The crystal structure of aripiprazole nitrate (systematic name: 4-(2,3-dichlorophenyl)-1-{4-[(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy]butyl}piperazin-1-ium nitrate), C
23H
28Cl
2N
3O
2+·NO
3- or AripH
+·NO
3-, is presented and the molecule compared with the aripiprazole molecules reported so far in the literature. Bond distances and angles appear very similar, except for a slight lengthening of the C-NH distances involving the protonated N atom, and the main differences are to be found in the molecular spatial arrangement (revealed by the sequence of torsion angles) and the intermolecular interactions (resulting from structural elements specific to this structure,
viz. the nitrate counter-ions on one hand and the extra protons on the other hand as hydrogen-bond acceptors and donors, respectively). The result is the formation of [100] strips, laterally linked by weak
-
and C-Cl
interactions, leading to a family of undulating sheets parallel to (010).
Supporting information
CCDC reference: 879444
Aripiprazole (1.5 × 10 -4 mol, 67 mg) was dissolved in a boiling
mixture of methanol (5 ml) and acetone (0.5 ml). When dissolution was
complete, an excess of HNO3(c) was added dropwise and the resulting
solution left to cool slowly. Excellent quality crystals of AripH+.NO3-,
in the form of colourless prisms, appeared within a few hours, and these were
used as obtained without further recrystallization.
All H atoms were found in a difference map and freely refined [methylene C—H
= 0.93 (2)–0.96 (2) Å, aromatic C—H = 0.94 (2)–1.01 (3) Å and N—H =
0.87 (2)–0.95 (2) Å].
Data collection: CrysAlis PRO (Oxford Diffraction, 2009); cell refinement: CrysAlis PRO (Oxford Diffraction, 2009); data reduction: CrysAlis PRO (Oxford Diffraction, 2009); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008) and PLATON (Spek, 2009).
4-(2,3-dichlorophenyl)-1-{4-[(2-oxo-1,2,3,4-tetrahydroquinolin-7-
yl)oxy]butyl}piperazin-1-ium nitrate
top
Crystal data top
C23H28Cl2N3O2+·NO3− | F(000) = 2144 |
Mr = 511.39 | Dx = 1.447 Mg m−3 |
Orthorhombic, Pbca | Mo Kα radiation, λ = 0.71073 Å |
Hall symbol: -P 2ac 2ab | Cell parameters from 13087 reflections |
a = 8.4644 (2) Å | θ = 3.6–28.9° |
b = 19.8264 (5) Å | µ = 0.32 mm−1 |
c = 27.9406 (7) Å | T = 295 K |
V = 4688.9 (2) Å3 | Prisms, colourless |
Z = 8 | 0.38 × 0.24 × 0.20 mm |
Data collection top
Oxford Diffraction Gemini CCD S Ultra diffractometer | 5809 independent reflections |
Radiation source: fine-focus sealed tube | 4721 reflections with I > 2σ(I) |
Graphite monochromator | Rint = 0.027 |
ω scans, thick slices | θmax = 29.0°, θmin = 3.6° |
Absorption correction: multi-scan (CrysAlis PRO; Oxford Diffraction, 2009) | h = −11→11 |
Tmin = 0.91, Tmax = 0.94 | k = −25→26 |
48362 measured reflections | l = −36→37 |
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)] = 0.042 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.103 | All H-atom parameters refined |
S = 1.09 | w = 1/[σ2(Fo2) + (0.0378P)2 + 2.3824P] where P = (Fo2 + 2Fc2)/3 |
5809 reflections | (Δ/σ)max = 0.001 |
419 parameters | Δρmax = 0.26 e Å−3 |
0 restraints | Δρmin = −0.35 e Å−3 |
Crystal data top
C23H28Cl2N3O2+·NO3− | V = 4688.9 (2) Å3 |
Mr = 511.39 | Z = 8 |
Orthorhombic, Pbca | Mo Kα radiation |
a = 8.4644 (2) Å | µ = 0.32 mm−1 |
b = 19.8264 (5) Å | T = 295 K |
