.0438 (3) | 0.0320 (3) | 0.0403 (3) | 0.0034 (2) | 0.0067 (2) | 0.0123 (2) |
S4 | 0.0376 (3) | 0.0380 (3) | 0.0345 (3) | 0.0007 (2) | −0.0030 (2) | 0.0068 (2) |
N4 | 0.0412 (10) | 0.0360 (9) | 0.0343 (9) | 0.0026 (7) | −0.0003 (7) | 0.0137 (7) |
N5 | 0.0322 (8) | 0.0319 (8) | 0.0314 (8) | 0.0028 (6) | −0.0027 (6) | 0.0118 (7) |
N6 | 0.0504 (12) | 0.0574 (12) | 0.0307 (9) | 0.0198 (10) | −0.0020 (8) | 0.0094 (8) |
O7 | 0.0558 (11) | 0.0549 (11) | 0.0510 (10) | 0.0011 (9) | 0.0198 (9) | 0.0150 (9) |
O8 | 0.0725 (14) | 0.0395 (9) | 0.0751 (14) | 0.0190 (9) | 0.0133 (11) | 0.0238 (9) |
O9 | 0.0863 (16) | 0.0675 (13) | 0.0424 (10) | 0.0283 (12) | 0.0063 (10) | 0.0274 (9) |
O10 | 0.0654 (14) | 0.0885 (17) | 0.0489 (11) | 0.0051 (12) | −0.0229 (10) | 0.0113 (11) |
O11 | 0.0500 (10) | 0.0497 (10) | 0.0387 (8) | 0.0017 (8) | −0.0034 (7) | 0.0169 (7) |
O12 | 0.0536 (10) | 0.0334 (8) | 0.0416 (8) | 0.0048 (7) | 0.0038 (7) | 0.0141 (6) |
C14 | 0.0335 (10) | 0.0330 (10) | 0.0346 (10) | 0.0047 (8) | 0.0045 (8) | 0.0049 (8) |
C15 | 0.0419 (12) | 0.0394 (12) | 0.0480 (13) | 0.0006 (9) | 0.0031 (10) | −0.0017 (10) |
C16 | 0.0460 (13) | 0.0580 (16) | 0.0401 (12) | 0.0037 (11) | −0.0090 (10) | −0.0058 (11) |
C17 | 0.0580 (15) | 0.0550 (15) | 0.0334 (11) | 0.0133 (12) | −0.0073 (10) | 0.0040 (10) |
C18 | 0.0435 (11) | 0.0386 (11) | 0.0342 (10) | 0.0101 (9) | 0.0018 (9) | 0.0101 (8) |
C19 | 0.0295 (9) | 0.0292 (9) | 0.0291 (9) | 0.0067 (7) | 0.0025 (7) | 0.0043 (7) |
C20 | 0.0292 (8) | 0.0275 (8) | 0.0314 (9) | 0.0061 (7) | 0.0013 (7) | 0.0062 (7) |
C21 | 0.0280 (8) | 0.0303 (9) | 0.0302 (9) | 0.0071 (7) | 0.0011 (7) | 0.0075 (7) |
C22 | 0.0347 (10) | 0.0341 (9) | 0.0322 (9) | 0.0096 (8) | 0.0021 (7) | 0.0110 (8) |
C23 | 0.0360 (10) | 0.0404 (10) | 0.0294 (9) | 0.0111 (8) | 0.0018 (8) | 0.0091 (8) |
C24 | 0.0308 (9) | 0.0338 (9) | 0.0287 (9) | 0.0061 (7) | 0.0016 (7) | 0.0103 (7) |
C25 | 0.0339 (10) | 0.0354 (10) | 0.0359 (10) | 0.0063 (8) | 0.0072 (8) | 0.0132 (8) |
C26 | 0.081 (2) | 0.0467 (14) | 0.0545 (16) | 0.0060 (14) | 0.0123 (14) | 0.0285 (12) |
S1—O1 | 1.4323 (18) | S3—O8 | 1.431 (2) |
S1—O2 | 1.4361 (18) | S3—O7 | 1.4338 (19) |
