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Many heterocycles have been developed as drugs due to their capacity to interact productively with biological systems. The present study aimed to synthesize cocrystals of the heterocyclic antitubercular agent pyrazinamide (PYZ, 1, BCS III) and the commercially available anticonvulsant drug carbamazepine (CBZ, 2, BCS class II) to study the effect of cocrystallization on the stability and biological activities of these drugs. Two new cocrystals, namely, pyrazinamide–homophthalic acid (1/1) (PYZ:HMA, 3) and carbamazepine–5-chlorosalicylic acid (1/1) (CBZ:5-SA, 4), were synthesized. The single-crystal X-ray diffraction-based structure of carbamazepine–trans-cinnamic acid (1/1) (CBZ:TCA, 5) was also studied for the first time, along with the known cocrystal carbamazepine–nicotinamide (1/1) (CBZ:NA, 6). From a combination drug perspective, these are interesting pharmaceutical cocrystals to overcome the known side effects of PYZ (1) therapy, and the poor biopharmaceutical properties of CBZ (2). The purity and homogeneity of all the synthesized cocrystals were confirmed by single-crystal X-ray diffraction, powder X-ray diffraction and FT–IR analysis, followed by thermal stability studies based on differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Detailed intermolecular interactions and the role of hydrogen bonding towards crystal stability were evaluated quantitatively via Hirshfeld surface analysis. The solubility of CBZ at pH 6.8 and 7.4 in 0.1 N HCl and H2O were compared with the values of cocrystal CBZ:5-SA (4). The solubility of CBZ:5-SA was found to be significantly improved at pH 6.8 and 7.4 in H2O. All the synthesized cocrystals 3–6 exhibited a potent urease inhibition (IC50 values range from 17.32 ± 0.89 to 12.3 ± 0.8 µM), several times more potent than standard acetohydroxamic acid (IC50 = 20.34 ± 0.43 µM). PYZ:HMA (3) also exhibited potent larvicidal activity against Aedes aegypti. Among the synthesized cocrystals, PYZ:HMA (3) and CBZ:TCA (5) were found to possess antileishmanial activity against the miltefosine-induced resistant strain of Leishmania major, with IC50 values of 111.98 ± 0.99 and 111.90 ± 1.44 µM, respectively, in comparison with miltefosine (IC50 = 169.55 ± 0.20 µM).
Supporting information
CCDC references: 2237311; 2234068; 2233995; 2233996
For all structures, data collection: APEX3 (Bruker, 2016); cell refinement: SAINT (Bruker, 2016); data reduction: SAINT (Bruker, 2016); program(s) used to solve structure: SHELXT2014 (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2018 (Sheldrick, 2015b); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012) and Mercury (Macrae et al., 2020); software used to prepare material for publication: PLATON (Spek, 2020).
Pyrazine-2-carboxamide; 2-(carboxymethyl)benzoic acid (PYZHMA)
top
Crystal data top
C5H5N3O·C9H8O4 | F(000) = 632 |
Mr = 303.27 | Dx = 1.469 Mg m−3 |
Monoclinic, P21/n | Cu Kα radiation, λ = 1.54178 Å |
a = 15.3082 (9) Å | Cell parameters from 9936 reflections |
b = 5.2020 (3) Å | θ = 4.8–72.6° |
c = 18.6832 (11) Å | µ = 0.96 mm−1 |
β = 112.809 (2)° | T = 100 K |
V = 1371.46 (14) Å3 | Plate, colourless |
Z = 4 | 0.20 × 0.17 × 0.06 mm |
Data collection top
Bruker APEXII CCD diffractometer | 2701 independent reflections |
Radiation source: Cu | 2409 reflections with I > 2σ(I) |
φ and ω scans | θmax = 72.6°, θmin = 3.2° |
Absorption correction: multi-scan (SADABS; Bruker, 2016) | h = −18→17 |
Tmin = 0.831, Tmax = 0.944 | k = 0→6 |
2701 measured reflections | l = 0→23 |
Refinement top
Refinement on F2 | 0 restraints |
Least-squares matrix: full | Hydrogen site location: inferred from neighbouring sites |
R[F2 > 2σ(F2)] = 0.061 | H-atom parameters constrained |
wR(F2) = 0.225 | w = 1/[σ2(Fo2) + (0.1217P)2 + 2.2971P] where P = (Fo2 + 2Fc2)/3 |
S = 1.20 | (Δ/σ)max < 0.001 |
2701 reflections | Δρmax = 0.39 e Å−3 |
202 parameters | Δρmin = −0.31 e Å−3 |
Special details top
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes)
are estimated using the full covariance matrix. The cell esds are taken
into account individually in the estimation of esds in distances, angles
and torsion angles; correlations between esds in cell parameters are only
used when they are defined by crystal symmetry. An approximate (isotropic)
treatment of cell esds is used for estimating esds involving l.s. planes. |
Refinement. Refined as a 2-component twin. For data collection and structure determination, suitable-sized crystals were
mounted on a Bruker APEXII CCD X-ray diffractometer. The mounted crystal was
irradiated with Cu Kα radiations (λ = 1.54178 Å) to collect the
diffraction data. The SAINT (Bruker, 1998) program was utilized to
reduce the collected data, followed by direct methods and Fourier
transformation techniques to solve the structures. The refined structures were
subjected to full-matrix least-square calculations on F2 using the
SHELXL program, with non-H atoms being refined anisotropically and
placed at geometrically idealized positions (Sheldrick, 2015b). |
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top | x | y | z | Uiso*/Ueq | |
O1 | 0.81778 (14) | −0.1424 (4) | 0.55153 (12) | 0.0142 (5) | |
O2 | 0.57323 (15) | −0.0654 (4) | 0.28945 (12) | 0.0172 (5) | |
O3 | 0.57199 (15) | −0.1657 (4) | 0.40542 (12) | 0.0173 (5) | |
H3C | 0.610436 | −0.278973 | 0.404103 | 0.026* | |
O4 | 0.48236 (15) | 0.1382 (4) | 0.10418 (12) | 0.0170 (5) | |
O5 | 0.37276 (14) | 0.0291 (4) | 0.15013 (12) | 0.0140 (5) | |
H5 | 0.360608 | −0.085722 | 0.116036 | 0.021* | |
N1 | 0.84566 (18) | 0.1608 (5) | 0.39119 (14) | 0.0147 (5) | |
N2 | 0.70078 (17) | 0.4682 (5) | 0.40127 (14) | 0.0155 (6) | |
N3 | 0.91888 (17) | −0.2280 (5) | 0.49235 (14) | 0.0143 (5) | |
H3B | 0.944964 | −0.358319 | 0.523304 | 0.017* | |
H3A | 0.938685 | −0.185716 | 0.455557 | 0.017* | |
C1 | 0.80965 (19) | 0.1217 (5) | 0.44526 (16) | 0.0115 (6) | |
C2 | 0.7381 (2) | 0.2740 (6) | 0.45111 (16) | 0.0137 (6) | |
H2 | 0.715310 | 0.240216 | 0.490809 | 0.016* | |
C3 | 0.7365 (2) | 0.5082 (6) | 0.34753 (17) | 0.0161 (6) | |
H3 | 0.711585 | 0.644002 | 0.311309 | 0.019* | |
C4 | 0.8093 (2) | 0.3574 (6) | 0.34273 (16) | 0.0152 (6) | |
H4 | 0.833640 | 0.395209 | 0.304213 | 0.018* | |
C5 | 0.85015 (19) | −0.0961 (6) | 0.50110 (16) | 0.0121 (6) | |
C6 | 0.5426 (2) | −0.0312 (6) | 0.33989 (16) | 0.0137 (6) | |
C7 | 0.4696 (2) | 0.1652 (6) | 0.33570 (16) | 0.0133 (6) | |
C8 | 0.4395 (2) | 0.3514 (5) | 0.27599 (16) | 0.0118 (6) | |
C9 | 0.3697 (2) | 0.5265 (6) | 0.27490 (17) | 0.0146 (6) | |
H9 | 0.348695 | 0.653115 | 0.235189 | 0.018* | |
C10 | 0.3304 (2) | 0.5198 (6) | 0.33026 (19) | 0.0179 (7) | |
H10 | 0.282920 | 0.640530 | 0.328142 | 0.021* | |
C11 | 0.3604 (2) | 0.3369 (6) | 0.38888 (18) | 0.0184 (7) | |
H11 | 0.333654 | 0.332033 | 0.427045 | 0.022* | |
C12 | 0.4296 (2) | 0.1615 (6) | 0.39129 (17) | 0.0163 (6) | |
H12 | 0.450200 | 0.036521 | 0.431493 | 0.020* | |
C13 | 0.4783 (2) | 0.3717 (5) | 0.21315 (16) | 0.0127 (6) | |