c = 27.9406 (7) Å | 0.38 × 0.24 × 0.20 mm |
Data collection top
Oxford Diffraction Gemini CCD S Ultra diffractometer | 5809 independent reflections |
Absorption correction: multi-scan (CrysAlis PRO; Oxford Diffraction, 2009) | 4721 reflections with I > 2σ(I) |
Tmin = 0.91, Tmax = 0.94 | Rint = 0.027 |
48362 measured reflections | |
Refinement top
R[F2 > 2σ(F2)] = 0.042 | 0 restraints |
wR(F2) = 0.103 | All H-atom parameters refined |
S = 1.09 | Δρmax = 0.26 e Å−3 |
5809 reflections | Δρmin = −0.35 e Å−3 |
419 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 | |
Cl1 | 0.81442 (5) | 0.42930 (2) | 0.249996 (16) | 0.04144 (12) | |
Cl2 | 0.69480 (7) | 0.48551 (3) | 0.152086 (17) | 0.05798 (15) | |
O1 | 1.58206 (16) | 0.20845 (7) | 0.75610 (4) | 0.0490 (3) | |
O2 | 1.01440 (14) | 0.31839 (7) | 0.59539 (4) | 0.0406 (3) | |
N1 | 0.71248 (16) | 0.45364 (7) | 0.43399 (5) | 0.0284 (3) | |
H1 | 0.610 (2) | 0.4550 (9) | 0.4418 (7) | 0.036 (5)* | |
N2 | 0.68512 (17) | 0.50098 (6) | 0.33677 (5) | 0.0328 (3) | |
N3 | 1.40058 (17) | 0.22563 (7) | 0.69874 (5) | 0.0331 (3) | |
H3 | 1.324 (2) | 0.2209 (10) | 0.7188 (8) | 0.044 (6)* | |
C1 | 0.7633 (2) | 0.52258 (9) | 0.41903 (6) | 0.0380 (4) | |
H1A | 0.874 (2) | 0.5180 (9) | 0.4111 (7) | 0.038 (5)* | |
H1B | 0.754 (2) | 0.5506 (11) | 0.4465 (8) | 0.048 (5)* | |
C2 | 0.6664 (3) | 0.54682 (9) | 0.37712 (6) | 0.0396 (4) | |
H2A | 0.554 (2) | 0.5518 (10) | 0.3882 (7) | 0.043 (5)* | |
H2B | 0.705 (2) | 0.5903 (11) | 0.3682 (7) | 0.046 (5)* | |
C3 | 0.6278 (2) | 0.43356 (8) | 0.35026 (6) | 0.0325 (3) | |
H3A | 0.642 (2) | 0.4028 (9) | 0.3238 (7) | 0.036 (5)* | |
H3B | 0.513 (2) | 0.4353 (9) | 0.3599 (6) | 0.033 (5)* | |
C4 | 0.7240 (2) | 0.40699 (8) | 0.39183 (6) | 0.0317 (3) | |
H4A | 0.687 (2) | 0.3647 (10) | 0.4014 (7) | 0.038 (5)* | |
H4B | 0.837 (2) | 0.4057 (9) | 0.3831 (7) | 0.035 (5)* | |
C5 | 0.6350 (2) | 0.52672 (8) | 0.29190 (6) | 0.0320 (3) | |
C6 | 0.68692 (19) | 0.49711 (8) | 0.24903 (6) | 0.0315 (3) | |
C7 | 0.6392 (2) | 0.52351 (9) | 0.20532 (6) | 0.0364 (4) | |
C8 | 0.5461 (3) | 0.58085 (10) | 0.20263 (7) | 0.0452 (4) | |
H8 | 0.519 (3) | 0.5986 (11) | 0.1719 (8) | 0.053 (6)* | |
C9 | 0.4979 (3) | 0.61073 (10) | 0.24445 (7) | 0.0484 (5) | |
H9 | 0.432 (3) | 0.6478 (12) | 0.2424 (8) | 0.058 (6)* | |
C10 | 0.5397 (2) | 0.58404 (9) | 0.28837 (7) | 0.0422 (4) | |
H10 | 0.503 (2) | 0.6059 (10) | 0.3170 (8) | 0.047 (5)* | |
C11 | 0.8053 (2) | 0.43014 (9) | 0.47681 (6) | 0.0346 (4) | |
H11A | 0.826 (2) | 0.4699 (10) | 0.4950 (7) | 0.040 (5)* | |
H11B | 0.900 (3) | 0.4123 (11) | 0.4640 (7) | 0.050 (6)* | |
C12 | 0.7142 (2) | 0.38038 (9) | 0.50721 (6) | 0.0361 (4) | |
H12A | 0.704 (2) | 0.3381 (11) | 0.4902 (7) | 0.046 (5)* | |
H12B | 0.610 (3) | 0.3997 (10) | 0.5134 (7) | 0.049 (6)* | |
C13 | 0.7982 (2) | 0.36741 (10) | 0.55474 (6) | 0.0380 (4) | |
H13A | 0.819 (3) | 0.4088 (12) | 0.5710 (8) | 0.055 (6)* | |
H13B | 0.727 (3) | 0.3439 (11) | 0.5766 (8) | 0.051 (6)* | |
C14 | 0.9500 (2) | 0.32915 (10) | 0.54885 (6) | 0.0382 (4) | |
H14A | 0.933 (2) | 0.2840 (11) | 0.5336 (8) | 0.052 (6)* | |
H14B | 1.025 (2) | 0.3544 (10) | 0.5301 (7) | 0.045 (5)* | |
C15 | 1.16303 (19) | 0.29162 (8) | 0.59860 (5) | 0.0304 (3) | |
C16 | 1.20582 (19) | 0.27068 (8) | 0.64432 (5) | 0.0287 (3) | |
H16 | 1.130 (2) | 0.2724 (9) | 0.6696 (7) | 0.037 (5)* | |