S1—N1 | 1.6507 (19) | S3—N4 | 1.649 (2) |
S1—C1 | 1.763 (2) | S3—C14 | 1.763 (2) |
S2—C10 | 1.697 (2) | S4—C23 | 1.700 (2) |
S2—C11 | 1.716 (2) | S4—C24 | 1.719 (2) |
N1—C7 | 1.308 (3) | N4—C20 | 1.310 (3) |
N2—C7 | 1.347 (3) | N5—C20 | 1.343 (3) |
N2—C8 | 1.399 (3) | N5—C21 | 1.400 (2) |
N2—H2A | 0.88 (3) | N5—H5A | 0.84 (3) |
N3—O3 | 1.217 (3) | N6—O9 | 1.222 (3) |
N3—O4 | 1.224 (3) | N6—O10 | 1.228 (3) |
N3—C10 | 1.443 (3) | N6—C23 | 1.442 (3) |
O5—C12 | 1.221 (3) | O11—C25 | 1.205 (3) |
O6—C12 | 1.322 (3) | O12—C25 | 1.334 (3) |
O6—C13 | 1.450 (3) | O12—C26 | 1.449 (3) |
C1—C2 | 1.381 (3) | C14—C19 | 1.381 (3) |
C1—C6 | 1.392 (3) | C14—C15 | 1.388 (3) |
C2—C3 | 1.391 (4) | C15—C16 | 1.383 (4) |
C2—H2 | 0.9300 | C15—H15 | 0.9300 |
C3—C4 | 1.392 (5) | C16—C17 | 1.386 (4) |
C3—H3 | 0.9300 | C16—H16 | 0.9300 |
C4—C5 | 1.389 (4) | C17—C18 | 1.395 (3) |
C4—H4 | 0.9300 | C17—H17 | 0.9300 |
C5—C6 | 1.389 (3) | C18—C19 | 1.386 (3) |
C5—H5 | 0.9300 | C18—H18 | 0.9300 |
C6—C7 | 1.484 (3) | C19—C20 | 1.490 (3) |
C8—C11 | 1.394 (3) | C21—C24 | 1.383 (3) |
C8—C9 | 1.412 (3) | C21—C22 | 1.423 (3) |
C9—C10 | 1.365 (3) | C22—C23 | 1.364 (3) |
C9—H9 | 0.9300 | C22—H22 | 0.9300 |
C11—C12 | 1.467 (3) | C24—C25 | 1.475 (3) |
C13—H13A | 0.9600 | C26—H26A | 0.9600 |
C13—H13B | 0.9600 | C26—H26B | 0.9600 |
C13—H13C | 0.9600 | C26—H26C | 0.9600 |
O1···C25i | 2.893 (3) | C12···O9ii | 3.063 (3) |
O1—S1—O2 | 116.41 (12) | O8—S3—O7 | 117.16 (13) |
O1—S1—N1 | 109.99 (11) | O8—S3—N4 | 109.67 (12) |
O2—S1—N1 | 109.26 (11) | O7—S3—N4 | 109.93 (11) |
O1—S1—C1 | 111.45 (11) | O8—S3—C14 | 110.86 (12) |
O2—S1—C1 | 111.32 (11) | O7—S3—C14 | 110.92 (12) |
N1—S1—C1 | 96.60 (9) | N4—S3—C14 | 96.31 (10) |
C10—S2—C11 | 89.52 (10) | C23—S4—C24 | 89.12 (10) |
C7—N1—S1 | 109.66 (14) | C20—N4—S3 | 109.72 (15) |
C7—N2—C8 | 126.69 (18) | C20—N5—C21 | 126.90 (18) |
C7—N2—H2A | 119 (2) | C20—N5—H5A | 118 (2) |
C8—N2—H2A | 115 (2) | C21—N5—H5A | 114 (2) |
O3—N3—O4 | 125.1 (2) | O9—N6—O10 | 124.5 (2) |
O3—N3—C10 | 118.6 (2) | O9—N6—C23 | 118.5 (2) |
O4—N3—C10 | 116.3 (2) | O10—N6—C23 | 117.1 (2) |
C12—O6—C13 | 117.00 (19) | C25—O12—C26 | 116.8 (2) |
C2—C1—C6 | 123.0 (2) | C19—C14—C15 | 122.7 (2) |