H13A | 0.548306 | 0.366262 | 0.237951 | 0.015* | |
H13B | 0.460248 | 0.541436 | 0.187716 | 0.015* | |
C14 | 0.4456 (2) | 0.1663 (5) | 0.15115 (16) | 0.0119 (6) | |
Atomic displacement parameters (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
O1 | 0.0144 (10) | 0.0174 (10) | 0.0125 (10) | 0.0035 (8) | 0.0070 (8) | 0.0022 (8) |
O2 | 0.0172 (10) | 0.0192 (11) | 0.0155 (10) | 0.0041 (8) | 0.0066 (8) | 0.0005 (8) |
O3 | 0.0181 (11) | 0.0194 (11) | 0.0137 (10) | 0.0057 (8) | 0.0054 (8) | 0.0041 (8) |
O4 | 0.0194 (11) | 0.0190 (11) | 0.0177 (10) | −0.0046 (9) | 0.0129 (9) | −0.0033 (8) |
O5 | 0.0133 (10) | 0.0162 (10) | 0.0138 (10) | −0.0038 (8) | 0.0066 (8) | −0.0031 (8) |
N1 | 0.0149 (12) | 0.0162 (12) | 0.0117 (11) | 0.0000 (10) | 0.0036 (10) | −0.0004 (9) |
N2 | 0.0123 (12) | 0.0160 (12) | 0.0137 (12) | 0.0012 (10) | 0.0002 (9) | 0.0021 (10) |
N3 | 0.0142 (12) | 0.0163 (12) | 0.0135 (12) | 0.0037 (10) | 0.0066 (9) | 0.0032 (9) |
C1 | 0.0115 (13) | 0.0117 (13) | 0.0096 (13) | −0.0002 (10) | 0.0024 (10) | 0.0001 (10) |
C2 | 0.0120 (13) | 0.0161 (14) | 0.0105 (13) | −0.0010 (11) | 0.0016 (10) | −0.0008 (11) |
C3 | 0.0165 (14) | 0.0161 (14) | 0.0114 (13) | −0.0006 (11) | 0.0008 (11) | 0.0020 (10) |
C4 | 0.0172 (14) | 0.0189 (14) | 0.0083 (13) | −0.0024 (11) | 0.0036 (11) | 0.0009 (10) |
C5 | 0.0108 (13) | 0.0134 (13) | 0.0096 (12) | −0.0017 (10) | 0.0010 (10) | −0.0017 (10) |
C6 | 0.0119 (13) | 0.0134 (13) | 0.0117 (13) | −0.0023 (11) | 0.0003 (10) | −0.0013 (10) |
C7 | 0.0131 (13) | 0.0146 (14) | 0.0103 (13) | −0.0012 (11) | 0.0025 (11) | −0.0014 (10) |
C8 | 0.0112 (13) | 0.0128 (13) | 0.0102 (13) | −0.0033 (10) | 0.0026 (10) | −0.0031 (10) |
C9 | 0.0127 (13) | 0.0143 (14) | 0.0151 (14) | 0.0006 (11) | 0.0034 (11) | 0.0012 (11) |
C10 | 0.0152 (13) | 0.0179 (15) | 0.0225 (15) | 0.0017 (12) | 0.0093 (12) | −0.0011 (12) |
C11 | 0.0175 (15) | 0.0256 (16) | 0.0159 (14) | −0.0007 (12) | 0.0108 (12) | −0.0011 (12) |
C12 | 0.0165 (14) | 0.0196 (15) | 0.0116 (13) | −0.0007 (11) | 0.0041 (11) | 0.0016 (11) |
C13 | 0.0126 (13) | 0.0127 (13) | 0.0121 (13) | −0.0020 (11) | 0.0041 (11) | 0.0009 (11) |
C14 | 0.0110 (13) | 0.0134 (13) | 0.0104 (13) | 0.0014 (10) | 0.0031 (10) | 0.0027 (10) |
Geometric parameters (Å, º) top
O1—C5 | 1.246 (4) | C3—H3 | 0.9500 |
O2—C6 | 1.217 (4) | C4—H4 | 0.9500 |
O3—C6 | 1.328 (4) | C6—C7 | 1.493 (4) |
O3—H3C | 0.8400 | C7—C12 | 1.395 (4) |
O4—C14 | 1.221 (4) | C7—C8 | 1.413 (4) |
O5—C14 | 1.318 (3) | C8—C9 | 1.398 (4) |
O5—H5 | 0.8400 | C8—C13 | 1.511 (4) |
N1—C4 | 1.336 (4) | C9—C10 | 1.383 (4) |
N1—C1 | 1.341 (4) | C9—H9 | 0.9500 |
N2—C3 | 1.333 (4) | C10—C11 | 1.388 (4) |
N2—C2 | 1.342 (4) | C10—H10 | 0.9500 |
N3—C5 | 1.318 (4) | C11—C12 | 1.386 (4) |
N3—H3B | 0.8800 | C11—H11 | 0.9500 |
N3—H3A | 0.8800 | C12—H12 | 0.9500 |
C1—C2 | 1.390 (4) | C13—C14 | 1.511 (4) |
C1—C5 | 1.502 (4) | C13—H13A | 0.9900 |
C2—H2 | 0.9500 | C13—H13B | 0.9900 |
C3—C4 | 1.394 (4) | | |
| | | |
C6—O3—H3C | 109.5 | C12—C7—C6 | 119.1 (3) |
C14—O5—H5 | 109.5 | C8—C7—C6 | 121.3 (3) |
C4—N1—C1 | 116.2 (3) | C9—C8—C7 | 118.2 (3) |
C3—N2—C2 | 116.9 (3) | C9—C8—C13 | 118.1 (3) |
C5—N3—H3B | 120.0 | C7—C8—C13 | 123.7 (3) |
C5—N3—H3A | 120.0 | C10—C9—C8 | 121.6 (3) |
H3B—N3—H3A | 120.0 | C10—C9—H9 | 119.2 |
N1—C1—C2 | 122.7 (3) | C8—C9—H9 | 119.2 |
N1—C1—C5 | 117.3 (3) | C9—C10—C11 | 120.1 (3) |
C2—C1—C5 | 120.1 (3) | C9—C10—H10 | 120.0 |
N2—C2—C1 | 120.7 (3) | C11—C10—H10 | 120.0 |
N2—C2—H2 | 119.7 | C12—C11—C10 | 119.4 (3) |
C1—C2—H2 | 119.7 | C12—C11—H11 | 120.3 |
N2—C3—C4 | 122.2 (3) | C10—C11—H11 | 120.3 |
N2—C3—H3 | 118.9 | C11—C12—C7 | 121.2 (3) |
C4—C3—H3 | 118.9 | C11—C12—H12 | 119.4 |
N1—C4—C3 | 121.4 (3) | C7—C12—H12 | 119.4 |
N1—C4—H4 | 119.3 | C8—C13—C14 | 115.7 (2) |
C3—C4—H4 | 119.3 | C8—C13—H13A | 108.4 |
O1—C5—N3 | 124.3 (3) | C14—C13—H13A | 108.4 |
O1—C5—C1 | 119.5 (3) | C8—C13—H13B | 108.4 |
N3—C5—C1 | 116.2 (3) | C14—C13—H13B | 108.4 |
O2—C6—O3 | 122.8 (3) | H13A—C13—H13B | 107.4 |
O2—C6—C7 | 124.3 (3) | O4—C14—O5 | 123.2 (3) |
O3—C6—C7 | 112.8 (2) | O4—C14—C13 | 121.9 (3) |
C12—C7—C8 | 119.6 (3) | O5—C14—C13 | 114.8 (2) |
| | | |
C4—N1—C1—C2 | 0.5 (4) | C12—C7—C8—C9 | −0.1 (4) |
C4—N1—C1—C5 | −179.2 (2) | C6—C7—C8—C9 | 178.9 (3) |
C3—N2—C2—C1 | −0.9 (4) | C12—C7—C8—C13 | 180.0 (3) |
N1—C1—C2—N2 | 0.8 (4) | C6—C7—C8—C13 | −1.0 (4) |
C5—C1—C2—N2 | −179.6 (2) | C7—C8—C9—C10 | −0.1 (4) |
C2—N2—C3—C4 | −0.1 (4) | C13—C8—C9—C10 | 179.8 (3) |
C1—N1—C4—C3 | −1.5 (4) | C8—C9—C10—C11 | 0.2 (5) |
N2—C3—C4—N1 | 1.4 (5) | C9—C10—C11—C12 | −0.1 (5) |
N1—C1—C5—O1 | −178.8 (2) | C10—C11—C12—C7 | −0.1 (5) |
C2—C1—C5—O1 | 1.5 (4) | C8—C7—C12—C11 | 0.3 (4) |
N1—C1—C5—N3 | 0.8 (4) | C6—C7—C12—C11 | −178.8 (3) |
C2—C1—C5—N3 | −178.8 (3) | C9—C8—C13—C14 | −106.2 (3) |
O2—C6—C7—C12 | 170.5 (3) | C7—C8—C13—C14 | 73.7 (4) |
O3—C6—C7—C12 | −10.1 (4) | C8—C13—C14—O4 | −168.8 (3) |
O2—C6—C7—C8 | −8.5 (4) | C8—C13—C14—O5 | 13.8 (4) |
O3—C6—C7—C8 | 170.9 (3) | | |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
O5—H5···O1i | 0.84 | 1.81 | 2.636 (3) | 168 |
O3—H3C···N2ii | 0.84 | 1.92 | 2.764 (3) | 179 |
N3—H3B···O4iii | 0.88 | 2.01 | 2.879 (3) | 167 |
N3—H3A···O4iv | 0.88 | 2.14 | 2.853 (3) | 137 |
C4—H4···O2v | 0.95 | 2.66 | 3.596 (4) | 169 |
C3—H3···O2vi | 0.95 | 2.50 | 3.201 (4) | 130 |
Symmetry codes: (i) x−1/2, −y−1/2, z−1/2; (ii) x, y−1, z; (iii) x+1/2, −y−1/2, z+1/2; (iv) −x+3/2, y−1/2, −z+1/2; (v) −x+3/2, y+1/2, −z+1/2; (vi) x, y+1, z. |
2-Azatricyclo[9.4.0.0
3,8]pentadeca-
1(11),3,5,7,9,12,14-heptaene-2-carboxamide; 5-chloro-2-hydroxybenzoic acid (CBZ5SA)
top
Crystal data top
C15H12N2O·C7H5ClO3 | F(000) = 848 |
Mr = 408.83 | Dx = 1.401 Mg m−3 |
Monoclinic, P21/n | Cu Kα radiation, λ = 1.54178 Å |
a = 5.1567 (3) Å | Cell parameters from 9986 reflections |
b = 21.1373 (10) Å | θ = 3.3–68.3° |
c = 17.8054 (9) Å | µ = 2.02 mm−1 |
β = 92.826 (2)° | T = 285 K |
V = 1938.41 (18) Å3 | PLATE, colourless |
Z = 4 | 0.52 × 0.11 × 0.05 mm |
Data collection top
Bruker APEXII CCD diffractometer | 2994 reflections with I > 2σ(I) |
Radiation source: Cu | Rint = 0.062 |
φ and ω scans | θmax = 68.2°, θmin = 3.3° |
Absorption correction: multi-scan (SADABS; Bruker, 2016) | h = −6→6 |
Tmin = 0.424, Tmax = 0.907 | k = −25→25 |
24609 measured reflections | l = −21→21 |
3545 independent reflections | |
Refinement top
Refinement on F2 | Hydrogen site location: mixed |
Least-squares matrix: full | H atoms treated by a mixture of independent and constrained refinement |
R[F2 > 2σ(F2)] = 0.044 | w = 1/[σ2(Fo2) + (0.0554P)2 + 0.7152P] where P = (Fo2 + 2Fc2)/3 |
wR(F2) = 0.119 | (Δ/σ)max = 0.001 |
S = 1.03 | Δρmax = 0.24 e Å−3 |
3545 reflections | Δρmin = −0.34 e Å−3 |
276 parameters | Extinction correction: SHELXL2018 (Sheldrick, 2015b), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4 |
0 restraints | Extinction coefficient: 0.0150 (9) |
Special details top
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes)
are estimated using the full covariance matrix. The cell esds are taken