C17 | 1.35706 (18) | 0.24685 (7) | 0.65248 (5) | 0.0274 (3) | |
C18 | 1.46796 (19) | 0.24225 (8) | 0.61558 (6) | 0.0319 (3) | |
C19 | 1.4214 (2) | 0.26309 (9) | 0.57057 (6) | 0.0367 (4) | |
H19 | 1.491 (3) | 0.2599 (10) | 0.5450 (8) | 0.050 (6)* | |
C20 | 1.2704 (2) | 0.28776 (9) | 0.56121 (6) | 0.0360 (4) | |
H20 | 1.245 (2) | 0.3021 (10) | 0.5300 (7) | 0.039 (5)* | |
C21 | 1.5517 (2) | 0.22082 (8) | 0.71413 (6) | 0.0365 (4) | |
C22 | 1.6774 (2) | 0.23350 (11) | 0.67722 (7) | 0.0449 (4) | |
H22A | 1.771 (3) | 0.2108 (11) | 0.6874 (8) | 0.054 (6)* | |
H22B | 1.694 (3) | 0.2798 (13) | 0.6782 (9) | 0.064 (7)* | |
C23 | 1.6265 (2) | 0.21228 (11) | 0.62727 (7) | 0.0411 (4) | |
H23A | 1.706 (3) | 0.2244 (11) | 0.6037 (8) | 0.052 (6)* | |
H23B | 1.618 (3) | 0.1634 (13) | 0.6276 (8) | 0.058 (6)* | |
N1A | 0.32505 (17) | 0.40867 (9) | 0.45407 (5) | 0.0430 (4) | |
O1A | 0.39414 (16) | 0.46440 (8) | 0.45695 (6) | 0.0587 (4) | |
O2A | 0.18335 (17) | 0.40494 (11) | 0.46415 (6) | 0.0738 (5) | |
O3A | 0.40023 (19) | 0.35850 (9) | 0.44199 (7) | 0.0689 (5) | |
Atomic displacement parameters (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
Cl1 | 0.0421 (2) | 0.0391 (2) | 0.0431 (2) | 0.00459 (18) | 0.00356 (18) | 0.00168 (18) |
Cl2 | 0.0694 (4) | 0.0740 (4) | 0.0305 (2) | 0.0124 (3) | 0.0015 (2) | −0.0038 (2) |
O1 | 0.0491 (8) | 0.0659 (8) | 0.0321 (7) | 0.0195 (7) | −0.0118 (5) | −0.0031 (6) |
O2 | 0.0399 (7) | 0.0582 (7) | 0.0236 (6) | 0.0157 (6) | −0.0065 (5) | 0.0006 (5) |
N1 | 0.0245 (7) | 0.0335 (7) | 0.0272 (6) | 0.0009 (5) | 0.0002 (5) | 0.0023 (5) |
N2 | 0.0452 (8) | 0.0265 (6) | 0.0268 (6) | −0.0041 (6) | −0.0027 (6) | 0.0000 (5) |
N3 | 0.0325 (7) | 0.0416 (7) | 0.0251 (7) | 0.0072 (6) | −0.0005 (5) | 0.0043 (5) |
C1 | 0.0487 (11) | 0.0341 (8) | 0.0310 (8) | −0.0082 (8) | −0.0022 (8) | −0.0015 (7) |
C2 | 0.0616 (13) | 0.0272 (8) | 0.0300 (8) | −0.0024 (8) | −0.0041 (8) | −0.0006 (6) |
C3 | 0.0393 (9) | 0.0270 (7) | 0.0311 (8) | −0.0036 (7) | −0.0017 (7) | 0.0001 (6) |
C4 | 0.0350 (9) | 0.0284 (7) | 0.0318 (8) | 0.0028 (7) | 0.0020 (6) | 0.0009 (6) |
C5 | 0.0381 (9) | 0.0275 (7) | 0.0304 (8) | −0.0057 (6) | −0.0028 (6) | 0.0022 (6) |
C6 | 0.0321 (8) | 0.0290 (7) | 0.0334 (8) | −0.0040 (6) | −0.0011 (6) | 0.0019 (6) |
C7 | 0.0395 (9) | 0.0415 (9) | 0.0280 (8) | −0.0054 (7) | −0.0001 (7) | 0.0008 (7) |
C8 | 0.0583 (12) | 0.0421 (10) | 0.0353 (9) | 0.0019 (9) | −0.0105 (8) | 0.0083 (8) |
C9 | 0.0651 (13) | 0.0356 (9) | 0.0444 (11) | 0.0113 (9) | −0.0096 (9) | 0.0027 (8) |
C10 | 0.0584 (12) | 0.0330 (8) | 0.0352 (9) | 0.0054 (8) | −0.0036 (8) | −0.0019 (7) |
C11 | 0.0264 (8) | 0.0460 (9) | 0.0313 (8) | 0.0007 (7) | −0.0055 (6) | 0.0049 (7) |
C12 | 0.0320 (9) | 0.0437 (9) | 0.0326 (8) | 0.0010 (7) | −0.0065 (7) | 0.0066 (7) |
C13 | 0.0386 (9) | 0.0476 (10) | 0.0279 (8) | 0.0053 (8) | −0.0044 (7) | 0.0040 (7) |
C14 | 0.0392 (9) | 0.0505 (10) | 0.0248 (8) | 0.0055 (8) | −0.0075 (7) | 0.0030 (7) |
C15 | 0.0341 (8) | 0.0312 (7) | 0.0260 (7) | 0.0023 (6) | −0.0051 (6) | −0.0016 (6) |
C16 | 0.0313 (8) | 0.0320 (7) | 0.0227 (7) | 0.0034 (6) | −0.0001 (6) | −0.0014 (6) |
C17 | 0.0324 (8) | 0.0260 (7) | 0.0238 (7) | 0.0002 (6) | −0.0024 (6) | −0.0009 (5) |
C18 | 0.0318 (8) | 0.0344 (8) | 0.0293 (8) | −0.0004 (6) | 0.0003 (6) | −0.0028 (6) |
C19 | 0.0369 (9) | 0.0478 (9) | 0.0255 (8) | −0.0015 (8) | 0.0045 (7) | −0.0021 (7) |
