The title compounds, C16H15BrN3O3+·Cl-·CH4O (WHI-P154) and C16H16N3O3+·Cl- (WHI-P180), are potent inhibitors [WHI-P154 with IC50 = 5.6 µM and WHI-P180 with IC50 = 4.0 µM for epidermal growth factor receptor (EGFR) kinase inhibition] of the EGFR tyrosine kinase as well as Janus Kinase 3. The molecular structures of these compounds are very similar except for the dihedral angle between the anilino and quinazoline moieties which is 1.10 (5)° for WHI-P154, and 45.66 (6) and 25.29 (7)° for the two molecules of WHI-P180 in the asymmetric unit. The nitrogen at the N3 position is protonated in both structures and participates in hydrogen bonding with the chlorine anions.
Supporting information
CCDC references: 158257; 158258
The synthesis and characterization of WHI-P154 and WHI-P180 have been reported
earlier (Narla et al., 1998). Single crystals of WHI-P154 were obtained
by liquid-liquid diffusion from solutions of methanol and dichloromethane at
room temperature and those of WHI-P180 by slow evaporation from a methanol
solution at 289 K.
The H atoms attached to the N and O atoms for both compounds appeared well
resolved in the difference Fourier maps, and were refined isotropically, with
the exception of the H atoms bonded to O1 and O1A in WHI-P154, which proved
difficult to refine freely. These two H atoms were refined by restrained
methods using the DFIX command, where the OOH distance was restrained
to 0.82 Å and their Ueq values were allowed to refine freely.
All hydrogen atoms attached to carbon atoms were placed in ideal positions and
refined using a riding model with aromatic C—H = 0.96 Å me thyl C—H =
0.98 Å, and with fixed isotropic displacement parameters equal to 1.2 (1.5
for methyl H atoms) times the equivalent isotropic displacement parameter of
the atom to which they were attached. The methyl groups were allowed to rotate
about their local threefold axis during refinement.
Data collection: SMART (Bruker, 1998) for WHI-P154; SMART (Bruker, 1998a) for WHI-P180. Cell refinement: SAINT (Bruker, 1998) for WHI-P154; SAINT (Bruker, 1998a) for WHI-P180. Data reduction: SAINT for WHI-P154; SAINT (Bruker, 1998a) for WHI-P180. For both compounds, program(s) used to solve structure: SHELXS97 (Sheldrick, 1990); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL (Bruker, 1998b). Software used to prepare material for publication: SHELXTL for WHI-P154; SHELXTL (Bruker, 1998b) for WHI-P180.
(WHI-P154) 4-(3'-bromo-4' -hydroxyphenyl)-amino-6,7 -dimethoxyquinazoline
top
Crystal data top
C16H15BrN3O3+·Cl−·CH4O | Z = 2 |
Mr = 444.71 | F(000) = 452 |
Triclinic, P1 | Dx = 1.565 Mg m−3 |
a = 7.113 (5) Å | Mo Kα radiation, λ = 0.71073 Å |
b = 9.339 (7) Å | Cell parameters from 4929 reflections |
c = 14.526 (10) Å | θ = 2.9–27.1° |
α = 79.14 (1)° | µ = 2.35 mm−1 |
β = 85.37 (1)° | T = 298 K |
γ = 86.49 (1)° | Needle, yellow |
V = 943.5 (12) Å3 | 0.42 × 0.29 × 0.06 mm |
Data collection top
Bruker SMART CCD area detector diffractometer | 4245 independent reflections |
Radiation source: fine-focus sealed tube | 3230 reflections with I > 2σ(I) |
Graphite monochromator | Rint = 0.047 |
phi and ω scans | θmax = 27.8°, θmin = 1.4° |
Absorption correction: empirical (SADABS; Sheldrick, 1996) | h = −9→9 |
Tmin = 0.44, Tmax = 0.87 | k = −12→12 |
10811 measured reflections | l = −18→18 |
Refinement top
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)] = 0.037 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.100 | H atoms treated by a mixture of independent and constrained refinement |
S = 0.99 | w = 1/[σ2(Fo2) + (0.0574P)2] where P = (Fo2 + 2Fc2)/3 |
4245 reflections | (Δ/σ)max = 0.008 |
264, 2 restraints parameters | Δρmax = 0.62 e Å−3 |
0 restraints | Δρmin = −0.47 e Å−3 |
Crystal data top
C16H15BrN3O3+·Cl−·CH4O | γ = 86.49 (1)° |
Mr = 444.71 | V = 943.5 (12) Å3 |
Triclinic, P1 | Z = 2 |
a = 7.113 (5) Å | Mo Kα radiation |
b = 9.339 (7) Å | µ = 2.35 mm−1 |
c = 14.526 (10) Å | T = 298 K |
α = 79.14 (1)° | 0.42 × 0.29 × 0.06 mm |
β = 85.37 (1)° | |
Data collection top
Bruker SMART CCD area detector diffractometer | 4245 independent reflections |
Absorption correction: empirical (SADABS; Sheldrick, 1996) | 3230 reflections with I > 2σ(I) |
Tmin = 0.44, Tmax = 0.87 | Rint = 0.047 |
10811 measured reflections | |
Refinement top
R[F2 > 2σ(F2)] = 0.037 | 0 restraints |
wR(F2) = 0.100 | H atoms treated by a mixture of independent and constrained refinement |
S = 0.99 | Δρmax = 0.62 e Å−3 |
4245 reflections | Δρmin = −0.47 e Å−3 |
264, 2 restraints parameters | |
Special details top
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. |
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top | x | y | z | Uiso*/Ueq | Occ. (<1) |
Br1A | 0.30177 (4) | 0.69507 (3) | 0.15032 (2) | 0.0534 (1) | 0.974 (1) |
Br1B | 0.1225 (18) | 1.1266 (14) | 0.3361 (9) | 0.081 (5) | 0.026 (10) |
Cl1 | 0.66410 (11) | 1.15712 (6) | 0.33797 (4) | 0.05326 (19) | |
O1 | 0.2176 (4) | 1.0023 (2) | 0.17990 (14) | 0.0718 (6) | |
H1B | 0.261 (5) | 1.081 (2) | 0.180 (3) | 0.096 (14)* | |