into account individually in the estimation of esds in distances, angles
and torsion angles; correlations between esds in cell parameters are only
used when they are defined by crystal symmetry. An approximate (isotropic)
treatment of cell esds is used for estimating esds involving l.s. planes. |
Refinement. For data collection and structure determination, suitable-sized crystals were
mounted on a Bruker APEXII CCD X-ray diffractometer. The mounted crystal was
irradiated with Cu Kα radiations (λ = 1.54178 Å) to collect the
diffraction data. The SAINT (Bruker, 1998) program was utilized to
reduce the collected data, followed by direct methods and Fourier
transformation techniques to solve the structures. The refined structures were
subjected to full-matrix least-square calculations on F2 using the
SHELXL program, with non-H atoms being refined anisotropically and
placed at geometrically idealized positions (Sheldrick, 2015b). |
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top | x | y | z | Uiso*/Ueq | |
Cl | 1.21944 (16) | 0.43407 (3) | 0.86940 (5) | 0.0982 (3) | |
O1 | 0.1000 (3) | 0.30786 (6) | 0.61414 (6) | 0.0470 (3) | |
O2 | 0.4486 (3) | 0.44255 (7) | 0.58391 (8) | 0.0621 (4) | |
O3 | 0.4702 (3) | 0.37096 (6) | 0.67534 (8) | 0.0540 (4) | |
O4 | 0.7627 (5) | 0.53683 (9) | 0.58902 (10) | 0.0932 (7) | |
H4A | 0.637488 | 0.515941 | 0.573288 | 0.140* | |
N1 | −0.1371 (3) | 0.27012 (7) | 0.51362 (7) | 0.0379 (3) | |
N2 | 0.0267 (4) | 0.37143 (8) | 0.51371 (10) | 0.0503 (4) | |
C1 | −0.1689 (3) | 0.21011 (8) | 0.54975 (9) | 0.0371 (4) | |
C2 | −0.3481 (4) | 0.20436 (10) | 0.60481 (10) | 0.0461 (4) | |
H2 | −0.447423 | 0.239035 | 0.617839 | 0.055* | |
C3 | −0.3787 (4) | 0.14700 (11) | 0.64023 (11) | 0.0544 (5) | |
H3 | −0.499542 | 0.142843 | 0.676983 | 0.065* | |
C4 | −0.2296 (4) | 0.09577 (11) | 0.62106 (12) | 0.0581 (6) | |
H4 | −0.249955 | 0.057175 | 0.645141 | 0.070* | |
C5 | −0.0514 (4) | 0.10150 (10) | 0.56663 (12) | 0.0534 (5) | |
H5 | 0.049186 | 0.066749 | 0.554626 | 0.064* | |
C6 | −0.0188 (3) | 0.15895 (8) | 0.52890 (10) | 0.0408 (4) | |
C7 | 0.1638 (4) | 0.16245 (9) | 0.46865 (11) | 0.0470 (4) | |
H7 | 0.313787 | 0.138155 | 0.474598 | 0.056* | |
C8 | 0.1367 (4) | 0.19699 (9) | 0.40614 (11) | 0.0475 (5) | |
H8 | 0.270026 | 0.193964 | 0.373016 | 0.057* | |
C9 | −0.0779 (4) | 0.23900 (9) | 0.38356 (10) | 0.0423 (4) | |
C10 | −0.1555 (5) | 0.24507 (11) | 0.30731 (11) | 0.0562 (5) | |
H10 | −0.066435 | 0.222756 | 0.271664 | 0.067* | |
C11 | −0.3595 (5) | 0.28311 (12) | 0.28397 (11) | 0.0626 (6) | |
H11 | −0.408684 | 0.285763 | 0.233113 | 0.075* | |
C12 | −0.4915 (4) | 0.31735 (11) | 0.33561 (12) | 0.0576 (6) | |
H12 | −0.628194 | 0.343560 | 0.319615 | 0.069* | |
C13 | −0.4202 (4) | 0.31267 (9) | 0.41165 (11) | 0.0474 (4) | |
H13 | −0.509729 | 0.335487 | 0.446757 | 0.057* | |
C14 | −0.2158 (3) | 0.27400 (8) | 0.43495 (9) | 0.0378 (4) | |
C15 | 0.0022 (3) | 0.31659 (8) | 0.54956 (9) | 0.0357 (4) | |
H3A | 0.335 (6) | 0.3510 (14) | 0.6490 (16) | 0.087 (9)* | |
H1A | 0.138 (4) | 0.3990 (11) | 0.5338 (12) | 0.052 (6)* | |
H1B | −0.038 (4) | 0.3754 (10) | 0.4707 (13) | 0.053 (6)* | |
C16 | 0.5489 (4) | 0.42198 (8) | 0.64295 (10) | 0.0430 (4) | |
C17 | 0.7677 (3) | 0.45485 (8) | 0.68269 (10) | 0.0405 (4) | |
C18 | 0.8629 (4) | 0.51091 (10) | 0.65335 (11) | 0.0536 (5) | |
C19 | 1.0674 (5) | 0.54195 (11) | 0.69094 (12) | 0.0623 (6) | |
H19 | 1.130310 | 0.579423 | 0.671395 | 0.075* | |
C20 | 1.1777 (4) | 0.51822 (10) | 0.75634 (12) | 0.0534 (5) | |
H20 | 1.316455 | 0.539041 | 0.780831 | 0.064* | |
C21 | 1.0816 (4) | 0.46307 (9) | 0.78576 (12) | 0.0511 (5) | |
C22 | 0.8794 (4) | 0.43162 (9) | 0.74970 (11) | 0.0480 (5) | |
H22 | 0.816590 | 0.394509 | 0.770187 | 0.058* | |
Atomic displacement parameters (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
Cl | 0.1061 (6) | 0.0770 (5) | 0.1047 (6) | −0.0120 (4) | −0.0639 (5) | 0.0219 (4) |
O1 | 0.0591 (8) | 0.0449 (7) | 0.0362 (6) | −0.0171 (6) | −0.0051 (6) | 0.0006 (5) |
O2 | 0.0770 (10) | 0.0582 (9) | 0.0491 (8) | −0.0251 (7) | −0.0171 (7) | 0.0096 (7) |
O3 | 0.0598 (8) | 0.0447 (8) | 0.0561 (8) | −0.0183 (6) | −0.0107 (7) | 0.0080 (6) |
O4 | 0.1345 (17) | 0.0828 (12) | 0.0590 (10) | −0.0615 (12) | −0.0295 (10) | 0.0294 (9) |
N1 | 0.0474 (8) | 0.0349 (7) | 0.0312 (7) | −0.0080 (6) | −0.0004 (6) | 0.0000 (6) |
N2 | 0.0648 (11) | 0.0403 (9) | 0.0446 (10) | −0.0163 (8) | −0.0090 (8) | 0.0040 (7) |
C1 | 0.0400 (9) | 0.0371 (9) | 0.0333 (8) | −0.0086 (7) | −0.0059 (7) | 0.0017 (7) |
C2 | 0.0482 (10) | 0.0507 (11) | 0.0393 (9) | −0.0040 (8) | 0.0014 (8) | 0.0038 (8) |
C3 | 0.0506 (11) | 0.0650 (13) | 0.0475 (11) | −0.0101 (10) | 0.0017 (8) | 0.0174 (9) |
C4 | 0.0558 (12) | 0.0540 (12) | 0.0633 (13) | −0.0142 (10) | −0.0078 (10) | 0.0254 (10) |
C5 | 0.0533 (11) | 0.0420 (10) | 0.0639 (12) | −0.0018 (9) | −0.0079 (9) | 0.0091 (9) |
C6 | 0.0384 (9) | 0.0411 (9) | 0.0419 (9) | −0.0069 (7) | −0.0070 (7) | 0.0020 (7) |
C7 | 0.0418 (9) | 0.0442 (10) | 0.0549 (11) | −0.0009 (8) | 0.0014 (8) | −0.0059 (8) |
C8 | 0.0479 (10) | 0.0493 (11) | 0.0462 (10) | −0.0100 (8) | 0.0111 (8) | −0.0105 (8) |
C9 | 0.0493 (10) | 0.0423 (10) | 0.0354 (9) | −0.0142 (8) | 0.0027 (7) | −0.0020 (7) |
C10 | 0.0726 (14) | 0.0613 (13) | 0.0348 (10) | −0.0166 (11) | 0.0019 (9) | −0.0040 (9) |
C11 | 0.0757 (14) | 0.0750 (15) | 0.0358 (10) | −0.0263 (12) | −0.0118 (10) | 0.0088 (10) |
C12 | 0.0526 (11) | 0.0611 (13) | 0.0573 (12) | −0.0149 (10) | −0.0147 (9) | 0.0194 (10) |
C13 | 0.0453 (10) | 0.0489 (11) | 0.0478 (10) | −0.0082 (8) | −0.0009 (8) | 0.0075 (8) |
C14 | 0.0430 (9) | 0.0379 (9) | 0.0323 (8) | −0.0127 (7) | −0.0017 (7) | 0.0023 (7) |
C15 | 0.0371 (8) | 0.0362 (9) | 0.0341 (8) | −0.0040 (7) | 0.0049 (7) | −0.0034 (7) |
C16 | 0.0488 (10) | 0.0381 (9) | 0.0421 (10) | −0.0050 (8) | 0.0025 (8) | −0.0029 (7) |
C17 | 0.0439 (9) | 0.0353 (9) | 0.0424 (9) | −0.0034 (7) | 0.0035 (7) | −0.0047 (7) |
C18 | 0.0681 (13) | 0.0510 (11) | 0.0415 (10) | −0.0188 (10) | 0.0010 (9) | 0.0010 (9) |
C19 | 0.0743 (14) | 0.0574 (13) | 0.0553 (12) | −0.0308 (11) | 0.0035 (10) | −0.0012 (10) |
C20 | 0.0456 (10) | 0.0530 (12) | 0.0614 (12) | −0.0086 (9) | −0.0003 (9) | −0.0166 (10) |
C21 | 0.0488 (10) | 0.0452 (10) | 0.0581 (12) | 0.0059 (8) | −0.0097 (9) | −0.0056 (9) |
C22 | 0.0495 (10) | 0.0370 (10) | 0.0567 (11) | −0.0022 (8) | −0.0053 (9) | 0.0022 (8) |
Geometric parameters (Å, º) top
Cl—C21 | 1.730 (2) | C7—C8 | 1.333 (3) |
O1—C15 | 1.246 (2) | C7—H7 | 0.9300 |
O2—C16 | 1.228 (2) | C8—C9 | 1.460 (3) |
O3—C16 | 1.297 (2) | C8—H8 | 0.9300 |
O3—H3A | 0.92 (3) | C9—C14 | 1.398 (3) |
O4—C18 | 1.349 (3) | C9—C10 | 1.402 (3) |
O4—H4A | 0.8200 | C10—C11 | 1.372 (4) |
N1—C15 | 1.358 (2) | C10—H10 | 0.9300 |
N1—C1 | 1.435 (2) | C11—C12 | 1.376 (3) |
N1—C14 | 1.441 (2) | C11—H11 | 0.9300 |
N2—C15 | 1.332 (2) | C12—C13 | 1.389 (3) |
N2—H1A | 0.88 (2) | C12—H12 | 0.9300 |
N2—H1B | 0.82 (2) | C13—C14 | 1.381 (3) |
C1—C2 | 1.385 (3) | C13—H13 | 0.9300 |