C2—C1—S1 | 129.99 (19) | C19—C14—S3 | 107.78 (15) |
C6—C1—S1 | 107.04 (14) | C15—C14—S3 | 129.52 (19) |
C1—C2—C3 | 116.5 (2) | C16—C15—C14 | 117.0 (2) |
C1—C2—H2 | 121.8 | C16—C15—H15 | 121.5 |
C3—C2—H2 | 121.8 | C14—C15—H15 | 121.5 |
C2—C3—C4 | 121.7 (2) | C15—C16—C17 | 120.9 (2) |
C2—C3—H3 | 119.2 | C15—C16—H16 | 119.5 |
C4—C3—H3 | 119.2 | C17—C16—H16 | 119.5 |
C5—C4—C3 | 120.8 (2) | C16—C17—C18 | 121.7 (2) |
C5—C4—H4 | 119.6 | C16—C17—H17 | 119.2 |
C3—C4—H4 | 119.6 | C18—C17—H17 | 119.2 |
C4—C5—C6 | 118.3 (2) | C19—C18—C17 | 117.4 (2) |
C4—C5—H5 | 120.9 | C19—C18—H18 | 121.3 |
C6—C5—H5 | 120.9 | C17—C18—H18 | 121.3 |
C5—C6—C1 | 119.77 (19) | C14—C19—C18 | 120.26 (19) |
C5—C6—C7 | 130.5 (2) | C14—C19—C20 | 109.28 (18) |
C1—C6—C7 | 109.67 (17) | C18—C19—C20 | 130.45 (19) |
N1—C7—N2 | 123.96 (18) | N4—C20—N5 | 123.65 (18) |
N1—C7—C6 | 116.99 (18) | N4—C20—C19 | 116.87 (18) |
N2—C7—C6 | 119.05 (18) | N5—C20—C19 | 119.48 (18) |
C11—C8—N2 | 121.07 (19) | C24—C21—N5 | 121.09 (18) |
C11—C8—C9 | 112.35 (18) | C24—C21—C22 | 112.71 (18) |
N2—C8—C9 | 126.54 (19) | N5—C21—C22 | 126.20 (18) |
C10—C9—C8 | 109.73 (19) | C23—C22—C21 | 108.87 (19) |
C10—C9—H9 | 125.1 | C23—C22—H22 | 125.6 |
C8—C9—H9 | 125.1 | C21—C22—H22 | 125.6 |
C9—C10—N3 | 124.6 (2) | C22—C23—N6 | 124.6 (2) |
C9—C10—S2 | 115.90 (17) | C22—C23—S4 | 116.54 (16) |
N3—C10—S2 | 119.44 (16) | N6—C23—S4 | 118.88 (17) |
C8—C11—C12 | 125.68 (19) | C21—C24—C25 | 126.73 (18) |
C8—C11—S2 | 112.46 (16) | C21—C24—S4 | 112.76 (15) |
C12—C11—S2 | 121.70 (16) | C25—C24—S4 | 120.43 (15) |
O5—C12—O6 | 125.7 (2) | O11—C25—O12 | 125.3 (2) |
O5—C12—C11 | 122.7 (2) | O11—C25—C24 | 123.3 (2) |
O6—C12—C11 | 111.63 (19) | O12—C25—C24 | 111.37 (18) |
O6—C13—H13A | 109.5 | O12—C26—H26A | 109.5 |
O6—C13—H13B | 109.5 | O12—C26—H26B | 109.5 |
H13A—C13—H13B | 109.5 | H26A—C26—H26B | 109.5 |
O6—C13—H13C | 109.5 | O12—C26—H26C | 109.5 |
H13A—C13—H13C | 109.5 | H26A—C26—H26C | 109.5 |
H13B—C13—H13C | 109.5 | H26B—C26—H26C | 109.5 |
O1—S1—N1—C7 | −117.46 (18) | O8—S3—N4—C20 | −113.04 (18) |
O2—S1—N1—C7 | 113.60 (17) | O7—S3—N4—C20 | 116.77 (18) |
C1—S1—N1—C7 | −1.75 (18) | C14—S3—N4—C20 | 1.79 (18) |