O1A | 0.3689 (4) | 1.2514 (3) | 0.18658 (18) | 0.0857 (7) | |
H1AA | 0.451 (4) | 1.233 (4) | 0.224 (2) | 0.093 (13)* | |
O2 | 0.1323 (3) | 0.46599 (18) | 0.89080 (11) | 0.0491 (4) | |
O3 | 0.1967 (3) | 0.18874 (19) | 0.92484 (11) | 0.0518 (4) | |
N1 | 0.2255 (3) | 0.6174 (2) | 0.52419 (13) | 0.0389 (4) | |
H1A | 0.222 (3) | 0.671 (3) | 0.5690 (18) | 0.048 (7)* | |
N2 | 0.2803 (3) | 0.3921 (2) | 0.48164 (13) | 0.0448 (5) | |
N3 | 0.3010 (3) | 0.1802 (2) | 0.59530 (13) | 0.0407 (4) | |
H3A | 0.322 (3) | 0.087 (3) | 0.6074 (17) | 0.038 (6)* | |
C1 | 0.2570 (3) | 0.6599 (2) | 0.34848 (15) | 0.0393 (5) | |
H1 | 0.2815 | 0.5612 | 0.3473 | 0.047* | |
C1A | 0.4494 (5) | 1.3183 (4) | 0.0969 (2) | 0.0747 (9) | |
H1AD | 0.5026 | 1.4082 | 0.1019 | 0.112* | |
H1AC | 0.3531 | 1.3377 | 0.0529 | 0.112* | |
H1AB | 0.5466 | 1.2539 | 0.0754 | 0.112* | |
C2 | 0.2535 (3) | 0.7611 (3) | 0.26543 (16) | 0.0406 (5) | |
H2 | 0.2747 | 0.7284 | 0.2087 | 0.049* | 0.0265 (10) |
C3 | 0.2195 (4) | 0.9093 (3) | 0.26380 (16) | 0.0480 (6) | |
C4 | 0.1824 (4) | 0.9542 (3) | 0.34924 (18) | 0.0529 (6) | |
H4 | 0.1553 | 1.0527 | 0.3501 | 0.064* | 0.9735 (10) |
C5 | 0.1847 (4) | 0.8564 (3) | 0.43296 (17) | 0.0460 (6) | |
H5 | 0.1603 | 0.8895 | 0.4894 | 0.055* | |
C6 | 0.2234 (3) | 0.7079 (2) | 0.43359 (15) | 0.0368 (5) | |
C7 | 0.2455 (3) | 0.4719 (2) | 0.54935 (14) | 0.0342 (5) | |
C8 | 0.3075 (4) | 0.2503 (3) | 0.50704 (17) | 0.0489 (6) | |
H8 | 0.3331 | 0.1954 | 0.4599 | 0.059* | |
C9 | 0.2096 (3) | 0.2508 (2) | 0.83302 (15) | 0.0387 (5) | |
C10 | 0.2504 (3) | 0.1773 (2) | 0.76108 (15) | 0.0386 (5) | |
H10 | 0.2716 | 0.0765 | 0.7734 | 0.046* | |
C11 | 0.2605 (3) | 0.2538 (2) | 0.66834 (15) | 0.0343 (5) | |
C12 | 0.2305 (3) | 0.4055 (2) | 0.64723 (14) | 0.0334 (5) | |
C13 | 0.1852 (3) | 0.4798 (2) | 0.72319 (15) | 0.0374 (5) | |
H13 | 0.1628 | 0.5805 | 0.7112 | 0.045* | |
C14 | 0.1740 (3) | 0.4052 (2) | 0.81404 (15) | 0.0384 (5) | |
C15 | 0.0621 (4) | 0.6150 (3) | 0.87584 (19) | 0.0569 (7) | |
H15A | 0.0298 | 0.6438 | 0.9354 | 0.085* | |
H15B | −0.0480 | 0.6250 | 0.8406 | 0.085* | |
H15C | 0.1576 | 0.6761 | 0.8415 | 0.085* | |
C16 | 0.2392 (5) | 0.0341 (3) | 0.94622 (19) | 0.0690 (9) | |
H16A | 0.2346 | 0.0022 | 1.0131 | 0.103* | |
H16B | 0.3632 | 0.0126 | 0.9195 | 0.103* | |
H16C | 0.1481 | −0.0159 | 0.9203 | 0.103* | |
Atomic displacement parameters (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
Br1A | 0.0640 (2) | 0.0659 (2) | 0.02974 (14) | −0.00815 (13) | 0.00134 (11) | −0.00789 (11) |
Br1B | 0.076 (8) | 0.080 (8) | 0.064 (8) | 0.040 (6) | 0.007 (6) | 0.031 (6) |
Cl1 | 0.0850 (5) | 0.0362 (3) | 0.0391 (3) | −0.0061 (3) | −0.0093 (3) | −0.0053 (2) |
O1 | 0.1216 (19) | 0.0541 (12) | 0.0350 (10) | −0.0167 (12) | −0.0153 (11) | 0.0120 (9) |
O1A | 0.0940 (18) | 0.0823 (16) | 0.0762 (17) | −0.0229 (14) | −0.0323 (14) | 0.0147 (13) |
O2 | 0.0739 (12) | 0.0457 (9) | 0.0269 (8) | 0.0004 (8) | 0.0008 (8) | −0.0080 (7) |
O3 | 0.0742 (12) | 0.0494 (9) | 0.0267 (8) | 0.0004 (8) | −0.0041 (8) | 0.0050 (7) |
N1 | 0.0515 (12) | 0.0383 (10) | 0.0255 (9) | −0.0008 (8) | −0.0030 (8) | −0.0029 (8) |
N2 | 0.0622 (13) | 0.0413 (10) | 0.0294 (10) | −0.0022 (9) | 0.0020 (9) | −0.0046 (8) |
N3 | 0.0517 (12) | 0.0333 (10) | 0.0354 (10) | 0.0000 (9) | 0.0001 (8) | −0.0037 (8) |
C1 | 0.0433 (13) | 0.0417 (12) | 0.0313 (11) | −0.0049 (10) | −0.0028 (9) | −0.0019 (9) |
C1A | 0.077 (2) | 0.0690 (19) | 0.075 (2) | −0.0053 (16) | −0.0064 (17) | −0.0031 (17) |
C2 | 0.0406 (13) | 0.0509 (13) | 0.0294 (11) | −0.0088 (10) | −0.0026 (9) | −0.0026 (10) |
C3 | 0.0608 (16) | 0.0484 (14) | 0.0318 (12) | −0.0109 (12) | −0.0099 (11) | 0.0059 (10) |
C4 | 0.0731 (18) | 0.0394 (13) | 0.0448 (14) | −0.0013 (12) | −0.0139 (13) | −0.0005 (11) |
C5 | 0.0622 (16) | 0.0428 (12) | 0.0324 (12) | −0.0002 (11) | −0.0080 (11) | −0.0043 (10) |
C6 | 0.0400 (12) | 0.0407 (12) | 0.0281 (10) | −0.0053 (9) | −0.0042 (9) | −0.0004 (9) |
C7 | 0.0335 (11) | 0.0381 (11) | 0.0301 (11) | −0.0033 (9) | −0.0021 (8) | −0.0034 (9) |
C8 | 0.0699 (17) | 0.0446 (13) | 0.0325 (12) | −0.0021 (12) | 0.0037 (11) | −0.0107 (10) |
C9 | 0.0453 (13) | 0.0420 (12) | 0.0265 (10) | −0.0059 (10) | −0.0037 (9) | 0.0013 (9) |
C10 | 0.0450 (13) | 0.0345 (11) | 0.0331 (11) | −0.0026 (9) | −0.0033 (9) | 0.0022 (9) |
C11 | 0.0356 (11) | 0.0365 (11) | 0.0303 (11) | −0.0048 (9) | −0.0003 (9) | −0.0047 (9) |
C12 | 0.0337 (11) | 0.0366 (11) | 0.0286 (10) | −0.0029 (9) | −0.0016 (8) | −0.0021 (8) |
C13 | 0.0467 (13) | 0.0347 (11) | 0.0293 (11) | −0.0034 (9) | 0.0012 (9) | −0.0036 (9) |
C14 | 0.0443 (13) | 0.0432 (12) | 0.0275 (11) | −0.0052 (10) | −0.0015 (9) | −0.0057 (9) |
C15 | 0.0764 (19) | 0.0522 (15) | 0.0410 (14) | 0.0050 (13) | 0.0075 (13) | −0.0133 (12) |
C16 | 0.111 (3) | 0.0535 (15) | 0.0343 (14) | 0.0040 (16) | −0.0050 (15) | 0.0108 (12) |
Geometric parameters (Å, º) top
Br1A—C2 | 1.888 (3) | C1—C2 | 1.386 (3) |
Br1B—C4 | 1.620 (13) | C1—C6 | 1.391 (3) |
O1—C3 | 1.357 (3) | C2—C3 | 1.386 (4) |
O1A—C1A | 1.426 (4) | C3—C4 | 1.384 (4) |
O2—C14 | 1.348 (3) | C4—C5 | 1.377 (3) |