C1—C6 | 1.391 (3) | C16—C17 | 1.476 (3) |
C2—C3 | 1.379 (3) | C17—C22 | 1.389 (3) |
C2—H2 | 0.9300 | C17—C18 | 1.394 (3) |
C3—C4 | 1.381 (3) | C18—C19 | 1.386 (3) |
C3—H3 | 0.9300 | C19—C20 | 1.366 (3) |
C4—C5 | 1.373 (3) | C19—H19 | 0.9300 |
C4—H4 | 0.9300 | C20—C21 | 1.380 (3) |
C5—C6 | 1.402 (3) | C20—H20 | 0.9300 |
C5—H5 | 0.9300 | C21—C22 | 1.369 (3) |
C6—C7 | 1.464 (3) | C22—H22 | 0.9300 |
| | | |
C16—O3—H3A | 113.5 (18) | C9—C10—H10 | 119.2 |
C18—O4—H4A | 109.5 | C10—C11—C12 | 120.20 (18) |
C15—N1—C1 | 119.83 (14) | C10—C11—H11 | 119.9 |
C15—N1—C14 | 122.25 (13) | C12—C11—H11 | 119.9 |
C1—N1—C14 | 116.94 (13) | C11—C12—C13 | 119.9 (2) |
C15—N2—H1A | 117.1 (14) | C11—C12—H12 | 120.1 |
C15—N2—H1B | 119.4 (16) | C13—C12—H12 | 120.1 |
H1A—N2—H1B | 122 (2) | C14—C13—C12 | 119.76 (19) |
C2—C1—C6 | 121.34 (16) | C14—C13—H13 | 120.1 |
C2—C1—N1 | 119.33 (16) | C12—C13—H13 | 120.1 |
C6—C1—N1 | 119.34 (15) | C13—C14—C9 | 121.46 (16) |
C3—C2—C1 | 119.73 (19) | C13—C14—N1 | 119.98 (16) |
C3—C2—H2 | 120.1 | C9—C14—N1 | 118.55 (16) |
C1—C2—H2 | 120.1 | O1—C15—N2 | 121.82 (16) |
C2—C3—C4 | 119.94 (19) | O1—C15—N1 | 120.53 (15) |
C2—C3—H3 | 120.0 | N2—C15—N1 | 117.64 (15) |
C4—C3—H3 | 120.0 | O2—C16—O3 | 123.17 (17) |
C5—C4—C3 | 120.36 (19) | O2—C16—C17 | 121.58 (16) |
C5—C4—H4 | 119.8 | O3—C16—C17 | 115.25 (16) |
C3—C4—H4 | 119.8 | C22—C17—C18 | 118.94 (17) |
C4—C5—C6 | 121.0 (2) | C22—C17—C16 | 121.36 (16) |
C4—C5—H5 | 119.5 | C18—C17—C16 | 119.69 (17) |
C6—C5—H5 | 119.5 | O4—C18—C19 | 117.91 (18) |
C1—C6—C5 | 117.66 (17) | O4—C18—C17 | 122.43 (18) |
C1—C6—C7 | 122.88 (16) | C19—C18—C17 | 119.66 (19) |
C5—C6—C7 | 119.44 (17) | C20—C19—C18 | 120.85 (19) |
C8—C7—C6 | 126.50 (18) | C20—C19—H19 | 119.6 |
C8—C7—H7 | 116.8 | C18—C19—H19 | 119.6 |
C6—C7—H7 | 116.7 | C19—C20—C21 | 119.43 (18) |
C7—C8—C9 | 127.61 (17) | C19—C20—H20 | 120.3 |
C7—C8—H8 | 116.2 | C21—C20—H20 | 120.3 |
C9—C8—H8 | 116.2 | C22—C21—C20 | 120.77 (19) |
C14—C9—C10 | 117.08 (18) | C22—C21—Cl | 120.17 (16) |
C14—C9—C8 | 123.01 (16) | C20—C21—Cl | 119.06 (15) |
C10—C9—C8 | 119.90 (18) | C21—C22—C17 | 120.34 (18) |
C11—C10—C9 | 121.6 (2) | C21—C22—H22 | 119.8 |
C11—C10—H10 | 119.2 | C17—C22—H22 | 119.8 |
| | | |
C15—N1—C1—C2 | 78.0 (2) | C8—C9—C14—C13 | −179.12 (16) |
C14—N1—C1—C2 | −113.11 (18) | C10—C9—C14—N1 | −178.46 (15) |
C15—N1—C1—C6 | −101.90 (18) | C8—C9—C14—N1 | 2.2 (2) |
C14—N1—C1—C6 | 67.0 (2) | C15—N1—C14—C13 | −76.2 (2) |
C6—C1—C2—C3 | 0.3 (3) | C1—N1—C14—C13 | 115.19 (18) |
N1—C1—C2—C3 | −179.52 (16) | C15—N1—C14—C9 | 102.58 (19) |
C1—C2—C3—C4 | 0.4 (3) | C1—N1—C14—C9 | −66.1 (2) |
C2—C3—C4—C5 | −0.3 (3) | C1—N1—C15—O1 | −0.9 (2) |
C3—C4—C5—C6 | −0.7 (3) | C14—N1—C15—O1 | −169.25 (15) |
C2—C1—C6—C5 | −1.2 (2) | C1—N1—C15—N2 | 179.91 (16) |
N1—C1—C6—C5 | 178.62 (15) | C14—N1—C15—N2 | 11.6 (2) |
C2—C1—C6—C7 | 177.14 (16) | O2—C16—C17—C22 | 179.58 (19) |
N1—C1—C6—C7 | −3.0 (2) | O3—C16—C17—C22 | 0.4 (3) |
C4—C5—C6—C1 | 1.4 (3) | O2—C16—C17—C18 | 0.6 (3) |
C4—C5—C6—C7 | −177.01 (18) | O3—C16—C17—C18 | −178.59 (18) |
C1—C6—C7—C8 | −33.5 (3) | C22—C17—C18—O4 | −179.2 (2) |
C5—C6—C7—C8 | 144.8 (2) | C16—C17—C18—O4 | −0.2 (3) |
C6—C7—C8—C9 | 0.3 (3) | C22—C17—C18—C19 | 0.6 (3) |
C7—C8—C9—C14 | 33.6 (3) | C16—C17—C18—C19 | 179.6 (2) |
C7—C8—C9—C10 | −145.8 (2) | O4—C18—C19—C20 | −180.0 (2) |
C14—C9—C10—C11 | −0.7 (3) | C17—C18—C19—C20 | 0.2 (4) |
C8—C9—C10—C11 | 178.71 (18) | C18—C19—C20—C21 | −0.9 (3) |
C9—C10—C11—C12 | 1.0 (3) | C19—C20—C21—C22 | 0.8 (3) |
C10—C11—C12—C13 | −0.9 (3) | C19—C20—C21—Cl | −178.99 (17) |
C11—C12—C13—C14 | 0.5 (3) | C20—C21—C22—C17 | 0.0 (3) |
C12—C13—C14—C9 | −0.2 (3) | Cl—C21—C22—C17 | 179.79 (15) |
C12—C13—C14—N1 | 178.55 (16) | C18—C17—C22—C21 | −0.7 (3) |
C10—C9—C14—C13 | 0.3 (3) | C16—C17—C22—C21 | −179.70 (17) |
2-Azatricyclo[9.4.0.0
3,8]pentadeca-1(11),3,5,7,9,12,14-heptaene-2-carboxamide; 3-phenylprop-2-enoic acid (CBZTCA)
top
Crystal data top
C15H12N2O·C9H8O2 | F(000) = 808 |
Mr = 384.42 | Dx = 1.293 Mg m−3 |
Monoclinic, P21/c | Cu Kα radiation, λ = 1.54178 Å |
a = 15.3440 (6) Å | Cell parameters from 6596 reflections |
b = 5.4552 (3) Å | θ = 2.9–67.3° |
c = 23.7301 (9) Å | µ = 0.69 mm−1 |
β = 96.148 (2)° | T = 285 K |
V = 1974.89 (15) Å3 | NEEDLE, colourless |
Z = 4 | 0.21 × 0.05 × 0.04 mm |
Data collection top
Bruker APEXII CCD diffractometer | 2506 reflections with I > 2σ(I) |
Radiation source: Cu | Rint = 0.067 |
φ and ω scans | θmax = 68.2°, θmin = 2.9° |
Absorption correction: multi-scan (SADABS; Bruker, 2016) | h = −18→18 |
Tmin = 0.868, Tmax = 0.973 | k = −6→6 |
25468 measured reflections | l = −28→28 |
3559 independent reflections | |
Refinement top
Refinement on F2 | Hydrogen site location: mixed |
Least-squares matrix: full | H atoms treated by a mixture of independent and constrained refinement |
R[F2 > 2σ(F2)] = 0.043 | w = 1/[σ2(Fo2) + (0.0522P)2 + 0.4333P] where P = (Fo2 + 2Fc2)/3 |
wR(F2) = 0.113 | (Δ/σ)max < 0.001 |
S = 1.01 | Δρmax = 0.17 e Å−3 |
3559 reflections | Δρmin = −0.20 e Å−3 |
319 parameters | Extinction correction: SHELXL2018 (Sheldrick, 2015b), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4 |
197 restraints | Extinction coefficient: 0.0035 (3) |
Special details top
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes)
are estimated using the full covariance matrix. The cell esds are taken
into account individually in the estimation of esds in distances, angles
and torsion angles; correlations between esds in cell parameters are only
used when they are defined by crystal symmetry. An approximate (isotropic)
treatment of cell esds is used for estimating esds involving l.s. planes. |
Refinement. For data collection and structure determination, suitable-sized crystals were
mounted on a Bruker APEXII CCD X-ray diffractometer. The mounted crystal was
irradiated with Cu Kα radiations (λ = 1.54178 Å) to collect the
diffraction data. The SAINT (Bruker, 1998) program was utilized to
reduce the collected data, followed by direct methods and Fourier
transformation techniques to solve the structures. The refined structures were
subjected to full-matrix least-square calculations on F2 using the
SHELXL program, with non-H atoms being refined anisotropically and
placed at geometrically idealized positions (Sheldrick, 2015b). |
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top | x | y | z | Uiso*/Ueq | Occ. (<1) |
O1 | 0.40139 (7) | 0.1827 (2) | 0.48224 (5) | 0.0446 (3) | |
N1 | 0.37041 (8) | 0.4543 (3) | 0.55005 (5) | 0.0373 (3) | |
N2 | 0.50449 (9) | 0.2589 (3) | 0.55460 (7) | 0.0441 (4) | |
H2A | 0.540564 | 0.159188 | 0.541296 | 0.053* | 0.5 |
H2B | 0.519703 | 0.336733 | 0.585617 | 0.053* | 0.5 |
H2C | 0.528 (2) | 0.352 (8) | 0.5817 (16) | 0.053* | 0.5 |
H2D | 0.531 (2) | 0.135 (8) | 0.5395 (15) | 0.053* | 0.5 |
C1 | 0.28236 (10) | 0.4877 (3) | 0.52383 (7) | 0.0382 (4) | |
C2 | 0.26490 (12) | 0.6662 (4) | 0.48316 (8) | 0.0488 (5) | |
H2 | 0.309714 | 0.768018 | 0.473686 | 0.059* | |