O1—S1—C1—C2 | −61.9 (2) | O8—S3—C14—C19 | 112.61 (17) |
O2—S1—C1—C2 | 69.9 (2) | O7—S3—C14—C19 | −115.43 (16) |
N1—S1—C1—C2 | −176.5 (2) | N4—S3—C14—C19 | −1.26 (17) |
O1—S1—C1—C6 | 116.68 (16) | O8—S3—C14—C15 | −67.5 (3) |
O2—S1—C1—C6 | −111.53 (16) | O7—S3—C14—C15 | 64.5 (3) |
N1—S1—C1—C6 | 2.15 (16) | N4—S3—C14—C15 | 178.6 (2) |
C6—C1—C2—C3 | 1.1 (4) | C19—C14—C15—C16 | 0.6 (4) |
S1—C1—C2—C3 | 179.5 (2) | S3—C14—C15—C16 | −179.3 (2) |
C1—C2—C3—C4 | 1.1 (4) | C14—C15—C16—C17 | −0.6 (4) |
C2—C3—C4—C5 | −2.2 (5) | C15—C16—C17—C18 | 0.2 (4) |
C3—C4—C5—C6 | 1.0 (4) | C16—C17—C18—C19 | 0.3 (4) |
C4—C5—C6—C1 | 1.1 (3) | C15—C14—C19—C18 | −0.1 (3) |
C4—C5—C6—C7 | −177.8 (2) | S3—C14—C19—C18 | 179.79 (17) |
C2—C1—C6—C5 | −2.3 (3) | C15—C14—C19—C20 | −179.5 (2) |
S1—C1—C6—C5 | 179.00 (17) | S3—C14—C19—C20 | 0.4 (2) |
C2—C1—C6—C7 | 176.9 (2) | C17—C18—C19—C14 | −0.3 (3) |
S1—C1—C6—C7 | −1.9 (2) | C17—C18—C19—C20 | 178.9 (2) |
S1—N1—C7—N2 | −178.88 (17) | S3—N4—C20—N5 | 177.40 (17) |
S1—N1—C7—C6 | 0.9 (2) | S3—N4—C20—C19 | −1.9 (2) |
C8—N2—C7—N1 | −1.7 (4) | C21—N5—C20—N4 | 1.5 (3) |
C8—N2—C7—C6 | 178.53 (19) | C21—N5—C20—C19 | −179.26 (18) |
C5—C6—C7—N1 | 179.8 (2) | C14—C19—C20—N4 | 0.9 (3) |
C1—C6—C7—N1 | 0.8 (3) | C18—C19—C20—N4 | −178.4 (2) |
C5—C6—C7—N2 | −0.5 (3) | C14—C19—C20—N5 | −178.37 (19) |
C1—C6—C7—N2 | −179.47 (19) | C18—C19—C20—N5 | 2.3 (3) |
C7—N2—C8—C11 | 167.2 (2) | C20—N5—C21—C24 | 172.4 (2) |
C7—N2—C8—C9 | −15.3 (4) | C20—N5—C21—C22 | −7.9 (3) |
C11—C8—C9—C10 | 0.1 (3) | C24—C21—C22—C23 | −0.2 (3) |
N2—C8—C9—C10 | −177.6 (2) | N5—C21—C22—C23 | −179.8 (2) |
C8—C9—C10—N3 | 177.6 (2) | C21—C22—C23—N6 | 178.6 (2) |
C8—C9—C10—S2 | −1.4 (3) | C21—C22—C23—S4 | 0.0 (2) |
O3—N3—C10—C9 | −9.3 (4) | O9—N6—C23—C22 | 4.9 (4) |
O4—N3—C10—C9 | 171.6 (2) | O10—N6—C23—C22 | −174.4 (2) |
O3—N3—C10—S2 | 169.59 (19) | O9—N6—C23—S4 | −176.59 (19) |
O4—N3—C10—S2 | −9.5 (3) | O10—N6—C23—S4 | 4.1 (3) |
C11—S2—C10—C9 | 1.7 (2) | C24—S4—C23—C22 | 0.10 (18) |
C11—S2—C10—N3 | −177.3 (2) | C24—S4—C23—N6 | −178.52 (18) |
N2—C8—C11—C12 | 3.4 (3) | N5—C21—C24—C25 | 3.2 (3) |
C9—C8—C11—C12 | −174.5 (2) | C22—C21—C24—C25 | −176.52 (19) |
N2—C8—C11—S2 | 178.97 (16) | N5—C21—C24—S4 | 179.92 (15) |