O2—C15 | 1.432 (3) | C5—C6 | 1.395 (3) |
O3—C9 | 1.349 (3) | C7—C12 | 1.438 (3) |
O3—C16 | 1.437 (3) | C9—C10 | 1.358 (3) |
N1—C7 | 1.340 (3) | C9—C14 | 1.427 (3) |
N1—C6 | 1.425 (3) | C10—C11 | 1.400 (3) |
N2—C8 | 1.313 (3) | C11—C12 | 1.399 (3) |
N2—C7 | 1.341 (3) | C12—C13 | 1.416 (3) |
N3—C8 | 1.324 (3) | C13—C14 | 1.370 (3) |
N3—C11 | 1.372 (3) | | |
| | | |
C14—O2—C15 | 117.20 (18) | N1—C7—N2 | 118.48 (19) |
C9—O3—C16 | 116.2 (2) | N1—C7—C12 | 119.76 (19) |
C7—N1—C6 | 130.7 (2) | N2—C7—C12 | 121.8 (2) |
C8—N2—C7 | 118.1 (2) | N2—C8—N3 | 124.3 (2) |
C8—N3—C11 | 121.0 (2) | O3—C9—C10 | 124.9 (2) |
C2—C1—C6 | 119.1 (2) | O3—C9—C14 | 115.0 (2) |
C1—C2—C3 | 122.5 (2) | C10—C9—C14 | 120.12 (19) |
C1—C2—Br1A | 118.75 (19) | C9—C10—C11 | 119.8 (2) |
C3—C2—Br1A | 118.77 (17) | N3—C11—C12 | 118.25 (19) |
O1—C3—C4 | 123.2 (2) | N3—C11—C10 | 120.1 (2) |
O1—C3—C2 | 119.4 (2) | C12—C11—C10 | 121.7 (2) |
C4—C3—C2 | 117.4 (2) | C11—C12—C13 | 117.64 (19) |
C5—C4—C3 | 121.5 (2) | C11—C12—C7 | 116.55 (19) |
C5—C4—Br1B | 126.5 (5) | C13—C12—C7 | 125.8 (2) |
C3—C4—Br1B | 111.9 (5) | C14—C13—C12 | 120.9 (2) |
C4—C5—C6 | 120.4 (2) | O2—C14—C13 | 125.2 (2) |
C1—C6—C5 | 119.1 (2) | O2—C14—C9 | 114.85 (18) |
C1—C6—N1 | 125.4 (2) | C13—C14—C9 | 119.9 (2) |
C5—C6—N1 | 115.6 (2) | | |
| | | |
C6—C1—C2—C3 | 0.7 (4) | C16—O3—C9—C14 | −177.6 (2) |
C6—C1—C2—Br1A | 179.37 (16) | O3—C9—C10—C11 | −179.8 (2) |
C1—C2—C3—O1 | −179.8 (2) | C14—C9—C10—C11 | 1.0 (3) |
Br1A—C2—C3—O1 | 1.5 (3) | C8—N3—C11—C12 | −1.5 (3) |
C1—C2—C3—C4 | −2.0 (4) | C8—N3—C11—C10 | 178.7 (2) |
Br1A—C2—C3—C4 | 179.27 (19) | C9—C10—C11—N3 | −179.8 (2) |
O1—C3—C4—C5 | 179.7 (3) | C9—C10—C11—C12 | 0.4 (3) |
C2—C3—C4—C5 | 1.9 (4) | N3—C11—C12—C13 | 178.8 (2) |
O1—C3—C4—Br1B | 4.2 (7) | C10—C11—C12—C13 | −1.3 (3) |
C2—C3—C4—Br1B | −173.6 (6) | N3—C11—C12—C7 | −0.2 (3) |
C3—C4—C5—C6 | −0.5 (4) | C10—C11—C12—C7 | 179.7 (2) |
Br1B—C4—C5—C6 | 174.3 (7) | N1—C7—C12—C11 | −177.51 (19) |
C2—C1—C6—C5 | 0.8 (3) | N2—C7—C12—C11 | 2.2 (3) |
C2—C1—C6—N1 | −178.9 (2) | N1—C7—C12—C13 | 3.6 (3) |
C4—C5—C6—C1 | −0.9 (4) | N2—C7—C12—C13 | −176.7 (2) |
C4—C5—C6—N1 | 178.9 (2) | C11—C12—C13—C14 | 0.9 (3) |
C7—N1—C6—C1 | −5.0 (4) | C7—C12—C13—C14 | 179.8 (2) |
C7—N1—C6—C5 | 175.2 (2) | C15—O2—C14—C13 | 11.6 (3) |
C6—N1—C7—N2 | 4.3 (4) | C15—O2—C14—C9 | −169.0 (2) |
C6—N1—C7—C12 | −176.0 (2) | C12—C13—C14—O2 | 179.9 (2) |
C8—N2—C7—N1 | 177.2 (2) | C12—C13—C14—C9 | 0.4 (3) |
C8—N2—C7—C12 | −2.5 (3) | O3—C9—C14—O2 | −0.2 (3) |
C7—N2—C8—N3 | 0.8 (4) | C10—C9—C14—O2 | 179.1 (2) |
C11—N3—C8—N2 | 1.3 (4) | O3—C9—C14—C13 | 179.3 (2) |
C16—O3—C9—C10 | 3.2 (4) | C10—C9—C14—C13 | −1.4 (3) |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
O1—H1B···O1A | 0.82 (1) | 1.83 (1) | 2.643 (4) | 176 (4) |
O1A—H1AA···Cl1 | 0.82 (1) | 2.32 (1) | 3.132 (3) | 174 (4) |
N1—H1A···Cl1i | 0.89 (3) | 2.49 (3) | 3.333 (3) | 158 (2) |
N3—H3A···Cl1ii | 0.86 (3) | 2.27 (3) | 3.117 (3) | 169 (2) |
Symmetry codes: (i) −x+1, −y+2, −z+1; (ii) −x+1, −y+1, −z+1. |
(WHI-P180) 4-(3'-Hydroxyphenyl)-amino-6,7 -dimethoxyquinazoline
top
Crystal data top
C16H16N3O3+·Cl− | Z = 4 |
Mr = 333.77 | F(000) = 696 |
Triclinic, P1 | Dx = 1.442 Mg m−3 |
a = 9.4851 (7) Å | Mo Kα radiation, λ = 0.71073 Å |
b = 10.3688 (8) Å | Cell parameters from 3519 reflections |
c = 15.9106 (12) Å | θ = 2.3–24.1° |
α = 90.954 (1)° | µ = 0.27 mm−1 |
β = 99.108 (1)° | T = 297 K |
γ = 95.438 (1)° | Needle, pale yellow |
V = 1537.3 (2) Å3 | 0.30 × 0.25 × 0.01 mm |
Data collection top
Bruker SMART CCD area detector diffractometer | 6248 independent reflections |
Radiation source: fine-focus sealed tube | 3389 reflections with I > 2σ(I) |
Graphite monochromator | Rint = 0.049 |
phi and ω scans | θmax = 26.4°, θmin = 1.3° |
Absorption correction: empirical (SADABS; Sheldrick, 1996) | h = −11→11 |
Tmin = 0.92, Tmax = 1.00 | k = −12→12 |
16771 measured reflections | l = −19→19 |
Refinement top
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)] = 0.043 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.091 | H atoms treated by a mixture of independent and constrained refinement |
S = 0.90 | w = 1/[σ2(Fo2) + (0.0357P)2] where P = (Fo2 + 2Fc2)/3 |
6248 reflections | (Δ/σ)max = 0.006 |
443 parameters | Δρmax = 0.16 e Å−3 |
0 restraints | Δρmin = −0.22 e Å−3 |
Crystal data top
C16H16N3O3+·Cl− | γ = 95.438 (1)° |
Mr = 333.77 | V = 1537.3 (2) Å3 |
Triclinic, P1 | Z = 4 |
a = 9.4851 (7) Å | Mo Kα radiation |
b = 10.3688 (8) Å | µ = 0.27 mm−1 |
c = 15.9106 (12) Å | T = 297 K |
α = 90.954 (1)° | 0.30 × 0.25 × 0.01 mm |
β = 99.108 (1)° | |
Data collection top
Bruker SMART CCD area detector diffractometer | 6248 independent reflections |
Absorption correction: empirical (SADABS; Sheldrick, 1996) | 3389 reflections with I > 2σ(I) |
Tmin = 0.92, Tmax = 1.00 | Rint = 0.049 |
16771 measured reflections | |
Refinement top
R[F2 > 2σ(F2)] = 0.043 | 0 restraints |
wR(F2) = 0.091 | H atoms treated by a mixture of independent and constrained refinement |
S = 0.90 | Δρmax = 0.16 e Å−3 |
6248 reflections | Δρmin = −0.22 e Å−3 |