C3 | 0.18132 (13) | 0.6944 (4) | 0.45649 (9) | 0.0613 (6) | |
H3 | 0.169356 | 0.815665 | 0.429202 | 0.074* | |
C4 | 0.11576 (13) | 0.5420 (5) | 0.47053 (9) | 0.0664 (7) | |
H4 | 0.059520 | 0.557761 | 0.451952 | 0.080* | |
C5 | 0.13253 (12) | 0.3658 (5) | 0.51189 (9) | 0.0633 (6) | |
H5 | 0.087520 | 0.263091 | 0.520642 | 0.076* | |
C6 | 0.21637 (11) | 0.3393 (4) | 0.54095 (8) | 0.0472 (5) | |
C7 | 0.23114 (13) | 0.1734 (4) | 0.58898 (10) | 0.0638 (6) | |
H7 | 0.198466 | 0.029501 | 0.586949 | 0.077* | |
C8 | 0.28683 (13) | 0.2058 (4) | 0.63585 (9) | 0.0637 (6) | |
H8 | 0.287356 | 0.083377 | 0.663145 | 0.076* | |
C9 | 0.34635 (12) | 0.4092 (4) | 0.64907 (8) | 0.0503 (5) | |
C10 | 0.36617 (15) | 0.4918 (5) | 0.70528 (9) | 0.0726 (7) | |
H10 | 0.342633 | 0.410374 | 0.734585 | 0.087* | |
C11 | 0.42012 (17) | 0.6922 (6) | 0.71745 (10) | 0.0809 (8) | |
H11 | 0.430895 | 0.747317 | 0.754627 | 0.097* | |
C12 | 0.45766 (17) | 0.8097 (5) | 0.67543 (10) | 0.0764 (7) | |
H12 | 0.494431 | 0.943074 | 0.684014 | 0.092* | |
C13 | 0.44107 (13) | 0.7307 (4) | 0.62065 (8) | 0.0555 (5) | |
H13 | 0.467081 | 0.809889 | 0.592040 | 0.067* | |
C14 | 0.38613 (11) | 0.5348 (3) | 0.60758 (7) | 0.0408 (4) | |
C15 | 0.42488 (10) | 0.2930 (3) | 0.52711 (7) | 0.0347 (4) | |
C16A | 0.28984 (19) | 0.3835 (6) | 0.35628 (12) | 0.0500 (7) | 0.907 (4) |
O2A | 0.34838 (15) | 0.5333 (5) | 0.35944 (9) | 0.0676 (6) | 0.907 (4) |
O3A | 0.28359 (15) | 0.2049 (4) | 0.39373 (10) | 0.0661 (6) | 0.907 (4) |
H3A1 | 0.3323 (15) | 0.222 (5) | 0.4251 (9) | 0.099* | 0.907 (4) |
C17A | 0.21566 (14) | 0.3778 (5) | 0.31132 (9) | 0.0541 (7) | 0.907 (4) |
H17A | 0.176707 | 0.246818 | 0.310029 | 0.065* | 0.907 (4) |
C18A | 0.20282 (16) | 0.5513 (5) | 0.27313 (10) | 0.0492 (7) | 0.907 (4) |
H18A | 0.243133 | 0.679156 | 0.275531 | 0.059* | 0.907 (4) |
C16B | 0.3160 (19) | 0.494 (6) | 0.3479 (13) | 0.057 (5) | 0.093 (4) |
O2B | 0.3816 (14) | 0.618 (5) | 0.3591 (10) | 0.072 (6) | 0.093 (4) |
H2B1 | 0.402931 | 0.588271 | 0.391586 | 0.107* | 0.093 (4) |
O3B | 0.2963 (16) | 0.291 (5) | 0.3761 (10) | 0.061 (5) | 0.093 (4) |
C17B | 0.2521 (12) | 0.556 (4) | 0.3001 (8) | 0.055 (4) | 0.093 (4) |
H17B | 0.266764 | 0.692830 | 0.279801 | 0.066* | 0.093 (4) |
C18B | 0.1781 (13) | 0.454 (5) | 0.2805 (9) | 0.049 (5) | 0.093 (4) |
H18B | 0.155282 | 0.321038 | 0.298485 | 0.059* | 0.093 (4) |
C19 | 0.13096 (12) | 0.5641 (4) | 0.22677 (7) | 0.0481 (5) | |
C20 | 0.13083 (13) | 0.7571 (4) | 0.18926 (9) | 0.0578 (5) | |
H20 | 0.174643 | 0.875193 | 0.194558 | 0.069* | |
C21 | 0.06698 (14) | 0.7782 (4) | 0.14404 (9) | 0.0629 (6) | |
H21 | 0.068238 | 0.909515 | 0.119155 | 0.075* | |
C22 | 0.00179 (14) | 0.6070 (4) | 0.13558 (8) | 0.0604 (6) | |
H22 | −0.041291 | 0.621884 | 0.105080 | 0.073* | |
C23 | 0.00027 (14) | 0.4133 (4) | 0.17233 (9) | 0.0615 (6) | |
H23 | −0.043770 | 0.295904 | 0.166720 | 0.074* | |
C24 | 0.06431 (13) | 0.3928 (4) | 0.21771 (8) | 0.0560 (5) | |
H24 | 0.062616 | 0.261664 | 0.242604 | 0.067* | |
Atomic displacement parameters (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
O1 | 0.0396 (7) | 0.0458 (8) | 0.0471 (7) | 0.0057 (5) | −0.0012 (5) | −0.0064 (6) |
N1 | 0.0280 (7) | 0.0439 (9) | 0.0394 (8) | 0.0043 (6) | 0.0016 (6) | −0.0006 (6) |
N2 | 0.0327 (8) | 0.0442 (10) | 0.0541 (9) | 0.0063 (7) | −0.0017 (7) | −0.0042 (8) |
C1 | 0.0288 (8) | 0.0433 (11) | 0.0421 (9) | 0.0047 (7) | 0.0024 (7) | −0.0074 (8) |
C2 | 0.0424 (10) | 0.0542 (13) | 0.0484 (10) | 0.0055 (8) | −0.0016 (8) | 0.0019 (9) |
C3 | 0.0509 (12) | 0.0700 (15) | 0.0594 (12) | 0.0165 (11) | −0.0106 (10) | −0.0014 (11) |
C4 | 0.0377 (11) | 0.0919 (19) | 0.0655 (14) | 0.0170 (11) | −0.0134 (10) | −0.0196 (13) |
C5 | 0.0323 (10) | 0.0813 (17) | 0.0764 (15) | −0.0056 (10) | 0.0059 (10) | −0.0186 (13) |
C6 | 0.0347 (10) | 0.0522 (12) | 0.0546 (11) | 0.0009 (8) | 0.0049 (8) | −0.0066 (9) |
C7 | 0.0458 (11) | 0.0597 (15) | 0.0883 (16) | −0.0081 (10) | 0.0178 (11) | 0.0111 (12) |
C8 | 0.0501 (12) | 0.0761 (16) | 0.0671 (14) | 0.0056 (11) | 0.0159 (11) | 0.0298 (12) |
C9 | 0.0406 (10) | 0.0664 (14) | 0.0442 (10) | 0.0163 (9) | 0.0054 (8) | 0.0091 (9) |
C10 | 0.0643 (14) | 0.111 (2) | 0.0426 (12) | 0.0367 (14) | 0.0074 (10) | 0.0128 (13) |
C11 | 0.0844 (18) | 0.100 (2) | 0.0512 (13) | 0.0413 (16) | −0.0240 (12) | −0.0212 (14) |
C12 | 0.0869 (17) | 0.0678 (17) | 0.0667 (15) | 0.0146 (13) | −0.0276 (13) | −0.0133 (13) |
C13 | 0.0572 (12) | 0.0500 (13) | 0.0555 (11) | 0.0011 (10) | −0.0119 (9) | −0.0034 (10) |
C14 | 0.0361 (9) | 0.0467 (11) | 0.0383 (9) | 0.0116 (8) | −0.0016 (7) | −0.0012 (8) |
C15 | 0.0303 (9) | 0.0313 (10) | 0.0426 (9) | −0.0014 (7) | 0.0040 (7) | 0.0060 (7) |
C16A | 0.0462 (14) | 0.059 (2) | 0.0434 (16) | 0.0085 (12) | −0.0024 (12) | −0.0052 (12) |
O2A | 0.0512 (16) | 0.0880 (18) | 0.0608 (13) | −0.0095 (11) | −0.0077 (11) | 0.0062 (12) |
O3A | 0.0725 (13) | 0.0623 (14) | 0.0582 (14) | −0.0012 (10) | −0.0185 (10) | 0.0066 (9) |
C17A | 0.0507 (13) | 0.0610 (16) | 0.0478 (12) | −0.0030 (11) | −0.0066 (10) | −0.0008 (10) |
C18A | 0.0424 (15) | 0.0576 (18) | 0.0472 (12) | −0.0003 (11) | 0.0034 (11) | −0.0026 (11) |
C16B | 0.049 (8) | 0.072 (9) | 0.046 (8) | −0.012 (7) | −0.005 (6) | 0.002 (7) |
O2B | 0.057 (9) | 0.080 (11) | 0.073 (11) | −0.020 (8) | −0.014 (8) | 0.011 (9) |
O3B | 0.059 (10) | 0.081 (10) | 0.036 (10) | −0.028 (8) | −0.026 (7) | 0.004 (7) |
C17B | 0.047 (7) | 0.067 (8) | 0.049 (7) | −0.005 (6) | −0.003 (6) | 0.006 (6) |
C18B | 0.040 (7) | 0.054 (10) | 0.052 (9) | 0.003 (7) | 0.001 (7) | 0.003 (8) |
C19 | 0.0429 (10) | 0.0573 (13) | 0.0435 (10) | 0.0078 (9) | 0.0016 (8) | −0.0043 (9) |
C20 | 0.0494 (12) | 0.0588 (14) | 0.0636 (12) | −0.0038 (10) | −0.0007 (10) | 0.0036 (11) |
C21 | 0.0640 (13) | 0.0613 (15) | 0.0612 (13) | 0.0045 (11) | −0.0032 (10) | 0.0160 (11) |
C22 | 0.0593 (13) | 0.0677 (16) | 0.0506 (12) | 0.0040 (11) | −0.0116 (10) | 0.0032 (11) |
C23 | 0.0601 (13) | 0.0600 (15) | 0.0609 (13) | −0.0073 (10) | −0.0099 (10) | −0.0002 (11) |
C24 | 0.0619 (13) | 0.0567 (14) | 0.0477 (11) | 0.0019 (10) | −0.0014 (9) | 0.0089 (9) |
Geometric parameters (Å, º) top
O1—C15 | 1.2424 (19) | C12—H12 | 0.9300 |
N1—C15 | 1.366 (2) | C13—C14 | 1.376 (3) |
N1—C14 | 1.430 (2) | C13—H13 | 0.9300 |
N1—C1 | 1.437 (2) | C16A—O2A | 1.211 (4) |
N2—C15 | 1.335 (2) | C16A—O3A | 1.329 (4) |
N2—H2A | 0.8600 | C16A—C17A | 1.475 (3) |
N2—H2B | 0.8600 | O3A—H3A1 | 1.001 (17) |
N2—H2C | 0.87 (4) | C17A—C18A | 1.310 (3) |
N2—H2D | 0.89 (4) | C17A—H17A | 0.9300 |
C1—C2 | 1.377 (2) | C18A—C19 | 1.474 (3) |
C1—C6 | 1.391 (2) | C18A—H18A | 0.9300 |
C2—C3 | 1.377 (2) | C16B—O2B | 1.218 (18) |
C2—H2 | 0.9300 | C16B—O3B | 1.346 (18) |
C3—C4 | 1.374 (3) | C16B—C17B | 1.458 (17) |
C3—H3 | 0.9300 | O2B—H2B1 | 0.8200 |
C4—C5 | 1.378 (3) | C17B—C18B | 1.303 (17) |
C4—H4 | 0.9300 | C17B—H17B | 0.9300 |
C5—C6 | 1.400 (3) | C18B—C19 | 1.520 (16) |
C5—H5 | 0.9300 | C18B—H18B | 0.9300 |
C6—C7 | 1.454 (3) | C19—C20 | 1.378 (3) |
C7—C8 | 1.340 (3) | C19—C24 | 1.385 (3) |
C7—H7 | 0.9300 | C20—C21 | 1.378 (3) |