C20 | 0.0446 (10) | 0.0426 (9) | 0.0207 (7) | 0.0000 (7) | −0.0026 (7) | 0.0012 (6) |
C21 | 0.0385 (9) | 0.0358 (8) | 0.0353 (9) | 0.0098 (7) | −0.0074 (7) | −0.0046 (7) |
C22 | 0.0321 (9) | 0.0562 (12) | 0.0462 (11) | 0.0066 (9) | −0.0072 (8) | −0.0001 (9) |
C23 | 0.0340 (9) | 0.0510 (11) | 0.0383 (9) | 0.0076 (8) | 0.0043 (7) | −0.0008 (8) |
N1A | 0.0286 (7) | 0.0705 (11) | 0.0298 (7) | −0.0046 (8) | −0.0024 (6) | −0.0003 (7) |
O1A | 0.0361 (7) | 0.0547 (8) | 0.0853 (11) | −0.0006 (6) | 0.0087 (7) | −0.0019 (8) |
O2A | 0.0329 (8) | 0.1176 (15) | 0.0708 (11) | −0.0183 (8) | 0.0140 (7) | −0.0129 (10) |
O3A | 0.0468 (9) | 0.0660 (10) | 0.0938 (13) | −0.0029 (8) | −0.0071 (8) | −0.0228 (9) |
Geometric parameters (Å, º) top
Cl1—C6 | 1.7241 (16) | C9—H9 | 0.92 (2) |
Cl2—C7 | 1.7325 (17) | C10—H10 | 0.96 (2) |
O1—C21 | 1.225 (2) | C11—C12 | 1.514 (2) |
O2—C15 | 1.3683 (19) | C11—H11A | 0.95 (2) |
O2—C14 | 1.4261 (19) | C11—H11B | 0.95 (2) |
N1—C1 | 1.493 (2) | C12—C13 | 1.528 (2) |
N1—C4 | 1.501 (2) | C12—H12A | 0.97 (2) |
N1—C11 | 1.505 (2) | C12—H12B | 0.98 (2) |
N1—H1 | 0.90 (2) | C13—C14 | 1.501 (3) |
N2—C5 | 1.418 (2) | C13—H13A | 0.95 (2) |
N2—C2 | 1.457 (2) | C13—H13B | 0.97 (2) |
N2—C3 | 1.471 (2) | C14—H14A | 1.00 (2) |
N3—C21 | 1.353 (2) | C14—H14B | 0.96 (2) |
N3—C17 | 1.4083 (19) | C15—C20 | 1.387 (2) |
N3—H3 | 0.86 (2) | C15—C16 | 1.391 (2) |
C1—C2 | 1.509 (3) | C16—C17 | 1.383 (2) |
C1—H1A | 0.97 (2) | C16—H16 | 0.96 (2) |
C1—H1B | 0.95 (2) | C17—C18 | 1.397 (2) |
C2—H2A | 1.01 (2) | C18—C19 | 1.381 (2) |
C2—H2B | 0.96 (2) | C18—C23 | 1.504 (2) |
C3—C4 | 1.513 (2) | C19—C20 | 1.393 (3) |
C3—H3A | 0.967 (19) | C19—H19 | 0.93 (2) |
C3—H3B | 1.011 (19) | C20—H20 | 0.942 (19) |
C4—H4A | 0.93 (2) | C21—C22 | 1.503 (3) |
C4—H4B | 0.984 (19) | C22—C23 | 1.520 (3) |
C5—C10 | 1.397 (2) | C22—H22A | 0.95 (2) |
C5—C6 | 1.404 (2) | C22—H22B | 0.93 (2) |
C6—C7 | 1.389 (2) | C23—H23A | 0.97 (2) |
C7—C8 | 1.385 (3) | C23—H23B | 0.97 (2) |
C8—C9 | 1.372 (3) | N1A—O3A | 1.228 (2) |
C8—H8 | 0.96 (2) | N1A—O2A | 1.234 (2) |
C9—C10 | 1.382 (3) | N1A—O1A | 1.253 (2) |
| | | |
C15—O2—C14 | 118.00 (13) | N1—C11—H11B | 105.0 (13) |
C1—N1—C4 | 109.02 (12) | C12—C11—H11B | 113.6 (13) |
C1—N1—C11 | 110.82 (13) | H11A—C11—H11B | 110.5 (17) |
C4—N1—C11 | 113.52 (13) | C11—C12—C13 | 111.10 (15) |
C1—N1—H1 | 108.7 (12) | C11—C12—H12A | 109.4 (12) |
C4—N1—H1 | 105.9 (12) | C13—C12—H12A | 108.8 (12) |
C11—N1—H1 | 108.7 (12) | C11—C12—H12B | 107.6 (12) |
C5—N2—C2 | 115.29 (13) | C13—C12—H12B | 109.5 (12) |
C5—N2—C3 | 117.05 (13) | H12A—C12—H12B | 110.5 (17) |
C2—N2—C3 | 109.42 (13) | C14—C13—C12 | 112.85 (15) |
C21—N3—C17 | 124.06 (15) | C14—C13—H13A | 109.5 (14) |
C21—N3—H3 | 119.6 (14) | C12—C13—H13A | 110.7 (14) |
C17—N3—H3 | 115.8 (14) | C14—C13—H13B | 110.7 (13) |
N1—C1—C2 | 110.62 (14) | C12—C13—H13B | 109.8 (13) |
N1—C1—H1A | 104.9 (11) | H13A—C13—H13B | 102.9 (18) |
C2—C1—H1A | 112.3 (11) | O2—C14—C13 | 107.64 (14) |
N1—C1—H1B | 106.5 (13) | O2—C14—H14A | 108.0 (12) |
C2—C1—H1B | 113.1 (13) | C13—C14—H14A | 112.1 (12) |
H1A—C1—H1B | 109.0 (17) | O2—C14—H14B | 108.9 (12) |
N2—C2—C1 | 110.04 (15) | C13—C14—H14B | 111.1 (12) |
N2—C2—H2A | 113.7 (12) | H14A—C14—H14B | 109.0 (17) |
C1—C2—H2A | 108.0 (11) | O2—C15—C20 | 125.06 (14) |
N2—C2—H2B | 108.9 (12) | O2—C15—C16 | 114.55 (14) |