443 parameters | |
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top | x | y | z | Uiso*/Ueq | |
Cl1 | 0.47042 (6) | 0.55496 (6) | 0.12526 (4) | 0.0561 (2) | |
Cl2 | 0.35908 (6) | 0.46067 (6) | 0.37584 (4) | 0.0553 (2) | |
O1B | 1.55278 (18) | 0.8182 (2) | 0.59034 (12) | 0.0614 (6) | |
H1B | 1.566 (2) | 0.739 (2) | 0.5979 (15) | 0.048 (8)* | |
O1A | 1.4646 (2) | 0.1631 (2) | −0.07114 (12) | 0.0666 (6) | |
H1A | 1.489 (4) | 0.252 (3) | −0.086 (2) | 0.145 (16)* | |
O2B | 0.96563 (16) | 0.18275 (15) | 0.26574 (11) | 0.0525 (5) | |
O2A | 1.19491 (16) | 0.81933 (16) | 0.25909 (11) | 0.0555 (5) | |
O3B | 0.69419 (15) | 0.17470 (15) | 0.21821 (10) | 0.0486 (4) | |
O3A | 0.93606 (16) | 0.85820 (16) | 0.26128 (10) | 0.0542 (5) | |
N1B | 1.10698 (19) | 0.63431 (19) | 0.42822 (12) | 0.0367 (5) | |
H1BB | 1.160 (2) | 0.580 (2) | 0.4085 (13) | 0.043 (7)* | |
N1A | 1.1690 (2) | 0.3685 (2) | 0.09807 (13) | 0.0433 (5) | |
H1AA | 1.247 (2) | 0.420 (2) | 0.1167 (14) | 0.059 (8)* | |
N2B | 0.88425 (19) | 0.68612 (18) | 0.44835 (12) | 0.0419 (5) | |
N2A | 0.92588 (19) | 0.32322 (18) | 0.05938 (12) | 0.0418 (5) | |
N3B | 0.6759 (2) | 0.56542 (18) | 0.37941 (13) | 0.0424 (5) | |
H3BB | 0.571 (3) | 0.549 (2) | 0.3720 (14) | 0.065 (8)* | |
N3A | 0.7674 (2) | 0.46258 (19) | 0.09985 (13) | 0.0390 (5) | |
H3AA | 0.677 (2) | 0.477 (2) | 0.1034 (14) | 0.056 (8)* | |
C1B | 1.4154 (2) | 0.8302 (2) | 0.55159 (14) | 0.0408 (6) | |
C1A | 1.3580 (3) | 0.1542 (3) | −0.02203 (15) | 0.0477 (7) | |
C2B | 1.3655 (3) | 0.9500 (2) | 0.55532 (15) | 0.0484 (7) | |
H2BB | 1.4236 | 1.0191 | 0.5843 | 0.058* | |
C2A | 1.2920 (3) | 0.0342 (3) | −0.00899 (17) | 0.0595 (8) | |
H2AB | 1.3201 | −0.0397 | −0.0330 | 0.071* | |
C3B | 1.2288 (3) | 0.9669 (2) | 0.51575 (16) | 0.0527 (7) | |
H3BA | 1.1961 | 1.0485 | 0.5175 | 0.063* | |
C3A | 1.1838 (3) | 0.0235 (3) | 0.03987 (18) | 0.0616 (8) | |
H3AB | 1.1400 | −0.0582 | 0.0486 | 0.074* | |
C4B | 1.1395 (2) | 0.8657 (2) | 0.47371 (15) | 0.0471 (7) | |
H4BA | 1.0473 | 0.8783 | 0.4473 | 0.056* | |
C4A | 1.1393 (3) | 0.1310 (2) | 0.07598 (16) | 0.0534 (7) | |
H4AA | 1.0669 | 0.1229 | 0.1093 | 0.064* | |
C5B | 1.1895 (2) | 0.7453 (2) | 0.47158 (14) | 0.0344 (6) | |
C5A | 1.2050 (2) | 0.2509 (2) | 0.06147 (15) | 0.0414 (6) | |
C6B | 1.3283 (2) | 0.7276 (2) | 0.50907 (14) | 0.0372 (6) | |
H6BA | 1.3626 | 0.6469 | 0.5056 | 0.045* | |
C6A | 1.3150 (2) | 0.2634 (2) | 0.01377 (14) | 0.0409 (6) | |
H6AA | 1.3600 | 0.3449 | 0.0058 | 0.049* | |
C7B | 0.9652 (2) | 0.6049 (2) | 0.41459 (13) | 0.0335 (6) | |
C7A | 1.0381 (2) | 0.4041 (2) | 0.09925 (14) | 0.0357 (6) | |
C8B | 0.7446 (2) | 0.6606 (2) | 0.43092 (16) | 0.0448 (6) | |
H8BA | 0.6892 | 0.7137 | 0.4568 | 0.054* | |
C8A | 0.7977 (2) | 0.3567 (2) | 0.06177 (15) | 0.0440 (6) | |
H8AA | 0.7207 | 0.3012 | 0.0343 | 0.053* | |
C9B | 0.7516 (2) | 0.4757 (2) | 0.34615 (14) | 0.0342 (6) | |
C9A | 0.8767 (2) | 0.5502 (2) | 0.14041 (13) | 0.0317 (5) | |
C10B | 0.9008 (2) | 0.4894 (2) | 0.36653 (13) | 0.0311 (5) | |
C10A | 1.0186 (2) | 0.5239 (2) | 0.14015 (13) | 0.0339 (5) | |
C11B | 0.9762 (2) | 0.3907 (2) | 0.33836 (14) | 0.0360 (6) | |
H11A | 1.0757 | 0.3971 | 0.3515 | 0.043* | |
C11A | 1.1293 (2) | 0.6148 (2) | 0.18057 (14) | 0.0380 (6) | |
H11B | 1.2245 | 0.5996 | 0.1811 | 0.046* | |
C12B | 0.9045 (2) | 0.2856 (2) | 0.29185 (14) | 0.0369 (6) | |
C12A | 1.0985 (2) | 0.7248 (2) | 0.21887 (14) | 0.0385 (6) | |
C13B | 0.7533 (2) | 0.2785 (2) | 0.26771 (14) | 0.0366 (6) | |
C13A | 0.9529 (2) | 0.7482 (2) | 0.21942 (14) | 0.0379 (6) | |
C14B | 0.6777 (2) | 0.3728 (2) | 0.29462 (14) | 0.0370 (6) | |
H14A | 0.5786 | 0.3685 | 0.2789 | 0.044* | |
C14A | 0.8440 (2) | 0.6618 (2) | 0.18049 (14) | 0.0377 (6) | |
H14B | 0.7489 | 0.6770 | 0.1806 | 0.045* | |
C15B | 1.1109 (2) | 0.1689 (2) | 0.30321 (18) | 0.0660 (8) | |
H15A | 1.1369 | 0.0864 | 0.2859 | 0.099* | |
H15B | 1.1195 | 0.1740 | 0.3641 | 0.099* | |
H15C | 1.1736 | 0.2369 | 0.2846 | 0.099* | |
C15A | 1.3429 (2) | 0.8054 (3) | 0.26069 (19) | 0.0754 (9) | |
H15D | 1.3996 | 0.8745 | 0.2950 | 0.113* | |
H15E | 1.3644 | 0.8086 | 0.2037 | 0.113* | |
H15F | 1.3648 | 0.7237 | 0.2844 | 0.113* | |
C16B | 0.5410 (2) | 0.1570 (3) | 0.19746 (16) | 0.0620 (8) | |
H16A | 0.5126 | 0.0791 | 0.1631 | 0.093* | |
H16B | 0.5074 | 0.2297 | 0.1664 | 0.093* | |
H16C | 0.5002 | 0.1504 | 0.2489 | 0.093* | |
C16A | 0.7931 (3) | 0.8911 (2) | 0.26136 (17) | 0.0580 (8) | |
H16D | 0.7957 | 0.9689 | 0.2954 | 0.087* | |
H16E | 0.7386 | 0.8217 | 0.2847 | 0.087* | |
H16F | 0.7489 | 0.9049 | 0.2041 | 0.087* | |
Atomic displacement parameters (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
Cl1 | 0.0276 (3) | 0.0612 (5) | 0.0800 (5) | 0.0020 (3) | 0.0125 (3) | −0.0096 (4) |
Cl2 | 0.0258 (3) | 0.0533 (4) | 0.0864 (5) | 0.0030 (3) | 0.0092 (3) | −0.0089 (4) |
O1B | 0.0386 (11) | 0.0519 (13) | 0.0836 (15) | −0.0044 (10) | −0.0160 (10) | 0.0030 (11) |
O1A | 0.0685 (14) | 0.0686 (15) | 0.0726 (14) | 0.0327 (11) | 0.0271 (11) | −0.0021 (12) |
O2B | 0.0309 (9) | 0.0481 (11) | 0.0740 (12) | 0.0098 (8) | −0.0064 (9) | −0.0199 (9) |