C8—C9 | 1.450 (3) | C20—H20 | 0.9300 |
C8—H8 | 0.9300 | C21—C22 | 1.367 (3) |
C9—C14 | 1.393 (3) | C21—H21 | 0.9300 |
C9—C10 | 1.410 (3) | C22—C23 | 1.372 (3) |
C10—C11 | 1.383 (4) | C22—H22 | 0.9300 |
C10—H10 | 0.9300 | C23—C24 | 1.382 (3) |
C11—C12 | 1.364 (4) | C23—H23 | 0.9300 |
C11—H11 | 0.9300 | C24—H24 | 0.9300 |
C12—C13 | 1.367 (3) | | |
| | | |
C15—N1—C14 | 122.03 (13) | C12—C13—C14 | 120.4 (2) |
C15—N1—C1 | 119.74 (13) | C12—C13—H13 | 119.8 |
C14—N1—C1 | 115.41 (12) | C14—C13—H13 | 119.8 |
C15—N2—H2A | 120.0 | C13—C14—C9 | 121.81 (18) |
C15—N2—H2B | 120.0 | C13—C14—N1 | 119.37 (17) |
H2A—N2—H2B | 120.0 | C9—C14—N1 | 118.81 (17) |
C15—N2—H2C | 124 (3) | O1—C15—N2 | 121.19 (16) |
H2A—N2—H2C | 114.3 | O1—C15—N1 | 121.31 (14) |
H2B—N2—H2C | 12.3 | N2—C15—N1 | 117.50 (15) |
C15—N2—H2D | 110 (2) | O2A—C16A—O3A | 124.0 (3) |
H2A—N2—H2D | 12.9 | O2A—C16A—C17A | 124.7 (3) |
H2B—N2—H2D | 128.9 | O3A—C16A—C17A | 111.3 (3) |
H2C—N2—H2D | 125 (4) | C16A—O3A—H3A1 | 109.2 (17) |
C2—C1—C6 | 121.56 (16) | C18A—C17A—C16A | 122.2 (3) |
C2—C1—N1 | 119.76 (15) | C18A—C17A—H17A | 118.9 |
C6—C1—N1 | 118.67 (15) | C16A—C17A—H17A | 118.9 |
C3—C2—C1 | 120.20 (19) | C17A—C18A—C19 | 126.6 (2) |
C3—C2—H2 | 119.9 | C17A—C18A—H18A | 116.7 |
C1—C2—H2 | 119.9 | C19—C18A—H18A | 116.7 |
C4—C3—C2 | 119.4 (2) | O2B—C16B—O3B | 125 (2) |
C4—C3—H3 | 120.3 | O2B—C16B—C17B | 121 (2) |
C2—C3—H3 | 120.3 | O3B—C16B—C17B | 114.1 (19) |
C3—C4—C5 | 120.61 (19) | C16B—O2B—H2B1 | 109.5 |
C3—C4—H4 | 119.7 | C18B—C17B—C16B | 131.9 (19) |
C5—C4—H4 | 119.7 | C18B—C17B—H17B | 114.0 |
C4—C5—C6 | 121.0 (2) | C16B—C17B—H17B | 114.0 |
C4—C5—H5 | 119.5 | C17B—C18B—C19 | 116.7 (18) |
C6—C5—H5 | 119.5 | C17B—C18B—H18B | 121.6 |
C1—C6—C5 | 117.07 (18) | C19—C18B—H18B | 121.6 |
C1—C6—C7 | 122.28 (16) | C20—C19—C24 | 117.71 (17) |
C5—C6—C7 | 120.55 (18) | C20—C19—C18A | 117.9 (2) |
C8—C7—C6 | 126.9 (2) | C24—C19—C18A | 124.4 (2) |
C8—C7—H7 | 116.5 | C20—C19—C18B | 144.1 (9) |
C6—C7—H7 | 116.5 | C24—C19—C18B | 98.1 (9) |
C7—C8—C9 | 127.71 (19) | C21—C20—C19 | 121.2 (2) |
C7—C8—H8 | 116.1 | C21—C20—H20 | 119.4 |
C9—C8—H8 | 116.1 | C19—C20—H20 | 119.4 |
C14—C9—C10 | 116.4 (2) | C22—C21—C20 | 120.3 (2) |
C14—C9—C8 | 122.49 (18) | C22—C21—H21 | 119.8 |
C10—C9—C8 | 121.1 (2) | C20—C21—H21 | 119.8 |
C11—C10—C9 | 120.9 (2) | C21—C22—C23 | 119.65 (19) |
C11—C10—H10 | 119.5 | C21—C22—H22 | 120.2 |
C9—C10—H10 | 119.5 | C23—C22—H22 | 120.2 |
C12—C11—C10 | 120.6 (2) | C22—C23—C24 | 119.9 (2) |
C12—C11—H11 | 119.7 | C22—C23—H23 | 120.1 |
C10—C11—H11 | 119.7 | C24—C23—H23 | 120.1 |
C11—C12—C13 | 119.8 (3) | C23—C24—C19 | 121.20 (19) |
C11—C12—H12 | 120.1 | C23—C24—H24 | 119.4 |
C13—C12—H12 | 120.1 | C19—C24—H24 | 119.4 |
| | | |
C15—N1—C1—C2 | −90.9 (2) | C8—C9—C14—N1 | −2.5 (3) |
C14—N1—C1—C2 | 107.77 (18) | C15—N1—C14—C13 | 85.6 (2) |
C15—N1—C1—C6 | 89.91 (19) | C1—N1—C14—C13 | −113.47 (18) |
C14—N1—C1—C6 | −71.4 (2) | C15—N1—C14—C9 | −93.25 (19) |
C6—C1—C2—C3 | −2.9 (3) | C1—N1—C14—C9 | 67.6 (2) |
N1—C1—C2—C3 | 177.90 (16) | C14—N1—C15—O1 | 163.73 (16) |
C1—C2—C3—C4 | −0.4 (3) | C1—N1—C15—O1 | 3.6 (2) |
C2—C3—C4—C5 | 1.6 (3) | C14—N1—C15—N2 | −16.5 (2) |
C3—C4—C5—C6 | 0.6 (3) | C1—N1—C15—N2 | −176.63 (15) |
C2—C1—C6—C5 | 4.9 (3) | O2A—C16A—C17A—C18A | −6.3 (4) |
N1—C1—C6—C5 | −175.88 (16) | O3A—C16A—C17A—C18A | 172.6 (2) |
C2—C1—C6—C7 | −171.42 (19) | C16A—C17A—C18A—C19 | −179.7 (2) |
N1—C1—C6—C7 | 7.8 (3) | O2B—C16B—C17B—C18B | −179 (4) |
C4—C5—C6—C1 | −3.8 (3) | O3B—C16B—C17B—C18B | 2 (6) |
C4—C5—C6—C7 | 172.7 (2) | C16B—C17B—C18B—C19 | −177 (3) |
C1—C6—C7—C8 | 31.7 (3) | C17A—C18A—C19—C20 | −177.3 (2) |
C5—C6—C7—C8 | −144.5 (2) | C17A—C18A—C19—C24 | 1.5 (4) |
C6—C7—C8—C9 | −1.5 (4) | C17B—C18B—C19—C20 | −8 (4) |
C7—C8—C9—C14 | −32.7 (3) | C17B—C18B—C19—C24 | 174 (2) |
C7—C8—C9—C10 | 146.6 (2) | C24—C19—C20—C21 | −0.4 (3) |
C14—C9—C10—C11 | 2.0 (3) | C18A—C19—C20—C21 | 178.4 (2) |
C8—C9—C10—C11 | −177.30 (19) | C18B—C19—C20—C21 | −178.0 (19) |
C9—C10—C11—C12 | −2.1 (3) | C19—C20—C21—C22 | 0.2 (3) |
C10—C11—C12—C13 | 0.8 (4) | C20—C21—C22—C23 | −0.1 (3) |
C11—C12—C13—C14 | 0.6 (3) | C21—C22—C23—C24 | 0.3 (3) |
C12—C13—C14—C9 | −0.6 (3) | C22—C23—C24—C19 | −0.5 (3) |
C12—C13—C14—N1 | −179.46 (17) | C20—C19—C24—C23 | 0.6 (3) |
C10—C9—C14—C13 | −0.7 (3) | C18A—C19—C24—C23 | −178.2 (2) |
C8—C9—C14—C13 | 178.63 (18) | C18B—C19—C24—C23 | 179.1 (11) |
C10—C9—C14—N1 | 178.18 (16) | | |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
N2—H2A···O1i | 0.86 | 2.17 | 2.987 (2) | 160 |
N2—H2C···O2Aaii | 0.87 (4) | 2.32 (4) | 3.091 (3) | 148 (3) |
N2—H2C···O2Bbii | 0.87 (4) | 1.87 (4) | 2.63 (2) | 145 (4) |
N2—H2C···O2Aaii | 0.87 (4) | 2.32 (4) | 3.091 (3) | 148 (3) |
N2—H2C···O2Bbii | 0.87 (4) | 1.87 (4) | 2.63 (2) | 145 (4) |
N2—H2A···O1i | 0.86 | 2.17 | 2.987 (2) | 160 |
C13—H13···N2iii | 0.93 | 2.69 | 3.469 (3) | 142 |
O3Aa—H3A1a···O1 | 1.00 (2) | 1.64 (2) | 2.623 (2) | 165 (3) |
O2Bb—H2B1b···N2ii | 0.82 | 1.99 | 2.63 (2) | 135 |
Symmetry codes: (i) −x+1, −y, −z+1; (ii) −x+1, −y+1, −z+1; (iii) x, y+1, z. |
2-Azatricyclo[9.4.0.0
3,8]pentadeca-1(11),3,5,7,9,12,14-heptaene-2-carboxamide; pyridine-3-carboxamide (CBZNA)
top
Crystal data top
C15H12N2O·C6H6N2O | F(000) = 752 |
Mr = 358.39 | Dx = 1.328 Mg m−3 |
Monoclinic, P21/n | Cu Kα radiation, λ = 1.54178 Å |
a = 5.1236 (1) Å | Cell parameters from 7391 reflections |
b = 17.7396 (5) Å | θ = 3.4–68.2° |
c = 19.7236 (6) Å | µ = 0.71 mm−1 |
β = 91.090 (2)° | T = 285 K |
V = 1792.37 (8) Å3 | Needle, colourless |
Z = 4 | 0.43 × 0.06 × 0.05 mm |
Data collection top
Bruker APEXII CCD diffractometer | 2538 reflections with I > 2σ(I) |
Radiation source: Cu | Rint = 0.070 |
φ and ω scans | θmax = 68.2°, θmin = 3.4° |
Absorption correction: multi-scan (SADABS; Bruker, 2016) | h = −6→5 |
Tmin = 0.749, Tmax = 0.965 | k = −21→21 |
24350 measured reflections | l = −23→23 |
3284 independent reflections | |
Refinement top
Refinement on F2 | Hydrogen site location: inferred from neighbouring sites |
Least-squares matrix: full | H-atom parameters constrained |
R[F2 > 2σ(F2)] = 0.040 | w = 1/[σ2(Fo2) + (0.0489P)2 + 0.3659P] where P = (Fo2 + 2Fc2)/3 |
wR(F2) = 0.107 | (Δ/σ)max = 0.001 |
S = 1.05 | Δρmax = 0.20 e Å−3 |
3284 reflections | Δρmin = −0.15 e Å−3 |
254 parameters | Extinction correction: SHELXL2018 (Sheldrick, 2015b), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4 |
0 restraints | Extinction coefficient: 0.0104 (6) |
Special details top
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes)
are estimated using the full covariance matrix. The cell esds are taken
into account individually in the estimation of esds in distances, angles
and torsion angles; correlations between esds in cell parameters are only
used when they are defined by crystal symmetry. An approximate (isotropic)
treatment of cell esds is used for estimating esds involving l.s. planes. |
Refinement. For data collection and structure determination, suitable-sized crystals were