C1—C2—H2B | 107.6 (12) | C20—C15—C16 | 120.30 (15) |
H2A—C2—H2B | 108.4 (17) | C17—C16—C15 | 119.62 (14) |
N2—C3—C4 | 109.61 (13) | C17—C16—H16 | 121.0 (11) |
N2—C3—H3A | 109.5 (11) | C15—C16—H16 | 119.4 (11) |
C4—C3—H3A | 107.5 (11) | C16—C17—C18 | 121.49 (14) |
N2—C3—H3B | 110.8 (10) | C16—C17—N3 | 119.69 (14) |
C4—C3—H3B | 109.0 (10) | C18—C17—N3 | 118.82 (14) |
H3A—C3—H3B | 110.3 (15) | C19—C18—C17 | 117.42 (15) |
N1—C4—C3 | 110.67 (13) | C19—C18—C23 | 124.80 (15) |
N1—C4—H4A | 107.9 (12) | C17—C18—C23 | 117.72 (15) |
C3—C4—H4A | 110.7 (12) | C18—C19—C20 | 122.54 (15) |
N1—C4—H4B | 105.9 (11) | C18—C19—H19 | 120.1 (13) |
C3—C4—H4B | 109.9 (11) | C20—C19—H19 | 117.4 (13) |
H4A—C4—H4B | 111.7 (16) | C15—C20—C19 | 118.62 (15) |
C10—C5—C6 | 117.42 (15) | C15—C20—H20 | 121.9 (12) |
C10—C5—N2 | 121.84 (15) | C19—C20—H20 | 119.5 (12) |
C6—C5—N2 | 120.67 (14) | O1—C21—N3 | 121.09 (17) |
C7—C6—C5 | 120.10 (15) | O1—C21—C22 | 122.81 (16) |
C7—C6—Cl1 | 119.33 (13) | N3—C21—C22 | 116.07 (15) |
C5—C6—Cl1 | 120.55 (12) | C21—C22—C23 | 112.51 (16) |
C8—C7—C6 | 121.51 (16) | C21—C22—H22A | 107.7 (13) |
C8—C7—Cl2 | 117.69 (13) | C23—C22—H22A | 112.2 (13) |
C6—C7—Cl2 | 120.80 (14) | C21—C22—H22B | 104.7 (15) |
C9—C8—C7 | 118.49 (17) | C23—C22—H22B | 110.1 (15) |
C9—C8—H8 | 122.5 (13) | H22A—C22—H22B | 109 (2) |
C7—C8—H8 | 119.0 (13) | C18—C23—C22 | 110.07 (15) |
C8—C9—C10 | 120.98 (18) | C18—C23—H23A | 112.0 (12) |
C8—C9—H9 | 118.0 (14) | C22—C23—H23A | 110.8 (13) |
C10—C9—H9 | 120.9 (14) | C18—C23—H23B | 109.2 (14) |
C9—C10—C5 | 121.45 (17) | C22—C23—H23B | 106.7 (13) |
C9—C10—H10 | 119.1 (12) | H23A—C23—H23B | 107.9 (18) |
C5—C10—H10 | 119.5 (12) | O3A—N1A—O2A | 121.17 (19) |
N1—C11—C12 | 112.44 (13) | O3A—N1A—O1A | 119.36 (15) |
N1—C11—H11A | 105.4 (12) | O2A—N1A—O1A | 119.46 (19) |
C12—C11—H11A | 109.5 (12) | | |
| | | |
C4—N1—C1—C2 | 56.19 (19) | C4—N1—C11—C12 | −84.55 (18) |
C11—N1—C1—C2 | −178.17 (15) | N1—C11—C12—C13 | −169.65 (15) |
C5—N2—C2—C1 | −164.10 (15) | C11—C12—C13—C14 | −69.0 (2) |
C3—N2—C2—C1 | 61.50 (19) | C15—O2—C14—C13 | −172.10 (15) |
N1—C1—C2—N2 | −59.7 (2) | C12—C13—C14—O2 | −178.23 (15) |
C5—N2—C3—C4 | 165.42 (14) | C14—O2—C15—C20 | 15.1 (2) |
C2—N2—C3—C4 | −61.06 (18) | C14—O2—C15—C16 | −168.28 (15) |
C1—N1—C4—C3 | −56.08 (18) | O2—C15—C16—C17 | −175.83 (14) |
C11—N1—C4—C3 | 179.86 (13) | C20—C15—C16—C17 | 1.0 (2) |
N2—C3—C4—N1 | 58.85 (18) | C15—C16—C17—C18 | −1.0 (2) |
C2—N2—C5—C10 | −15.3 (2) | C15—C16—C17—N3 | 180.00 (14) |
C3—N2—C5—C10 | 115.58 (18) | C21—N3—C17—C16 | −159.47 (15) |
C2—N2—C5—C6 | 161.40 (16) | C21—N3—C17—C18 | 21.5 (2) |
C3—N2—C5—C6 | −67.8 (2) | C16—C17—C18—C19 | 0.6 (2) |
C10—C5—C6—C7 | −2.1 (2) | N3—C17—C18—C19 | 179.63 (15) |
N2—C5—C6—C7 | −178.87 (15) | C16—C17—C18—C23 | −176.78 (15) |
C10—C5—C6—Cl1 | 176.13 (13) | N3—C17—C18—C23 | 2.2 (2) |
N2—C5—C6—Cl1 | −0.7 (2) | C17—C18—C19—C20 | −0.2 (3) |
C5—C6—C7—C8 | 2.9 (3) | C23—C18—C19—C20 | 177.03 (17) |
Cl1—C6—C7—C8 | −175.32 (14) | O2—C15—C20—C19 | 175.91 (16) |
C5—C6—C7—Cl2 | −177.13 (13) | C16—C15—C20—C19 | −0.5 (2) |
Cl1—C6—C7—Cl2 | 4.7 (2) | C18—C19—C20—C15 | 0.1 (3) |
C6—C7—C8—C9 | −1.5 (3) | C17—N3—C21—O1 | 172.76 (16) |
Cl2—C7—C8—C9 | 178.53 (16) | C17—N3—C21—C22 | −5.5 (2) |
C7—C8—C9—C10 | −0.7 (3) | O1—C21—C22—C23 | 150.43 (18) |
C8—C9—C10—C5 | 1.4 (3) | N3—C21—C22—C23 | −31.3 (2) |