O2A | 0.0341 (10) | 0.0573 (12) | 0.0711 (12) | −0.0064 (9) | 0.0050 (9) | −0.0228 (10) |
O3B | 0.0325 (9) | 0.0470 (11) | 0.0600 (11) | −0.0009 (8) | −0.0070 (8) | −0.0149 (9) |
O3A | 0.0437 (10) | 0.0492 (11) | 0.0686 (12) | 0.0080 (9) | 0.0058 (9) | −0.0189 (9) |
N1B | 0.0259 (11) | 0.0367 (12) | 0.0460 (13) | 0.0006 (9) | 0.0033 (10) | −0.0048 (10) |
N1A | 0.0254 (12) | 0.0416 (13) | 0.0612 (15) | 0.0030 (10) | 0.0036 (10) | −0.0115 (11) |
N2B | 0.0306 (11) | 0.0401 (12) | 0.0561 (14) | 0.0019 (9) | 0.0114 (10) | −0.0032 (10) |
N2A | 0.0291 (11) | 0.0408 (12) | 0.0531 (13) | 0.0033 (10) | −0.0004 (10) | −0.0061 (10) |
N3B | 0.0268 (11) | 0.0366 (13) | 0.0636 (15) | 0.0025 (10) | 0.0072 (11) | −0.0011 (11) |
N3A | 0.0231 (11) | 0.0384 (13) | 0.0540 (14) | 0.0020 (10) | 0.0027 (10) | −0.0024 (10) |
C1B | 0.0315 (14) | 0.0458 (16) | 0.0425 (15) | −0.0020 (12) | 0.0010 (12) | 0.0027 (13) |
C1A | 0.0438 (16) | 0.0503 (18) | 0.0492 (17) | 0.0204 (14) | −0.0004 (13) | −0.0032 (14) |
C2B | 0.0434 (16) | 0.0414 (16) | 0.0553 (17) | −0.0078 (12) | 0.0005 (13) | −0.0071 (13) |
C2A | 0.0647 (19) | 0.0448 (18) | 0.070 (2) | 0.0234 (15) | 0.0028 (16) | −0.0115 (15) |
C3B | 0.0469 (16) | 0.0369 (15) | 0.0713 (19) | 0.0023 (13) | 0.0026 (14) | −0.0075 (14) |
C3A | 0.0582 (19) | 0.0388 (17) | 0.085 (2) | 0.0037 (14) | 0.0031 (17) | −0.0019 (16) |
C4B | 0.0349 (14) | 0.0407 (16) | 0.0622 (18) | 0.0022 (12) | −0.0014 (13) | −0.0025 (14) |
C4A | 0.0434 (16) | 0.0451 (17) | 0.073 (2) | 0.0055 (13) | 0.0115 (14) | −0.0013 (15) |
C5B | 0.0296 (13) | 0.0343 (14) | 0.0372 (14) | −0.0042 (11) | 0.0038 (11) | −0.0034 (11) |
C5A | 0.0321 (13) | 0.0404 (16) | 0.0498 (16) | 0.0098 (12) | −0.0021 (12) | −0.0081 (13) |
C6B | 0.0326 (13) | 0.0344 (14) | 0.0431 (15) | −0.0004 (11) | 0.0043 (11) | 0.0009 (12) |
C6A | 0.0360 (14) | 0.0400 (15) | 0.0461 (15) | 0.0129 (11) | −0.0004 (12) | −0.0003 (12) |
C7B | 0.0273 (13) | 0.0357 (14) | 0.0374 (14) | 0.0019 (11) | 0.0051 (11) | 0.0039 (11) |
C7A | 0.0265 (13) | 0.0402 (15) | 0.0404 (14) | 0.0019 (11) | 0.0060 (11) | 0.0017 (12) |
C8B | 0.0371 (15) | 0.0357 (15) | 0.0642 (18) | 0.0046 (12) | 0.0160 (13) | −0.0038 (13) |
C8A | 0.0332 (14) | 0.0398 (16) | 0.0551 (17) | −0.0014 (12) | −0.0016 (12) | −0.0031 (13) |
C9B | 0.0279 (13) | 0.0336 (14) | 0.0409 (15) | 0.0026 (10) | 0.0042 (11) | 0.0068 (12) |
C9A | 0.0280 (12) | 0.0323 (14) | 0.0340 (14) | 0.0034 (10) | 0.0023 (10) | 0.0012 (11) |
C10B | 0.0256 (12) | 0.0330 (13) | 0.0336 (14) | 0.0013 (10) | 0.0024 (10) | 0.0045 (11) |
C10A | 0.0293 (13) | 0.0361 (14) | 0.0356 (14) | 0.0024 (10) | 0.0035 (11) | 0.0026 (11) |
C11B | 0.0207 (12) | 0.0380 (14) | 0.0474 (15) | 0.0011 (10) | 0.0014 (11) | 0.0010 (12) |
C11A | 0.0234 (12) | 0.0454 (15) | 0.0446 (15) | 0.0018 (11) | 0.0050 (11) | −0.0051 (12) |
C12B | 0.0299 (13) | 0.0356 (14) | 0.0443 (15) | 0.0041 (11) | 0.0033 (11) | −0.0021 (12) |
C12A | 0.0297 (13) | 0.0412 (15) | 0.0420 (15) | −0.0050 (11) | 0.0033 (11) | −0.0058 (12) |
C13B | 0.0294 (13) | 0.0371 (14) | 0.0395 (15) | −0.0007 (11) | −0.0039 (11) | 0.0001 (12) |
C13A | 0.0376 (14) | 0.0369 (15) | 0.0402 (15) | 0.0083 (11) | 0.0071 (11) | −0.0022 (12) |
C14B | 0.0236 (12) | 0.0401 (14) | 0.0450 (15) | 0.0013 (11) | −0.0011 (11) | 0.0043 (12) |
C14A | 0.0252 (12) | 0.0442 (15) | 0.0439 (15) | 0.0068 (11) | 0.0038 (11) | 0.0020 (12) |
C15B | 0.0384 (16) | 0.0590 (19) | 0.097 (2) | 0.0179 (14) | −0.0056 (15) | −0.0186 (17) |
C15A | 0.0338 (16) | 0.077 (2) | 0.109 (3) | −0.0101 (15) | 0.0051 (16) | −0.0304 (19) |
C16B | 0.0370 (15) | 0.071 (2) | 0.0682 (19) | −0.0067 (14) | −0.0106 (14) | −0.0196 (16) |
C16A | 0.0531 (17) | 0.0510 (17) | 0.074 (2) | 0.0198 (14) | 0.0142 (15) | −0.0112 (15) |
Geometric parameters (Å, º) top
O1B—C1B | 1.368 (3) | C1A—C2A | 1.373 (3) |
O1A—C1A | 1.370 (3) | C1A—C6A | 1.383 (3) |
O2B—C12B | 1.350 (2) | C2B—C3B | 1.378 (3) |
O2B—C15B | 1.434 (3) | C2A—C3A | 1.379 (3) |
O2A—C12A | 1.353 (2) | C3B—C4B | 1.376 (3) |
O2A—C15A | 1.421 (3) | C3A—C4A | 1.377 (3) |
O3B—C13B | 1.346 (2) | C4B—C5B | 1.379 (3) |
O3B—C16B | 1.432 (2) | C4A—C5A | 1.376 (3) |
O3A—C13A | 1.347 (2) | C5B—C6B | 1.387 (3) |
O3A—C16A | 1.430 (3) | C5A—C6A | 1.382 (3) |
N1B—C7B | 1.333 (2) | C7B—C10B | 1.441 (3) |
N1B—C5B | 1.430 (3) | C7A—C10A | 1.434 (3) |
N1A—C7A | 1.331 (3) | C9B—C10B | 1.395 (3) |
N1A—C5A | 1.436 (3) | C9B—C14B | 1.396 (3) |
N2B—C8B | 1.310 (3) | C9A—C14A | 1.396 (3) |
N2B—C7B | 1.351 (3) | C9A—C10A | 1.399 (3) |
N2A—C8A | 1.302 (3) | C10B—C11B | 1.409 (3) |
N2A—C7A | 1.356 (3) | C10A—C11A | 1.408 (3) |
N3B—C8B | 1.324 (3) | C11B—C12B | 1.368 (3) |
N3B—C9B | 1.375 (3) | C11A—C12A | 1.361 (3) |
N3A—C8A | 1.322 (3) | C12B—C13B | 1.419 (3) |
N3A—C9A | 1.381 (3) | C12A—C13A | 1.426 (3) |
C1B—C2B | 1.374 (3) | C13B—C14B | 1.368 (3) |
C1B—C6B | 1.380 (3) | C13A—C14A | 1.363 (3) |
| | | |
C12B—O2B—C15B | 117.62 (18) | N1A—C7A—N2A | 117.0 (2) |
C12A—O2A—C15A | 117.79 (19) | N1A—C7A—C10A | 120.8 (2) |
C13B—O3B—C16B | 117.70 (18) | N2A—C7A—C10A | 122.14 (19) |