mounted on a Bruker APEXII CCD X-ray diffractometer. The mounted crystal was
irradiated with Cu Kα radiations (λ = 1.54178 Å) to collect the
diffraction data. The SAINT (Bruker, 1998) program was utilized to
reduce the collected data, followed by direct methods and Fourier
transformation techniques to solve the structures. The refined structures were
subjected to full-matrix least-square calculations on F2 using the
SHELXL program, with non-H atoms being refined anisotropically and
placed at geometrically idealized positions (Sheldrick, 2015b). |
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top | x | y | z | Uiso*/Ueq | Occ. (<1) |
O1 | 0.1862 (2) | 0.42226 (7) | 0.96461 (5) | 0.0430 (3) | |
O2 | 0.6747 (2) | 0.44075 (10) | 0.79846 (7) | 0.0688 (5) | |
N1 | 0.4204 (2) | 0.35826 (7) | 1.04406 (6) | 0.0349 (3) | |
N2 | 0.2242 (3) | 0.47186 (8) | 1.06930 (7) | 0.0422 (3) | |
H2A | 0.130777 | 0.510352 | 1.058187 | 0.051* | |
H2B | 0.286674 | 0.467752 | 1.109909 | 0.051* | |
N3 | 0.2544 (3) | 0.41713 (9) | 0.81963 (7) | 0.0526 (4) | |
H3A | 0.285876 | 0.410758 | 0.862227 | 0.063* | |
H3B | 0.097627 | 0.412692 | 0.803764 | 0.063* | |
N4 | 0.4948 (3) | 0.50177 (10) | 0.59960 (9) | 0.0636 (5) | |
C1 | 0.4645 (3) | 0.29815 (9) | 0.99719 (8) | 0.0378 (4) | |
C2 | 0.6552 (4) | 0.30634 (12) | 0.94927 (9) | 0.0520 (5) | |
H2 | 0.749347 | 0.350979 | 0.946162 | 0.062* | |
C6 | 0.3118 (3) | 0.23352 (9) | 1.00050 (8) | 0.0438 (4) | |
C7 | 0.1186 (4) | 0.22180 (10) | 1.05276 (10) | 0.0511 (5) | |
H7 | −0.029486 | 0.194580 | 1.039964 | 0.061* | |
C8 | 0.1302 (3) | 0.24575 (10) | 1.11695 (10) | 0.0486 (4) | |
H8 | −0.008866 | 0.232326 | 1.144076 | 0.058* | |
C9 | 0.3359 (3) | 0.29050 (9) | 1.14929 (8) | 0.0396 (4) | |
C10 | 0.3932 (4) | 0.28115 (12) | 1.21833 (9) | 0.0551 (5) | |
H10 | 0.294871 | 0.247486 | 1.243431 | 0.066* | |
C11 | 0.5913 (4) | 0.32056 (13) | 1.24990 (9) | 0.0595 (5) | |
H11 | 0.627583 | 0.312736 | 1.295738 | 0.071* | |
C12 | 0.7367 (4) | 0.37161 (12) | 1.21404 (10) | 0.0546 (5) | |
H12 | 0.870995 | 0.398217 | 1.235547 | 0.065* | |
C13 | 0.6823 (3) | 0.38310 (10) | 1.14620 (9) | 0.0439 (4) | |
H13 | 0.780110 | 0.417609 | 1.121882 | 0.053* | |
C14 | 0.4831 (3) | 0.34357 (9) | 1.11406 (8) | 0.0343 (4) | |
C15 | 0.2723 (3) | 0.41856 (9) | 1.02357 (7) | 0.0320 (3) | |
C16 | 0.4473 (3) | 0.43376 (11) | 0.77845 (8) | 0.0439 (4) | |
C18 | 0.5341 (3) | 0.48934 (11) | 0.66573 (9) | 0.0520 (5) | |
H18 | 0.676869 | 0.512568 | 0.686735 | 0.062* | |
C19 | 0.2914 (4) | 0.46768 (12) | 0.57056 (10) | 0.0562 (5) | |
H19 | 0.262149 | 0.474576 | 0.524291 | 0.067* | |
C20 | 0.1230 (4) | 0.42305 (12) | 0.60506 (10) | 0.0575 (5) | |
H20 | −0.019067 | 0.400986 | 0.582744 | 0.069* | |
C21 | 0.1656 (3) | 0.41096 (11) | 0.67333 (9) | 0.0475 (4) | |
H21 | 0.052700 | 0.380629 | 0.697657 | 0.057* | |
C17 | 0.3775 (3) | 0.44437 (9) | 0.70518 (8) | 0.0369 (4) | |
C3 | 0.704 (11) | 0.246 (3) | 0.905 (3) | 0.068 (3) | 0.5 |
H3 | 0.843787 | 0.246477 | 0.875547 | 0.081* | 0.5 |
C4 | 0.515 (3) | 0.1771 (10) | 0.9081 (10) | 0.055 (2) | 0.5 |
H4 | 0.531019 | 0.137919 | 0.877164 | 0.066* | 0.5 |
C5 | 0.332 (7) | 0.174 (3) | 0.954 (3) | 0.058 (3) | 0.5 |
H5 | 0.217301 | 0.133485 | 0.955199 | 0.070* | 0.5 |
C3A | 0.689 (10) | 0.254 (3) | 0.901 (3) | 0.068 (3) | 0.5 |
H3A1 | 0.802949 | 0.264367 | 0.866103 | 0.081* | 0.5 |
C4A | 0.579 (3) | 0.1937 (10) | 0.9008 (10) | 0.055 (2) | 0.5 |
H4A | 0.621450 | 0.156501 | 0.869633 | 0.066* | 0.5 |
C5A | 0.377 (7) | 0.181 (3) | 0.950 (3) | 0.058 (3) | 0.5 |
H5A | 0.286542 | 0.135350 | 0.948684 | 0.070* | 0.5 |
Atomic displacement parameters (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
O1 | 0.0483 (6) | 0.0515 (7) | 0.0289 (6) | 0.0110 (5) | −0.0023 (5) | 0.0027 (5) |
O2 | 0.0379 (6) | 0.1245 (13) | 0.0438 (8) | 0.0005 (7) | −0.0053 (5) | −0.0027 (8) |
N1 | 0.0434 (7) | 0.0351 (7) | 0.0260 (7) | 0.0026 (5) | −0.0017 (5) | 0.0008 (5) |
N2 | 0.0510 (8) | 0.0406 (8) | 0.0349 (8) | 0.0102 (6) | −0.0050 (6) | −0.0018 (6) |
N3 | 0.0430 (7) | 0.0855 (12) | 0.0295 (8) | 0.0001 (7) | 0.0013 (6) | 0.0030 (7) |
N4 | 0.0708 (11) | 0.0732 (12) | 0.0470 (10) | −0.0060 (9) | 0.0068 (8) | 0.0158 (9) |
C1 | 0.0422 (8) | 0.0432 (9) | 0.0276 (8) | 0.0093 (7) | −0.0075 (6) | −0.0020 (7) |
C2 | 0.0536 (10) | 0.0706 (13) | 0.0319 (9) | 0.0060 (9) | 0.0013 (7) | −0.0035 (9) |
C6 | 0.0541 (9) | 0.0399 (9) | 0.0369 (9) | 0.0083 (7) | −0.0144 (7) | −0.0026 (7) |
C7 | 0.0546 (10) | 0.0426 (10) | 0.0556 (12) | −0.0109 (8) | −0.0097 (8) | 0.0027 (9) |
C8 | 0.0471 (9) | 0.0474 (11) | 0.0515 (11) | −0.0046 (8) | 0.0061 (8) | 0.0082 (9) |
C9 | 0.0447 (8) | 0.0414 (9) | 0.0328 (9) | 0.0075 (7) | 0.0041 (7) | 0.0030 (7) |
C10 | 0.0674 (12) | 0.0635 (13) | 0.0347 (10) | 0.0044 (9) | 0.0054 (8) | 0.0091 (9) |
C11 | 0.0713 (12) | 0.0784 (15) | 0.0286 (10) | 0.0129 (11) | −0.0056 (9) | 0.0024 (9) |
C12 | 0.0497 (10) | 0.0718 (14) | 0.0417 (10) | 0.0070 (9) | −0.0118 (8) | −0.0128 (10) |
C13 | 0.0406 (8) | 0.0529 (11) | 0.0379 (9) | 0.0003 (7) | −0.0013 (7) | −0.0037 (8) |
C14 | 0.0366 (7) | 0.0380 (9) | 0.0283 (8) | 0.0076 (6) | 0.0001 (6) | −0.0011 (6) |
C15 | 0.0299 (7) | 0.0371 (9) | 0.0290 (8) | −0.0020 (6) | 0.0018 (6) | 0.0042 (6) |
C16 | 0.0377 (8) | 0.0597 (11) | 0.0342 (9) | 0.0029 (7) | −0.0001 (7) | −0.0043 (8) |
C18 | 0.0494 (10) | 0.0611 (12) | 0.0454 (11) | −0.0093 (8) | 0.0016 (8) | 0.0022 (9) |
C19 | 0.0646 (11) | 0.0695 (14) | 0.0346 (10) | 0.0123 (10) | −0.0001 (8) | 0.0040 (9) |
C20 | 0.0548 (10) | 0.0762 (15) | 0.0412 (11) | −0.0033 (10) | −0.0080 (8) | −0.0108 (10) |
C21 | 0.0486 (9) | 0.0568 (11) | 0.0373 (10) | −0.0091 (8) | 0.0022 (7) | −0.0043 (8) |
C17 | 0.0355 (7) | 0.0421 (9) | 0.0332 (8) | 0.0037 (6) | 0.0031 (6) | −0.0043 (7) |
C3 | 0.068 (4) | 0.097 (8) | 0.038 (5) | 0.027 (4) | −0.001 (3) | −0.015 (4) |
C4 | 0.068 (7) | 0.057 (7) | 0.040 (4) | 0.013 (4) | −0.002 (4) | −0.016 (4) |
C5 | 0.080 (10) | 0.041 (6) | 0.052 (4) | 0.005 (6) | −0.020 (7) | −0.011 (4) |
C3A | 0.068 (4) | 0.097 (8) | 0.038 (5) | 0.027 (4) | −0.001 (3) | −0.015 (4) |
C4A | 0.068 (7) | 0.057 (7) | 0.040 (4) | 0.013 (4) | −0.002 (4) | −0.016 (4) |
C5A | 0.080 (10) | 0.041 (6) | 0.052 (4) | 0.005 (6) | −0.020 (7) | −0.011 (4) |
Geometric parameters (Å, º) top
O1—C15 | 1.2376 (18) | C10—C11 | 1.372 (3) |
O2—C16 | 1.2294 (19) | C10—H10 | 0.9300 |
N1—C15 | 1.3683 (19) | C11—C12 | 1.377 (3) |
N1—C1 | 1.432 (2) | C11—H11 | 0.9300 |
N1—C14 | 1.4354 (19) | C12—C13 | 1.377 (3) |
N2—C15 | 1.333 (2) | C12—H12 | 0.9300 |
N2—H2A | 0.8600 | C13—C14 | 1.382 (2) |
N2—H2B | 0.8600 | C13—H13 | 0.9300 |
N3—C16 | 1.324 (2) | C16—C17 | 1.494 (2) |
N3—H3A | 0.8600 | C18—C17 | 1.382 (2) |
N3—H3B | 0.8600 | C18—H18 | 0.9300 |
N4—C19 | 1.325 (3) | C19—C20 | 1.363 (3) |
N4—C18 | 1.334 (2) | C19—H19 | 0.9300 |
C1—C2 | 1.380 (2) | C20—C21 | 1.377 (3) |
C1—C6 | 1.390 (2) | C20—H20 | 0.9300 |
C2—C3A | 1.35 (6) | C21—C17 | 1.378 (2) |
C2—C3 | 1.41 (6) | C21—H21 | 0.9300 |
C2—H2 | 0.9300 | C3—C4 | 1.56 (6) |
C6—C5 | 1.40 (5) | C3—H3 | 0.9300 |