C9—C8—C11—S2 | 1.1 (2) | C22—C21—C24—S4 | 0.2 (2) |
C10—S2—C11—C8 | −1.53 (18) | C23—S4—C24—C21 | −0.20 (17) |
C10—S2—C11—C12 | 174.2 (2) | C23—S4—C24—C25 | 176.80 (18) |
C13—O6—C12—O5 | 0.1 (4) | C26—O12—C25—O11 | 6.7 (4) |
C13—O6—C12—C11 | −179.2 (2) | C26—O12—C25—C24 | −173.1 (2) |
C8—C11—C12—O5 | 0.2 (4) | C21—C24—C25—O11 | 9.4 (4) |
S2—C11—C12—O5 | −175.0 (2) | S4—C24—C25—O11 | −167.15 (19) |
C8—C11—C12—O6 | 179.5 (2) | C21—C24—C25—O12 | −170.9 (2) |
S2—C11—C12—O6 | 4.3 (3) | S4—C24—C25—O12 | 12.6 (3) |
Symmetry codes: (i) −x+1, −y, −z+1; (ii) −x+2, −y, −z+1. |
D—H···A | D—H | H···A | D···A | D—H···A |
N2—H2A···O5 | 0.88 (3) | 2.08 (3) | 2.765 (2) | 134 (3) |
N5—H5A···O11 | 0.84 (3) | 2.17 (3) | 2.825 (3) | 134 (3) |
N5—H5A···O2ii | 0.84 (3) | 2.55 (3) | 3.141 (3) | 128 (3) |
C4—H4···O4iii | 0.93 | 2.48 | 3.376 (3) | 162 |
C5—H5···O10iii | 0.93 | 2.51 | 3.316 (3) | 146 |
C17—H17···O3iv | 0.93 | 2.38 | 3.223 (3) | 151 |
Symmetry codes: (ii) −x+2, −y, −z+1; (iii) x+1, y+1, z; (iv) x+1, y, z+1. |
Experimental details
Crystal data | |
Chemical formula | C13H9N3O6S2 |
Mr | 367.35 |
Crystal system, space group | Triclinic, P1 |
Temperature (K) | 293 |
a, b, c (Å) | 8.4462 (7), 12.5495 (11), 15.2557 (14) |
α, β, γ (°) | 100.754 (7), 96.956 (7), 105.287 (7) |
V (Å3) | 1507.5 (2) |
Z | 4 |
Radiation type | Mo Kα |
µ (mm−1) | 0.39 |
Crystal size (mm) | 0.44 × 0.29 × 0.12 |
Data collection | |
Diffractometer | Kuma Diffraction KM4CCD Sapphire2 diffractometer |
Absorption correction | – |
No. of measured, independent and observed [I > 2σ(I)] reflections | 14750, 8613, 7242 |
Rint | 0.033 |
(sin θ/λ)max (Å−1) | 0.703 |
Refinement | |
R[F2 > 2σ(F2)], wR(F2), S | 0.060, 0.165, 1.09 |
No. of reflections | 8613 |
No. of parameters | 443 |
H-atom treatment | H atoms treated by a mixture of independent and constrained refinement |
Δρmax, Δρmin (e Å−3) | 0.71, −0.32 |
Computer programs: CrysAlis PRO (Oxford Diffraction, 2009), SUPERFLIP (Palatinus & Chapuis, 2007), SHELXL97 (Sheldrick, 2008), ORTEP-3 (Farrugia, 1997), publCIF (Westrip, 2010), PLATON (Spek, 2003), WinGX (Farrugia, 1999) and Mercury (Macrae et al., 2006).