C13A—O3A—C16A | 117.80 (18) | N2B—C8B—N3B | 125.3 (2) |
C7B—N1B—C5B | 129.1 (2) | N2A—C8A—N3A | 125.7 (2) |
C7A—N1A—C5A | 127.1 (2) | N3B—C9B—C10B | 118.5 (2) |
C8B—N2B—C7B | 117.5 (2) | N3B—C9B—C14B | 119.5 (2) |
C8A—N2A—C7A | 117.2 (2) | C10B—C9B—C14B | 121.9 (2) |
C8B—N3B—C9B | 120.0 (2) | N3A—C9A—C14A | 119.8 (2) |
C8A—N3A—C9A | 120.1 (2) | N3A—C9A—C10A | 118.6 (2) |
O1B—C1B—C2B | 117.6 (2) | C14A—C9A—C10A | 121.6 (2) |
O1B—C1B—C6B | 122.3 (2) | C9B—C10B—C11B | 117.9 (2) |
C2B—C1B—C6B | 120.0 (2) | C9B—C10B—C7B | 116.7 (2) |
O1A—C1A—C2A | 119.0 (2) | C11B—C10B—C7B | 125.42 (19) |
O1A—C1A—C6A | 121.4 (3) | C9A—C10A—C11A | 118.1 (2) |
C2A—C1A—C6A | 119.6 (2) | C9A—C10A—C7A | 116.3 (2) |
C1B—C2B—C3B | 119.5 (2) | C11A—C10A—C7A | 125.6 (2) |
C1A—C2A—C3A | 119.8 (2) | C12B—C11B—C10B | 120.7 (2) |
C4B—C3B—C2B | 121.5 (2) | C12A—C11A—C10A | 120.7 (2) |
C4A—C3A—C2A | 121.5 (3) | O2B—C12B—C11B | 125.3 (2) |
C3B—C4B—C5B | 118.6 (2) | O2B—C12B—C13B | 114.72 (19) |
C5A—C4A—C3A | 118.2 (2) | C11B—C12B—C13B | 119.9 (2) |
C4B—C5B—C6B | 120.5 (2) | O2A—C12A—C11A | 126.2 (2) |
C4B—C5B—N1B | 123.2 (2) | O2A—C12A—C13A | 113.8 (2) |
C6B—C5B—N1B | 116.2 (2) | C11A—C12A—C13A | 120.0 (2) |
C4A—C5A—C6A | 121.2 (2) | O3B—C13B—C14B | 124.39 (19) |
C4A—C5A—N1A | 122.4 (2) | O3B—C13B—C12B | 115.2 (2) |
C6A—C5A—N1A | 116.3 (2) | C14B—C13B—C12B | 120.4 (2) |
C1B—C6B—C5B | 119.8 (2) | O3A—C13A—C14A | 125.1 (2) |
C5A—C6A—C1A | 119.8 (2) | O3A—C13A—C12A | 114.6 (2) |
N1B—C7B—N2B | 117.8 (2) | C14A—C13A—C12A | 120.3 (2) |
N1B—C7B—C10B | 121.0 (2) | C13B—C14B—C9B | 118.9 (2) |
N2B—C7B—C10B | 121.23 (19) | C13A—C14A—C9A | 119.2 (2) |
| | | |
O1B—C1B—C2B—C3B | 178.8 (2) | N1B—C7B—C10B—C9B | −171.8 (2) |
C6B—C1B—C2B—C3B | −0.6 (4) | N2B—C7B—C10B—C9B | 9.1 (3) |
O1A—C1A—C2A—C3A | −179.6 (2) | N1B—C7B—C10B—C11B | 7.8 (3) |
C6A—C1A—C2A—C3A | −0.2 (4) | N2B—C7B—C10B—C11B | −171.3 (2) |
C1B—C2B—C3B—C4B | 1.2 (4) | N3A—C9A—C10A—C11A | 179.0 (2) |
C1A—C2A—C3A—C4A | 0.3 (4) | C14A—C9A—C10A—C11A | −1.0 (3) |
C2B—C3B—C4B—C5B | −0.1 (4) | N3A—C9A—C10A—C7A | −1.9 (3) |
C2A—C3A—C4A—C5A | 0.6 (4) | C14A—C9A—C10A—C7A | 178.0 (2) |
C3B—C4B—C5B—C6B | −1.7 (4) | N1A—C7A—C10A—C9A | −177.8 (2) |
C3B—C4B—C5B—N1B | −178.6 (2) | N2A—C7A—C10A—C9A | 3.0 (3) |
C7B—N1B—C5B—C4B | −30.6 (4) | N1A—C7A—C10A—C11A | 1.2 (4) |
C7B—N1B—C5B—C6B | 152.4 (2) | N2A—C7A—C10A—C11A | −178.0 (2) |
C3A—C4A—C5A—C6A | −1.6 (4) | C9B—C10B—C11B—C12B | 0.6 (3) |
C3A—C4A—C5A—N1A | −178.3 (2) | C7B—C10B—C11B—C12B | −179.0 (2) |
C7A—N1A—C5A—C4A | −47.6 (4) | C9A—C10A—C11A—C12A | 0.1 (3) |
C7A—N1A—C5A—C6A | 135.5 (2) | C7A—C10A—C11A—C12A | −178.8 (2) |
O1B—C1B—C6B—C5B | 179.5 (2) | C15B—O2B—C12B—C11B | 13.3 (3) |
C2B—C1B—C6B—C5B | −1.2 (3) | C15B—O2B—C12B—C13B | −166.3 (2) |
C4B—C5B—C6B—C1B | 2.4 (3) | C10B—C11B—C12B—O2B | −176.3 (2) |
N1B—C5B—C6B—C1B | 179.5 (2) | C10B—C11B—C12B—C13B | 3.3 (3) |
C4A—C5A—C6A—C1A | 1.7 (3) | C15A—O2A—C12A—C11A | 1.4 (4) |
N1A—C5A—C6A—C1A | 178.6 (2) | C15A—O2A—C12A—C13A | −179.1 (2) |
O1A—C1A—C6A—C5A | 178.6 (2) | C10A—C11A—C12A—O2A | −179.6 (2) |
C2A—C1A—C6A—C5A | −0.7 (3) | C10A—C11A—C12A—C13A | 0.9 (3) |
C5B—N1B—C7B—N2B | −3.0 (3) | C16B—O3B—C13B—C14B | −4.7 (3) |
C5B—N1B—C7B—C10B | 177.9 (2) | C16B—O3B—C13B—C12B | 175.1 (2) |
C8B—N2B—C7B—N1B | 176.4 (2) | O2B—C12B—C13B—O3B | −3.8 (3) |
C8B—N2B—C7B—C10B | −4.5 (3) | C11B—C12B—C13B—O3B | 176.5 (2) |
C5A—N1A—C7A—N2A | −2.3 (4) | O2B—C12B—C13B—C14B | 176.0 (2) |
C5A—N1A—C7A—C10A | 178.5 (2) | C11B—C12B—C13B—C14B | −3.6 (3) |
C8A—N2A—C7A—N1A | 178.8 (2) | C16A—O3A—C13A—C14A | −3.5 (3) |
C8A—N2A—C7A—C10A | −2.1 (3) | C16A—O3A—C13A—C12A | 177.3 (2) |
C7B—N2B—C8B—N3B | −3.6 (4) | O2A—C12A—C13A—O3A | −1.4 (3) |
C9B—N3B—C8B—N2B | 6.7 (4) | C11A—C12A—C13A—O3A | 178.2 (2) |
C7A—N2A—C8A—N3A | −0.1 (4) | O2A—C12A—C13A—C14A | 179.3 (2) |
C9A—N3A—C8A—N2A | 1.2 (4) | C11A—C12A—C13A—C14A | −1.1 (3) |
C8B—N3B—C9B—C10B | −1.3 (3) | O3B—C13B—C14B—C9B | 179.8 (2) |
C8B—N3B—C9B—C14B | 177.5 (2) | C12B—C13B—C14B—C9B | −0.1 (3) |
C8A—N3A—C9A—C14A | −180.0 (2) | N3B—C9B—C14B—C13B | −174.7 (2) |
C8A—N3A—C9A—C10A | −0.1 (3) | C10B—C9B—C14B—C13B | 4.1 (3) |
N3B—C9B—C10B—C11B | 174.42 (19) | O3A—C13A—C14A—C9A | −179.0 (2) |
C14B—C9B—C10B—C11B | −4.3 (3) | C12A—C13A—C14A—C9A | 0.2 (3) |
N3B—C9B—C10B—C7B | −6.0 (3) | N3A—C9A—C14A—C13A | −179.2 (2) |
C14B—C9B—C10B—C7B | 175.26 (19) | C10A—C9A—C14A—C13A | 0.8 (3) |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
O1B—H1B···Cl2i | 0.85 (2) | 2.28 (2) | 3.117 (2) | 170 (2) |
O1A—H1A···Cl1ii | 0.98 (3) | 2.12 (3) | 3.095 (2) | 176 (3) |
N1B—H1BB···Cl2iii | 0.88 (2) | 2.47 (2) | 3.324 (2) | 165.5 (19) |
N1A—H1AA···Cl1iii | 0.88 (2) | 2.41 (2) | 3.261 (2) | 163 (2) |
N3B—H3BB···Cl2 | 0.98 (2) | 2.14 (2) | 3.088 (2) | 162.5 (19) |
N3A—H3AA···Cl1 | 0.89 (2) | 2.26 (2) | 3.142 (2) | 168 (2) |
Symmetry codes: (i) −x+2, −y+1, −z+1; (ii) −x+2, −y+1, −z; (iii) x+1, y, z. |
Experimental details
| (WHI-P154) | (WHI-P180) |
Crystal data |
Chemical formula | C16H15BrN3O3+·Cl−·CH4O | C16H16N3O3+·Cl− |
Mr | 444.71 | 333.77 |