C6—C5—C10—C9 | 0.0 (3) | C19—C18—C23—C22 | 145.85 (18) |
N2—C5—C10—C9 | 176.73 (18) | C17—C18—C23—C22 | −36.9 (2) |
C1—N1—C11—C12 | 152.37 (15) | C21—C22—C23—C18 | 50.8 (2) |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
C3—H3A···Cl1 | 0.97 (2) | 2.58 (2) | 3.217 (2) | 124 (2) |
N1—H1···O1A | 0.90 (2) | 1.89 (2) | 2.778 (2) | 176 (2) |
C11—H11B···O2Ai | 0.95 (2) | 2.40 (3) | 3.258 (2) | 150 (2) |
C14—H14B···O2Ai | 0.96 (2) | 2.49 (2) | 3.429 (2) | 165 (2) |
N3—H3···O1ii | 0.86 (2) | 2.18 (2) | 2.996 (2) | 158 (2) |
C16—H16···O1ii | 0.96 (2) | 2.47 (2) | 3.219 (2) | 136 (2) |
C2—H2B···Cg2iii | 0.96 (2) | 2.92 (2) | 3.720 (2) | 142.6 (14) |
C4—H4A···Cg2iv | 0.93 (2) | 2.84 (2) | 3.534 (2) | 132.6 (14) |
Symmetry codes: (i) x+1, y, z; (ii) x−1/2, y, −z+3/2; (iii) −x+2, −y+1, −z+1; (iv) x−1/2, −y+1/2, −z+1. |
Experimental details
Crystal data |
Chemical formula | C23H28Cl2N3O2+·NO3− |
Mr | 511.39 |
Crystal system, space group | Orthorhombic, Pbca |
Temperature (K) | 295 |
a, b, c (Å) | 8.4644 (2), 19.8264 (5), 27.9406 (7) |
V (Å3) | 4688.9 (2) |
Z | 8 |
Radiation type | Mo Kα |
µ (mm−1) | 0.32 |
Crystal size (mm) | 0.38 × 0.24 × 0.20 |
|
Data collection |
Diffractometer | Oxford Diffraction Gemini CCD S Ultra diffractometer |
Absorption correction | Multi-scan (CrysAlis PRO; Oxford Diffraction, 2009) |
Tmin, Tmax | 0.91, 0.94 |
No. of measured, independent and observed [I > 2σ(I)] reflections | 48362, 5809, 4721 |
Rint | 0.027 |
(sin θ/λ)max (Å−1) | 0.682 |
|
Refinement |
R[F2 > 2σ(F2)], wR(F2), S | 0.042, 0.103, 1.09 |
No. of reflections | 5809 |
No. of parameters | 419 |
H-atom treatment | All H-atom parameters refined |
Δρmax, Δρmin (e Å−3) | 0.26, −0.35 |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
C3—H3A···Cl1 | 0.97 (2) | 2.58 (2) | 3.217 (2) | 124 (2) |
N1—H1···O1A | 0.90 (2) | 1.89 (2) | 2.778 (2) | 176 (2) |
C11—H11B···O2Ai | 0.95 (2) | 2.40 (3) | 3.258 (2) | 150 (2) |
C14—H14B···O2Ai | 0.96 (2) | 2.49 (2) | 3.429 (2) | 165 (2) |
N3—H3···O1ii | 0.86 (2) | 2.18 (2) | 2.996 (2) | 158 (2) |
C16—H16···O1ii | 0.96 (2) | 2.47 (2) | 3.219 (2) | 136 (2) |
C2—H2B···Cg2iii | 0.96 (2) | 2.92 (2) | 3.720 (2) | 142.6 (14) |
C4—H4A···Cg2iv | 0.93 (2) | 2.84 (2) | 3.534 (2) | 132.6 (14) |
Symmetry codes: (i) x+1, y, z; (ii) x−1/2, y, −z+3/2; (iii) −x+2, −y+1, −z+1; (iv) x−1/2, −y+1/2, −z+1. |
Comparative bond distances (Å) topBond | d(I) | <d(A-K>(*) |
CL1-C6 | 1.7241 (16) | 1.728 (8) |
CL2-C7 | 1.7325 (17) | 1.736 (14) |
O1-C21 | 1.225 (2) | 1.228 (6) |
O2-C14 | 1.4261 (19) | 1.415 (40) |
O2-C15 | 1.3683 (19) | 1.374 (12) |
N1-C1 | 1.493 (2) | 1.453 (10) |
N1-C4 | 1.501 (2) | 1.458 (4) |
N1-C11 | 1.505 (2) | 1.464 (14) |
N2-C2 | 1.457 (2) | 1.459 (6) |
N2-C3 | 1.471 (2) | 1.464 (9) |
N2-C5 | 1.428 (2) | 1.413 (7) |
N3-C17 | 1.4083 (19) | 1.410 (7) |
N3-C21 | 1.352 (3) | 1.351 (8) |
C1-C2 | 1.509 (3) | 1.514 (8) |
C3-C4 | 1.513 (2) | 1.509 (10) |
C5-C6 | 1.404 (2) | 1.405 (12) |
C5-C10 | 1.397 (2) | 1.389 (9) |
C6-C7 | 1.389 (2) | 1.383 (20) |
C7-C8 | 1.385 (3) | 1.371 (18) |
C8-C9 | 1.372 (3) | 1.372 (16) |
C9-C10 | 1.382 (3) | 1.383 (12) |
C11-C12 | 1.514 (2) | 1.517 (19) |
C12-C13 | 1.528 (2) | 1.514 (34) |
C13-C14 | 1.501 (2) | 1.497 (30) |
C15-C16 | 1.391 (2) | 1.381 (12) |
C15-C20 | 1.387 (2) | 1.375 (11) |
C16-C17 | 1.383 (2) | 1.379 (11) |
C17-C18 | 1.397 (2) | 1.391 (7) |