D—H···A | D—H | H···A | D···A | D—H···A |
N2—H2A···O5 | 0.88 (3) | 2.08 (3) | 2.765 (2) | 134 (3) |
N5—H5A···O11 | 0.84 (3) | 2.17 (3) | 2.825 (3) | 134 (3) |
N5—H5A···O2i | 0.84 (3) | 2.55 (3) | 3.141 (3) | 128 (3) |
C4—H4···O4ii | 0.93 | 2.48 | 3.376 (3) | 162 |
C5—H5···O10ii | 0.93 | 2.51 | 3.316 (3) | 146 |
C17—H17···O3iii | 0.93 | 2.38 | 3.223 (3) | 151 |
Symmetry codes: (i) −x+2, −y, −z+1; (ii) x+1, y+1, z; (iii) x+1, y, z+1. |
Acknowledgements
We wish to thank Degussa AG for generous support of chemicals, E. Merck KGaG, Darmstadt, for support of
materials, and the "Fonds der Chemischen Industrie" for financial support. HBR thanks the University of Greifswald for financial support.References
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Elastases are endopeptidases (serine proteases) which by definition are able to solubilize elastin by proteolytic cleavage and are possibly the most destructive enzymes in the human body, having the ability to degrade virtually all connective tissue components (Bode et al. 1989). Uncontrolled proteolytic degradation by elastase has been implicated in a number of pathological conditions including ARDS (Adult Respiratory Distress Syndrome) and lung injury, cystic fibrosis, pulmonary emphysema, smoking related chronic bronchitis and rheumatoid arthritis (Edwards et al. 1994). Therefore considerable research has been focused on developing potent inhibitors or drugs against HLE (Human Leukocyte Elastase). Potent elastase inhibitors are based on peptidic, heterocyclic and non-heterocyclic scaffolds. Of interest are the heterocyclic inhibitors as these small molecules potentially offer advantages over the larger, peptide based inhibitors due to their increased proteinase stability, increased oral absorption and decreased structural complexity. In our earlier reports, we described peptidic and heterocyclic elastase inhibitors and illustrated that the pseudosaccharin amine derivatives are potential inhibitors of elastase (Rode et al. 2005, Rode et al. 2006). Pseudosaccharin amines were further explored to synthesize analogues containing thiophene and thiazole components. During the nitration of the thiophene analogue 2 (see Figure 1), we observed the electrophilic attack of a nitro group at the α - position of thiophene to produce 3. Here we report the structural assignment of the thiophene derivative 3 using NMR spectroscopy and single crystal XRD. Compound 3 show weak inhibition of PPE (Porcine Pancreatic Elastase) and HLE.
The synthesis of pseudosaccharin chloride 1 (see Figure 1) was carried out according to the literature procedure (Wade et al., 1979). The reaction between 1 and methyl 3-aminothiophene-2-carboxylate resulted in a brown colored solid 2. This solid was treated in a nitrating mixture at -30 °C yielding C13H9N3O6S2, 3. The compound was further analysed as decribed below.