Crystal system, space group | Triclinic, P1 | Triclinic, P1 |
Temperature (K) | 298 | 297 |
a, b, c (Å) | 7.113 (5), 9.339 (7), 14.526 (10) | 9.4851 (7), 10.3688 (8), 15.9106 (12) |
α, β, γ (°) | 79.14 (1), 85.37 (1), 86.49 (1) | 90.954 (1), 99.108 (1), 95.438 (1) |
V (Å3) | 943.5 (12) | 1537.3 (2) |
Z | 2 | 4 |
Radiation type | Mo Kα | Mo Kα |
µ (mm−1) | 2.35 | 0.27 |
Crystal size (mm) | 0.42 × 0.29 × 0.06 | 0.30 × 0.25 × 0.01 |
|
Data collection |
Diffractometer | Bruker SMART CCD area detector diffractometer | Bruker SMART CCD area detector diffractometer |
Absorption correction | Empirical (SADABS; Sheldrick, 1996) | Empirical (SADABS; Sheldrick, 1996) |
Tmin, Tmax | 0.44, 0.87 | 0.92, 1.00 |
No. of measured, independent and observed [I > 2σ(I)] reflections | 10811, 4245, 3230 | 16771, 6248, 3389 |
Rint | 0.047 | 0.049 |
(sin θ/λ)max (Å−1) | 0.655 | 0.625 |
|
Refinement |
R[F2 > 2σ(F2)], wR(F2), S | 0.037, 0.100, 0.99 | 0.043, 0.091, 0.90 |
No. of reflections | 4245 | 6248 |
No. of parameters | 264, 2 restraints | 443 |
H-atom treatment | H atoms treated by a mixture of independent and constrained refinement | H atoms treated by a mixture of independent and constrained refinement |
Δρmax, Δρmin (e Å−3) | 0.62, −0.47 | 0.16, −0.22 |
Selected geometric parameters (Å, º) for (WHI-P154) topBr1A—C2 | 1.888 (3) | N2—C7 | 1.341 (3) |
Br1B—C4 | 1.620 (13) | N3—C8 | 1.324 (3) |
O1—C3 | 1.357 (3) | N3—C11 | 1.372 (3) |
O1A—C1A | 1.426 (4) | C7—C12 | 1.438 (3) |
O2—C14 | 1.348 (3) | C9—C10 | 1.358 (3) |
O2—C15 | 1.432 (3) | C9—C14 | 1.427 (3) |
O3—C9 | 1.349 (3) | C10—C11 | 1.400 (3) |
O3—C16 | 1.437 (3) | C11—C12 | 1.399 (3) |
N1—C7 | 1.340 (3) | C12—C13 | 1.416 (3) |
N1—C6 | 1.425 (3) | C13—C14 | 1.370 (3) |
N2—C8 | 1.313 (3) | | |
| | | |
C14—O2—C15 | 117.20 (18) | N2—C8—N3 | 124.3 (2) |
C9—O3—C16 | 116.2 (2) | O3—C9—C10 | 124.9 (2) |
C7—N1—C6 | 130.7 (2) | O3—C9—C14 | 115.0 (2) |
C8—N2—C7 | 118.1 (2) | C10—C9—C14 | 120.12 (19) |
C8—N3—C11 | 121.0 (2) | C9—C10—C11 | 119.8 (2) |
C1—C2—Br1A | 118.75 (19) | N3—C11—C12 | 118.25 (19) |
C3—C2—Br1A | 118.77 (17) | N3—C11—C10 | 120.1 (2) |
O1—C3—C4 | 123.2 (2) | C12—C11—C10 | 121.7 (2) |
O1—C3—C2 | 119.4 (2) | C11—C12—C13 | 117.64 (19) |
C5—C4—Br1B | 126.5 (5) | C11—C12—C7 | 116.55 (19) |
C3—C4—Br1B | 111.9 (5) | C13—C12—C7 | 125.8 (2) |
C1—C6—N1 | 125.4 (2) | C14—C13—C12 | 120.9 (2) |
C5—C6—N1 | 115.6 (2) | O2—C14—C13 | 125.2 (2) |
N1—C7—N2 | 118.48 (19) | O2—C14—C9 | 114.85 (18) |
N1—C7—C12 | 119.76 (19) | C13—C14—C9 | 119.9 (2) |
N2—C7—C12 | 121.8 (2) | | |
Hydrogen-bond geometry (Å, º) for (WHI-P154) top
D—H···A | D—H | H···A | D···A | D—H···A |
O1—H1B···O1A | 0.817 (10) | 1.827 (11) | 2.643 (4) | 176 (4) |
O1A—H1AA···Cl1 | 0.816 (10) | 2.320 (11) | 3.132 (3) | 174 (4) |
N1—H1A···Cl1i | 0.89 (3) | 2.49 (3) | 3.333 (3) | 158 (2) |
N3—H3A···Cl1ii | 0.86 (3) | 2.27 (3) | 3.117 (3) | 169 (2) |
Symmetry codes: (i) −x+1, −y+2, −z+1; (ii) −x+1, −y+1, −z+1. |
Selected geometric parameters (Å, º) for (WHI-P180) topO1B—C1B | 1.368 (3) | N3B—C8B | 1.324 (3) |
O1A—C1A | 1.370 (3) | N3B—C9B | 1.375 (3) |
O2B—C12B | 1.350 (2) | N3A—C8A | 1.322 (3) |
O2B—C15B | 1.434 (3) | N3A—C9A | 1.381 (3) |
O2A—C12A | 1.353 (2) | C7B—C10B | 1.441 (3) |
O2A—C15A | 1.421 (3) | C7A—C10A | 1.434 (3) |
O3B—C13B | 1.346 (2) | C9B—C10B | 1.395 (3) |
O3B—C16B | 1.432 (2) | C9B—C14B | 1.396 (3) |
O3A—C13A | 1.347 (2) | C9A—C14A | 1.396 (3) |
O3A—C16A | 1.430 (3) | C9A—C10A | 1.399 (3) |
N1B—C7B | 1.333 (2) | C10B—C11B | 1.409 (3) |
N1B—C5B | 1.430 (3) | C10A—C11A | 1.408 (3) |
N1A—C7A | 1.331 (3) | C11B—C12B | 1.368 (3) |
N1A—C5A | 1.436 (3) | C11A—C12A | 1.361 (3) |
N2B—C8B | 1.310 (3) | C12B—C13B | 1.419 (3) |
N2B—C7B | 1.351 (3) | C12A—C13A | 1.426 (3) |
N2A—C8A | 1.302 (3) | C13B—C14B | 1.368 (3) |
N2A—C7A | 1.356 (3) | C13A—C14A | 1.363 (3) |
| | | |
C12B—O2B—C15B | 117.62 (18) | N3B—C9B—C14B | 119.5 (2) |
C12A—O2A—C15A | 117.79 (19) | C10B—C9B—C14B | 121.9 (2) |
C13B—O3B—C16B | 117.70 (18) | N3A—C9A—C14A | 119.8 (2) |
C13A—O3A—C16A | 117.80 (18) | N3A—C9A—C10A | 118.6 (2) |
C7B—N1B—C5B | 129.1 (2) | C14A—C9A—C10A | 121.6 (2) |
C7A—N1A—C5A | 127.1 (2) | C9B—C10B—C11B | 117.9 (2) |
C8B—N2B—C7B | 117.5 (2) | C9B—C10B—C7B | 116.7 (2) |
C8A—N2A—C7A | 117.2 (2) | C11B—C10B—C7B | 125.42 (19) |
C8B—N3B—C9B | 120.0 (2) | C9A—C10A—C11A | 118.1 (2) |
C8A—N3A—C9A | 120.1 (2) | C9A—C10A—C7A | 116.3 (2) |
O1B—C1B—C2B | 117.6 (2) | C11A—C10A—C7A | 125.6 (2) |
O1B—C1B—C6B | 122.3 (2) | C12B—C11B—C10B | 120.7 (2) |
O1A—C1A—C2A | 119.0 (2) | C12A—C11A—C10A | 120.7 (2) |
O1A—C1A—C6A | 121.4 (3) | O2B—C12B—C11B | 125.3 (2) |
C4B—C5B—N1B | 123.2 (2) | O2B—C12B—C13B | 114.72 (19) |
C6B—C5B—N1B | 116.2 (2) | C11B—C12B—C13B | 119.9 (2) |
C4A—C5A—N1A | 122.4 (2) | O2A—C12A—C11A | 126.2 (2) |
C6A—C5A—N1A | 116.3 (2) | O2A—C12A—C13A | 113.8 (2) |
N1B—C7B—N2B | 117.8 (2) | C11A—C12A—C13A | 120.0 (2) |
N1B—C7B—C10B | 121.0 (2) | O3B—C13B—C14B | 124.39 (19) |
N2B—C7B—C10B | 121.23 (19) | O3B—C13B—C12B | 115.2 (2) |
N1A—C7A—N2A | 117.0 (2) | C14B—C13B—C12B | 120.4 (2) |