C18-C19 | 1.381 (2) | 1.379 (14) |
C18-C23 | 1.504 (2) | 1.507 (10) |
C19-C20 | 1.393 (3) | 1.385 (15) |
C21-C22 | 1.503 (3) | 1.496 (11) |
C22-C23 | 1.520 (3) | 1.492 (23) |
(*): the column reports the un-weighted average value of equivalent distances
in the A-K group (as defined in the text),
with the usual standard deviation from the average shown in parenthesis. |
Comparison of selected torsion angles (°) topT.A.(°) | (1) | A | B | C | D | E | F | G | H | I | J | K |
T1 | -84.5 (2) | -167.3 (4) | -159.4 (8) | -168.1 (6) | -159.9 (8) | -167.5 (3) | -173.1 (3) | -156.1 (3) | -164.9 (4) | -171.1 (3) | -73.6 (3) | -167.1 (4) |
T2 | -169.6 (1) | 60.2 (7) | 178.0 (9) | 173.0 (6) | 174.2 (8) | 169.4 (3) | -179.6 (3) | -170.6 (3) | 173.4 (4) | 168.0 (3) | -171.1 (2) | 173.7 (4) |
T3 | -69.0 (2) | 174.7 (6) | -173.3 (9) | -175.9 (7) | -161.8 (9) | -176.5 (3) | -178.3 (9) | -169.6 (3) | -175.6 (4) | -175.4 (3) | 172.8 (2) | -177.8 (4) |
Torsion angle codes.
T1: C4-N1-C11-C12; T2: N1-C11-C12-C13; T3:
C11-C12-C13-C14 |
π–π and hal–π contacts (Å, °) for (I) topGroup 1/Group 2 | ccd(Å) | cpd(Å) | sa(°) |
Cg1···Cg1i | 4.238 (2) | 3.456 (2) | 35.37 |
Cl1···Cg1i | 3.404 (2) | 3.339 (2) | 11.27 |
Symmetry code: (i), 1/2+x,y,1/2-z
ccd: centre-to-centre distance ; cpd: centre to plane distance; sa:
slippage angle (angle subtended by the intercentroid vector to the plane
normal). Cg1: defined in Fig. 1. For details, see Janiak (2000). |
Aripiprazole (7-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy}-1,2,3,4-tetrahydroquinolin-2-one, Arip) is an antipsychotic drug, perhaps the most relevant representative of a modern family of atypical antipsychotics (Travis et al., 2005), with a therapeutic activity which is different from the classical antipsychotic drugs of standard use.
Regarding the forms in which Arip appears, the drug crystallizes in a number of different polymorphic and solvatomorphic varieties, including an amorphous phase, described in a large number of patents which indicate the commercial importance of the drug. However, and as expected in this type of documentation, the structural information provided is far from complete: the compounds appear as poorly characterized, and when their X-ray powder diffraction (XRPD) diagrams are reported, they usually fulfil the role of fingerprint identifiers. Only a few of these compounds have been studied from a structural point of view and included in the public domain, as entries in the Cambridge Structural Database (CSD; Allen, 2002). The main source of this information is the paper by Tessler & Goldberg (2006), complemented by two excellent works by Braun et al. (2009a,b). In the former work, a number of different forms of the Arip molecule in its free form are reported, included in the CSD with refcodes MELFIT01 [hereafter B; in what follows, independent Arip moieties, either in the same or in different structures, will be named with uppercase letters), MELFIT02 (C), MELFIT03 (D and E: one single structure, two independent moieties), MELFIT04 (F and G: one single structure, two independent moieties) and MELFIT05 (H); while the Braun et al. (2009b) publication deals with different solvates: MELFEP01 (ethanol solvate, A), MELFOZ01 (methanol solvate, I), MELFUF01 (monohydrate, J) and MOXDAF01 (1,2-dichloroethane solvate, K).