C6—C5A | 1.41 (5) | C4—C5 | 1.31 (4) |
C6—C7 | 1.458 (3) | C4—H4 | 0.9300 |
C7—C8 | 1.336 (3) | C5—H5 | 0.9300 |
C7—H7 | 0.9300 | C3A—C4A | 1.21 (6) |
C8—C9 | 1.457 (2) | C3A—H3A1 | 0.9300 |
C8—H8 | 0.9300 | C4A—C5A | 1.45 (4) |
C9—C10 | 1.397 (2) | C4A—H4A | 0.9300 |
C9—C14 | 1.399 (2) | C5A—H5A | 0.9300 |
| | | |
C15—N1—C1 | 119.00 (12) | C13—C14—C9 | 120.92 (15) |
C15—N1—C14 | 122.59 (12) | C13—C14—N1 | 119.92 (14) |
C1—N1—C14 | 116.79 (12) | C9—C14—N1 | 119.14 (13) |
C15—N2—H2A | 120.0 | O1—C15—N2 | 122.09 (14) |
C15—N2—H2B | 120.0 | O1—C15—N1 | 120.31 (14) |
H2A—N2—H2B | 120.0 | N2—C15—N1 | 117.60 (13) |
C16—N3—H3A | 120.0 | O2—C16—N3 | 122.65 (16) |
C16—N3—H3B | 120.0 | O2—C16—C17 | 120.37 (15) |
H3A—N3—H3B | 120.0 | N3—C16—C17 | 116.98 (14) |
C19—N4—C18 | 116.74 (17) | N4—C18—C17 | 124.57 (17) |
C2—C1—C6 | 121.68 (16) | N4—C18—H18 | 117.7 |
C2—C1—N1 | 119.09 (16) | C17—C18—H18 | 117.7 |
C6—C1—N1 | 119.22 (15) | N4—C19—C20 | 123.31 (18) |
C3A—C2—C1 | 121 (3) | N4—C19—H19 | 118.3 |
C1—C2—C3 | 119 (2) | C20—C19—H19 | 118.3 |
C1—C2—H2 | 120.7 | C19—C20—C21 | 119.28 (17) |
C3—C2—H2 | 120.7 | C19—C20—H20 | 120.4 |
C1—C6—C5 | 122.7 (15) | C21—C20—H20 | 120.4 |
C1—C6—C5A | 112.0 (14) | C20—C21—C17 | 119.19 (17) |
C1—C6—C7 | 122.76 (15) | C20—C21—H21 | 120.4 |
C5—C6—C7 | 114.5 (15) | C17—C21—H21 | 120.4 |
C5A—C6—C7 | 125.2 (15) | C21—C17—C18 | 116.90 (16) |
C8—C7—C6 | 127.32 (16) | C21—C17—C16 | 123.97 (16) |
C8—C7—H7 | 116.3 | C18—C17—C16 | 119.12 (15) |
C6—C7—H7 | 116.3 | C2—C3—C4 | 117 (4) |
C7—C8—C9 | 127.38 (16) | C2—C3—H3 | 121.6 |
C7—C8—H8 | 116.3 | C4—C3—H3 | 121.6 |
C9—C8—H8 | 116.3 | C5—C4—C3 | 121 (3) |
C10—C9—C14 | 117.30 (16) | C5—C4—H4 | 119.6 |
C10—C9—C8 | 119.92 (16) | C3—C4—H4 | 119.6 |
C14—C9—C8 | 122.78 (15) | C4—C5—C6 | 119 (3) |
C11—C10—C9 | 121.43 (18) | C4—C5—H5 | 120.6 |
C11—C10—H10 | 119.3 | C6—C5—H5 | 120.6 |
C9—C10—H10 | 119.3 | C4A—C3A—C2 | 123 (5) |
C10—C11—C12 | 120.33 (17) | C4A—C3A—H3A1 | 118.4 |
C10—C11—H11 | 119.8 | C2—C3A—H3A1 | 118.4 |
C12—C11—H11 | 119.8 | C3A—C4A—C5A | 118 (4) |
C11—C12—C13 | 119.68 (18) | C3A—C4A—H4A | 120.8 |
C11—C12—H12 | 120.2 | C5A—C4A—H4A | 120.8 |
C13—C12—H12 | 120.2 | C6—C5A—C4A | 123 (3) |
C12—C13—C14 | 120.31 (18) | C6—C5A—H5A | 118.3 |
C12—C13—H13 | 119.8 | C4A—C5A—H5A | 118.3 |
C14—C13—H13 | 119.8 | | |
| | | |
C15—N1—C1—C2 | 80.65 (18) | C15—N1—C14—C13 | −79.81 (19) |
C14—N1—C1—C2 | −113.45 (16) | C1—N1—C14—C13 | 114.83 (16) |
C15—N1—C1—C6 | −98.48 (17) | C15—N1—C14—C9 | 98.52 (17) |
C14—N1—C1—C6 | 67.43 (18) | C1—N1—C14—C9 | −66.83 (18) |
C6—C1—C2—C3A | 4 (2) | C1—N1—C15—O1 | −2.7 (2) |
N1—C1—C2—C3A | −175 (2) | C14—N1—C15—O1 | −167.76 (14) |
C6—C1—C2—C3 | −3 (2) | C1—N1—C15—N2 | 176.82 (14) |
N1—C1—C2—C3 | 177 (2) | C14—N1—C15—N2 | 11.8 (2) |
C2—C1—C6—C5 | −3 (3) | C19—N4—C18—C17 | −0.5 (3) |
N1—C1—C6—C5 | 176 (3) | C18—N4—C19—C20 | 1.4 (3) |
C2—C1—C6—C5A | 0 (2) | N4—C19—C20—C21 | −1.2 (3) |
N1—C1—C6—C5A | 179 (2) | C19—C20—C21—C17 | 0.0 (3) |
C2—C1—C6—C7 | 176.72 (16) | C20—C21—C17—C18 | 0.8 (3) |
N1—C1—C6—C7 | −4.2 (2) | C20—C21—C17—C16 | −178.34 (17) |
C1—C6—C7—C8 | −33.0 (3) | N4—C18—C17—C21 | −0.6 (3) |
C5—C6—C7—C8 | 147 (2) | N4—C18—C17—C16 | 178.58 (18) |
C5A—C6—C7—C8 | 143 (3) | O2—C16—C17—C21 | 153.62 (19) |
C6—C7—C8—C9 | 1.4 (3) | N3—C16—C17—C21 | −26.7 (3) |
C7—C8—C9—C10 | −148.59 (19) | O2—C16—C17—C18 | −25.5 (3) |
C7—C8—C9—C14 | 31.3 (3) | N3—C16—C17—C18 | 154.25 (17) |
C14—C9—C10—C11 | −2.1 (3) | C1—C2—C3—C4 | 7 (4) |
C8—C9—C10—C11 | 177.82 (18) | C2—C3—C4—C5 | −6 (5) |
C9—C10—C11—C12 | 1.1 (3) | C3—C4—C5—C6 | −1 (6) |
C10—C11—C12—C13 | 0.1 (3) | C1—C6—C5—C4 | 5 (5) |
C11—C12—C13—C14 | −0.1 (3) | C7—C6—C5—C4 | −175 (3) |
C12—C13—C14—C9 | −1.0 (2) | C1—C2—C3A—C4A | −8 (5) |
C12—C13—C14—N1 | 177.31 (15) | C2—C3A—C4A—C5A | 7 (6) |
C10—C9—C14—C13 | 2.0 (2) | C1—C6—C5A—C4A | −1 (5) |
C8—C9—C14—C13 | −177.86 (16) | C7—C6—C5A—C4A | −177 (3) |
C10—C9—C14—N1 | −176.29 (15) | C3A—C4A—C5A—C6 | −3 (6) |
C8—C9—C14—N1 | 3.8 (2) | | |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
N2—H2A···O1i | 0.86 | 2.06 | 2.8888 (17) | 162 |
N2—H2B···O2ii | 0.86 | 2.43 | 3.0698 (19) | 131 |
N3—H3A···O1 | 0.86 | 2.10 | 2.8887 (18) | 152 |
N3—H3B···O2iii | 0.86 | 2.22 | 3.0204 (18) | 154 |
C2—H2a···O1iv | 0.93 | 2.59 | 3.419 (2) | 149 |
C13—H13···N2iv | 0.93 | 2.70 | 3.556 (2) | 154 |
Symmetry codes: (i) −x, −y+1, −z+2; (ii) −x+1, −y+1, −z+2; (iii) x−1, y, z; (iv) x+1, y, z. |
Quantitative contribution of intermolecular interactions for
APIs PYZ (1) and
CBZ (2), and
cocrystals PYZ:HMA (3),
CBZ:5-SA (4),
CBZ:TCA (5) and
CBZ:NA (6) topQuantitative contributions of intermolecular interactions (%) | | | | | | | | | | |
Sample | H···H | O···H | H···N | H···C | C···N | C···O | O···N | H···Cl | C···Cl | C···C |
PYZ (1) | 30.9 | 18.5 | 26.7 | 7.7 | 6.1 | 3.9 | 1.2 | – | – | 5.5 |
CBZ (2) | 52.1 | 11.7 | 1.3 | 32.6 | – | – | 0.8 | – | – | 1.5 |
PYZ:HMA (3) | 30.9 | 26.4 | 17.9 | 12.1 | 4.6 | 4.5 | 1.4 | – | – | 2 |
CBZ:5-SA (4) | 38.2 | 17.5 | 31.5 | – | 1.6 | 1 | – | 6 | 2.7 | 1.5 |
CBZ:TCA (5) | 45.8 | 17.6 | 1.5 | 30.8 | 1.1 | 1.3 | – | – | – | 0.9 |
CBZ:NA (6) | 44.9 | 13.4 | 4 | 33.1 | 1.5 | 1.2 | – | – | – | 1.9 |
Summary of the melting endotherms and thermal stabilities for APIs
PYZ (1) and
CBZ (2),
co-formers HMA (7),
5-SA (8),
TCA (9) and
NA (10), and
cocrystals PYZ:HMA (3),
CBZ:5-SA (4),
CBZ:TCA (5) and
CBZ:NA (6). topSample | Melting endotherm (°C) | Thermal stability temperature (°C) | Weight loss (%) |
PYZ | 190.9 | 141.1 | 1.4 |
PYZ:HMA | 156.4 | 142.7 | 1.5 |
CBZ | 186.2 | 218.2 | 7.4 |
CBZ:5-SA | 178.8 | 169.8 | 3.1 |
CBZ:TCA | 139.8 | 154.9 | 2.9 |
CBZ:NA | 156.9 | 177.7 | 3.4 |
HMA | 187.3 | 176.2 | 0.8 |
5-SA | 172.0 | 148.4 | 2.6 |
TCA | 131.2 | 148.7 | 1.8 |
NA | 125.9 | 170.4 | 2.8 |
Biological activities for APIs
PYZ (1) and
CBZ (2),
co-formers HMA (7),
5-SA (8),
TCA (9) and
NA (10), and
cocrystals PYZ:HMA (3),
CBZ:5-SA (4),
CBZ:TCA (5) and
CBZ:NA (6) topSample | Cytotoxicity against BJ cell line (CC50±SEM µM) | Antileishmanial activity Leishmania tropica (IC50±SEM µM) | Urease inhibition (IC50±SEM µM) | Larvicidal activity Aedes Aegypti (% mortality |
Pyrazinamide (PYZ, 1) | Noncytotoxic | n.a. | 10.35±1.01 | 80 |
Homophthalic acid (HMA, 7) | Noncytotoxic | n.a. | 15.36±0.74 | n.a. |
PYZ:HMA (3) | Noncytotoxic | 111.98±0.99 | 17.32±0.89 | 100 |
Carbamazepine (CBZ, 2) | Noncytotoxic | 73.20±1.55 | 7.3±0.6 | n.a. |
5-Chlorosalicylic acid (5-SA, 8) | Noncytotoxic | 36.2±1.026 | 14.9±1.3 | n.a. |
CBZ:5-SA (4) | Noncytotoxic | n.a. | 13.6±1.4 | n.a. |
trans-Cinnamic acid (TCA, 9) | Noncytotoxic | n.a. | 6.8±1.3 | n.a. |
CBZ:TCA (5) | Noncytotoxic | 111.90±1.44 | 9.8±1.3 | n.a. |
Nicotinamide (NA, 10) | Noncytotoxic | n.a. | 9.3±1.6 | n.a. |
CBZ:NA (6) | Noncytotoxic | n.a. | 12.3±0.8 | n.a. |
Standard | 0.9±0.14a | 169.55±0.20b | 20.34±0.43c | 100d |
Notes: (a) doxorubicin;
(b) miltefosine;
(c) acetohydroxamc acid;
(d) permethrin. |
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