N1A—C7A—C10A | 120.8 (2) | O3A—C13A—C14A | 125.1 (2) |
N2A—C7A—C10A | 122.14 (19) | O3A—C13A—C12A | 114.6 (2) |
N2B—C8B—N3B | 125.3 (2) | C14A—C13A—C12A | 120.3 (2) |
N2A—C8A—N3A | 125.7 (2) | C13B—C14B—C9B | 118.9 (2) |
N3B—C9B—C10B | 118.5 (2) | C13A—C14A—C9A | 119.2 (2) |
Hydrogen-bond geometry (Å, º) for (WHI-P180) top
D—H···A | D—H | H···A | D···A | D—H···A |
O1B—H1B···Cl2i | 0.85 (2) | 2.28 (2) | 3.117 (2) | 170 (2) |
O1A—H1A···Cl1ii | 0.98 (3) | 2.12 (3) | 3.095 (2) | 176 (3) |
N1B—H1BB···Cl2iii | 0.88 (2) | 2.47 (2) | 3.324 (2) | 165.5 (19) |
N1A—H1AA···Cl1iii | 0.88 (2) | 2.41 (2) | 3.261 (2) | 163 (2) |
N3B—H3BB···Cl2 | 0.98 (2) | 2.14 (2) | 3.088 (2) | 162.5 (19) |
N3A—H3AA···Cl1 | 0.89 (2) | 2.26 (2) | 3.142 (2) | 168 (2) |
Symmetry codes: (i) −x+2, −y+1, −z+1; (ii) −x+2, −y+1, −z; (iii) x+1, y, z. |
The development of inhibitors of the epidermal growth factor receptor and Janus Kinase3 (JAK3) signalling pathways is an active area of translational cancer research. As part of our ongoing program in structure-based design of anti-cancer agents, we have designed and synthesized a series of potent 4-anilinoquinazoline derivatives targeting the ATP-binding site of EGFR. Our modeling studies included the construction of a homology model of the EGFR kinase domain (Ghosh et al., 1998) and the use of an advanced docking procedure to predict the energetically favorable positions of the quinazoline derivatives in the EGFR catalytic site (Ghosh et al., 1999). Based on the modeling studies, several 4-anilinoquinazoline derivatives were synthesized and tested for their kinase inhibitory activity on EGFR. The compounds WHI-P154 and WHI-P180 were subsequently found to inhibit EGFR with IC50 values of 5.6 and 4.0µM, respectively, in kinase inhibition assays. The modeling studies (Ghosh et al., 1999) of these compounds with the EGFR kinase domain revealed that the energetically favorable docked position of the quinazoline derivatives at the catalytic site of EGFR is such that the inhibitors maintain a close contact with the hinge region. The anilino group was oriented into the interior of the protein and clamped between the residues Thr766 and Asp831 from the sides, Thr830 from below, and Val702 on top and the 6,6 OCH3 groups of the inhibitors faced the solvent-accessible region. The torsion angles C12—C7—N1—C6 and C7—N1—C6—C1, in WHI-P154, defining the relative orientation of the quinazoline and aniliono moieties were found to be 162.0 and 16.2°, respectively, in the docking studies compared to -176.0 (2) and 175.2 (2)°, respectively, in the crystal structure of WHI-P154. The corresponding torsion angles (C10—C7—N1—C5 and C7—N1—C5—C4) for WHI-P180 were found to be 163.4 and 14.0° in docking studies, whereas they are 178.5 (2)°, -47.6 (4)° in molecule A and 177.9 (2), -30.6 (4)° in molecule B in the crystal structure if WHI-P180. In docking studies of the title compounds, the N3 nitrogen of the quinazoline group was involved in hydrogen bonding with the backbone carbonyl atom of Met769 and the OH group on the anilino moiety formed an additional hydrogen bond with Asp831 at the EGFR catalytic site. The bridging amino group (N1) was not involved in any hydrogen-bonding interactions with the EGFR catalytic site residues. Some of these compounds also inhibited JAK3 (Sudbeck et al., 1999). This study is the first report of the structural characterization of two such 4-anilinoquinazoline derivatives (WHI-P154 and WHI-P180) which target the catalytic site of the EGFR tyrosine kinase. \sch
The atom-numbering scheme and molecular conformation adopted by the molecules of WHI-P154 and WHI-P180 are shown in Figs. 1 and 2, respectively. There is one molecule of WHI-P154 and two molecules of WHI-P180 in the asymmetric unit and their molecular structures are similar except for the dihedral angle between the anilino and quinazoline moieties. The dihedral angle between the anilino and quinazoline moieties is 1.10 (05)° for WHI-P154, and 45.66 (06) and 25.29 (07)°, respectively, for the two molecules of WHI-P180 in the asymmetric unit. The structure of WHI-P154 was found as a chloride salt with a molecule of methanol solvent in the asymmetric unit. The crystal structure is stabilized by an extensive network of hydrogen bonding as detailed in Table 2. The N3 atom is protonated and all the nitrogen and oxygen atoms of the organic group are involved in hydrogen bonding with the chloride anion or the solvent molecule. The Br atom is disordered with major occupancy of 0.974 (1) at position 1 A and 0.0264 (10) at position 1B. The structure of WHI-P180 was also found as a HCl salt. The N3 positions are protonated for both unique organic groups in WHI-P180. In WHI-P154, the NH groups and methanol solvate are involved in hydrogen bonding with the chloride anion and there is an additional hydrogen-bond interaction between the OH group of the phenyl ring and the methanol solvate (Table 2). In WHI-P180, the OH and the NH groups are involved in hydrogen bonding with the chloride anions (Table 4).