With Arip salts, things are slightly different: there are also lots of patents describing Arip salts, basically derived from carboxylic acids (for example, Brand et al., 2007; Pongo et al., 2009), but none of these attempts have reached a structural level despite the fact that their study might deserve due attention: there are many examples of pharmaceutical drugs which are being delivered as salts, due to solubility or stability considerations. Thus, we present herein the crystal structure of Aripiprazole nitrate, AripH+.NO3-, (I), the first successful structural outcome of an intended series on Aripiprazole salts obtained from inorganic or organic acids.
Fig. 1 shows an ellipsoid plot of the asymmetric unit of (I), consisting of an AripH+ cation and an NO3- counter-ion completing the structure and providing for charge balance. The AripH+ unit is metrically similar to the many polymorphs and solvatomorphs already reported and disclosed above, and the only difference is the protonation of N1. This analogy is reflected in Table 1 which compares bond distances in (I) with the mean values of all the reported moieties (A–K): the general similarities are apparent, as well as the lengthening of the bonds involving the N1 atom, due to protonation.
More significant differences are detectable in the way the molecular groups evolve in space. Fig. 2 shows a fitting of (I) and the remaining 11 moieties in the A–K group. A similar comparison has already been made in Braun et al. (2009a) involving the different polymorphs of the free base reported therein.
The present comparison was made by forcing the best fit of the dichlorophenyl–piperazine region of the Arip molecules, ending up with a reasonable fit in that specific region for all 12 cases, with 11 of them bunching in the mid-region and structure (I) clearly evolving away from the bulk. From a strictly formal point of view, this is explained by the torsion angles in the N1—C13 region being distinctly different from those in the remaining lot, as disclosed in Table 2. Regarding the reasons, however, they should be looked for in the fact that it is in the N1+ neighbourhood where the structural differences reside, and this will be apparent when discussing the hydrogen-bonding scheme.
Intermolecular interactions defining the spatial arrangement are of variable type and strength. Table 3 presents the more significant hydrogen bonds, while Table 4 complements this with the remaining π–π and Cl···π contacts. The first entry in Table 3 corresponds to an intramolecular C—H···Cl interaction characteristic for the dichlorophenyl–piperazine group in all reported Arip variants (Fig. 1), being in (I) rather unexceptional. In addition, the present structure lacks any significant intermolecular C—H···Cl contact, contrasting with many reported Arip compounds where the terminal Cl atoms are acceptors for these types of interactions (see, for instance, Braun et al., 2009a). Fig. 3 shows an extended view of a [010] projection, along the medium-length axis, where three definite regions are clearly defined by their unique interactions and presented as shadowed [shaded] columns (A, B and C) in the figure. Regions A and B are determined by the hydrogen bonds appearing in Table 3 as entries 2 and 3 on one side and entries 4, 5 and 6 on the other, and both define broad strips running along [100].
The first of these interactions, the strong N3—H3···O1' hydrogen bond between amide groups of adjacent Arip molecules, is common to most of the reported Arip variants, the sole exception being the monohydrated species J (CSD refcode MELFOZ01) where they are (surprisingly) absent.
One explanation for the conformation of J involves an examination of the packing contacts and water solvate as an acceptor for the N3—H3 donor. Thus, in the packing organization of J, the (disordered by symmetry) water solvate serves as a prompt acceptor for the N3—H3 donor, thus blocking this interaction site and dramatically changing the whole subsequent three-dimensional arrangement.
In all the remaining cases, the interactions do exist, and result in one of two well defined supramolecular synthons. The first much more frequent synthon is a centrosymmetryc diamide R22(8) dimer, shown as an inset in Fig. 3 and occurring in all those Arip variants crystallizing in P1, viz. moieties A, D, E, H, I and K. The second synthon is a catemer, and appears only in moieties B, C and H, forms which crystallyze in space groups with a 21 axis running along a short cell dimension, and which serves for the `threading' of the resulting R12 (6) loops (for graph-set nomenclature, see Bernstein et al., 1995). The present case, (I), corresponds to this latter class of catemers and corresponds to column A in Fig. 3. There is, however, a substantial difference in that the symmetry element responsible for the chain formation is in this case the a glide plane instead of a 21 axis.
In contrast with the common character of the previous interaction, the second group (restricted to zone B) is more distinctive of the present structure (I), as some of the main structural elements (the nitrate counter-ion as an acceptor and the extra proton H1 as a donor) are privative of this structure, and even if the strips are common constructive bricks to most Arip structures, in the present case, this second interaction strengthens their mutual link and enhances their internal cohesion, to form a rather different entity (Fig. 3). The [100] strips are in turn laterally linked by the weak nonconventional π–π and C—Cl···π interactions presented in Table 4, and isolated in zone C (Fig. 3). The result is a family of parallel sheets shown laterally in Fig. 4, where their undulating character can be clearly appreciated. The intersheet separation is b/4 = ca 4.95 Å, and their mutual interaction is accordingly weak, mainly due to C—H···π bonds (in Table 3, entries 7 and 8, not shown in Fig. 4).
Finally, the results presented herein confirm some expected results, viz the protonated state of AripH+ and the inclusion of a strong hydrogen-bond acceptor (the required counter-anion) must necessarily introduce interesting new structural properties, which are frequently associated with new physical (and sometimes commercially useful) properties. Accordingly, with these expectations, further work along this line is in progress.