Compound 3 crystallizes with two independent molecules in the asymmetric unit (Z=4). An ORTEP view of the asymmetric unit is shown in Figure 2. The molecules are chemically identical and the most significant differences are in dihedral angles between related NO2 groups and the aromatic ring and dihedral angle between thiophene and benzene mean planes. To be more specific: the torsion angles differ by ca. 14° [C9—C10—N3—O3 -9.3 (4) ° and C22—C23—N6—O9 4.9 (4)°] and the dihedral angles by ca. 10° [benzene C1-C6 and thiophene C8-C11-S2 form angle 15.50 (13)°, the related rings 5.41 (13)°]. Apart from that the molecules are very similar, overlay of the molecules by fitting all 24 non-hydrogen atoms gives mean r.m.s. deviation of 0.217 Å with maximum distance of 0.552 Å between O9 and O3 in nitro groups (Mercury 3.0, Macrae et al. 2006).
The crystal packing is presented in Figure 3. Both molecules are placed in a layer parallel to the (-1 1 1) plane. Such planes spread throughout the crystal forming specific packing pattern. The only intramolecular hydrogen bonds are N2—H···O5 and N5—H···O11 in both molecules, respectively (Table 1). There are also weak C(aromatic)—H···O interactions between the molecules ( Table 1). One can also expect stacking interactions between the aromatic rings, but analysis with PLATON (Spek, 2003) reveals that most of the rings are too far away. The closest benzene rings C14–C19 are related by the symmetry center at 3/2, 0, 1 and their centroids are separated by the distance of 3.8660 (16) Å with perpendicular distance between the planes of 3.5883 (11) Å. Other ring centroids are separated by more than 4 Å. Noteworthy, short O1···C25i and O9ii···C12 contacts resemble transient states in early stages of the nucleophilic attack of negatively charged oxygen atoms on the partly positively loaded carbon atom in carbonyl groups.
General description and spectral properties
In the 1H NMR spectrum of 3, a sharp singlet appeared at δ 8.55 p.p.m. assignable to a proton of the thiophene ring. Information obtained from 1H NMR, 13C NMR, DEPT, HMQC and HMBC reveals that a carbon at δ 125.58 p.p.m. is assignable to a thiophene carbon bearing a proton, while carbons at δ 123.06, 133.65, 134.30, 121.74 p.p.m. are assignable to CH of the pseudosaccharin scaffold. A coupling is observed between a proton of the pseudosaccharin scaffold and a carbon at δ 157 p.p.m., allowing us to assign δ 157 p.p.m. for the carbon of C=N. Also a coupling between the methoxy group signal at δ 3.93 p.p.m. of thiophene scaffold and that of the carbonyl group at δ 161 p.p.m. was observed in HMBC. No coupling was observed between a proton at δ 8.55 p.p.m. (thiophene bearing proton) and any of the carbons of thiophene ring. If both the nitro-isomers i.e. 4-nitro analog (structure not shown) and 5-nitro analog (3) could have been isolated, that would have helped to solve the structure of 3 based on the relative chemical shifts. But only one isomer was obtained. Although the possibility of formation of the other isomer cannot be ruled out as in the 1H NMR spectrum of the crude product, more products were indicated but these products could easily be neglected in crystallization and only one isomer was obtained as a major product. Therefore the structure of the nitro thiophene analogue was determined by X-ray crystallography and in fact the product was found to be the 5'-nitro analogue 3. It is important to note that the thiophene undergoes electrophilic substitution reactions slowly and selectively at an α-position to sulfur rather than at β-position. The preferential electrophilic attack at an α-position in thiophene may be explained on the basis of stability of the transition state (Gupta et al., 1999).
Compound 3 was tested for its ability to inhibit PPE (Porcine Pancreatic Elastase) and HLE (Human Leukocyte Elastase) activity in the biochemical assay. More information on elastase can be found elsewhere (e.g. Bode et al. (1989); Edwards & Bernstein, 1994; Rode et al., 2005). The detailed description of these biochemical assays is reported in our earlier work (Rode et al., 2006). It is important to note that compound 3 inhibited 32% activity of PPE at 100 µM concentration and 15% activity of HLE at 200 µM concentrations. Although 3 has shown weak inhibition of HLE and PPE, it may serve as a starting point for developing potent HLE inhibitors.