Supporting information
Crystallographic Information File (CIF) https://doi.org/10.1107/S0108270103012241/fa1020sup1.cif | |
Structure factor file (CIF format) https://doi.org/10.1107/S0108270103012241/fa1020IIcsup2.hkl |
CCDC reference: 219562
Compound (IIc) was synthesized by cyclocondensation of 4-(4-methylphenyl)but-3-en-2-one with aminoguanidine hydrogencarbonate, as described by Světlík & Sallai (2002). Briefly, a suspension of both reactants (10 mmol each) in n-butanol (30 ml) was stirred under reflux for 3 h. The resulting solution was concentrated on a vacuum rotary evaporator, and the syrupy residue was dissolved in ethyl acetate (10 ml) and left to stand at room temperature. The crystalline material that appeared was collected by filtration and recrystallized from dioxane (yield 0.27 g, 26%; m.p. 471—473 K).
H atoms were refined as riding on their carrier atoms, with Uiso values set to 1.2 (1.5 for the methyl H atoms) times the Ueq values of the parent atom.
Data collection: Syntex P21 diffractometer software; cell refinement: Syntex P21 diffractometer software; data reduction: XP21 (Pavelčík, 1987); program(s) used to solve structure: SHELXS97 (Sheldrick, 1990); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEPII (Johnson, 1976); software used to prepare material for publication: SHELXL97 (Sheldrick, 1997).
Fig. 1. Displacement ellipsoid plot of (IIc), with the labelling scheme for the non-H atoms, which are drawn as 35% probability ellipsoids. |
C12H15N3O | F(000) = 232 |
Mr = 217.27 | Dx = 1.251 Mg m−3 Dm = 1.25 (1) Mg m−3 Dm measured by flotation in bromoform/c-hexane |
Triclinic, P1 | Melting point: 472 K |
a = 6.080 (3) Å | Mo Kα radiation, λ = 0.71073 Å |
b = 6.815 (3) Å | Cell parameters from 15 reflections |
c = 14.314 (5) Å | θ = 7–18° |
α = 96.86 (4)° | µ = 0.08 mm−1 |
β = 91.28 (4)° | T = 293 K |
γ = 101.40 (5)° | Prism, colourless |
V = 576.6 (4) Å3 | 0.35 × 0.30 × 0.25 mm |
Z = 2 |
Syntex P21 diffractometer | Rint = 0.000 |
Radiation source: fine-focus sealed tube | θmax = 25.1°, θmin = 2.9° |
Graphite monochromator | h = −5→7 |
θ/2θ scans | k = −5→8 |
2041 measured reflections | l = −17→16 |
2041 independent reflections | 2 standard reflections every 98 reflections |
1276 reflections with I > 2σ(I) | intensity decay: 2% |
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)] = 0.052 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.146 | H-atom parameters constrained |
S = 1.02 | w = 1/[σ2(Fo2) + (0.0821P)2] where P = (Fo2 + 2Fc2)/3 |
2041 reflections | (Δ/σ)max = 0.002 |
147 parameters | Δρmax = 0.20 e Å−3 |
0 restraints | Δρmin = −0.20 e Å−3 |
C12H15N3O | γ = 101.40 (5)° |
Mr = 217.27 | V = 576.6 (4) Å3 |
Triclinic, P1 | Z = 2 |
a = 6.080 (3) Å | Mo Kα radiation |
b = 6.815 (3) Å | µ = 0.08 mm−1 |
c = 14.314 (5) Å | T = 293 K |
α = 96.86 (4)° | 0.35 × 0.30 × 0.25 mm |
β = 91.28 (4)° |
Syntex P21 diffractometer | Rint = 0.000 |
2041 measured reflections | 2 standard reflections every 98 reflections |
2041 independent reflections | intensity decay: 2% |
1276 reflections with I > 2σ(I) |
R[F2 > 2σ(F2)] = 0.052 | 0 restraints |
wR(F2) = 0.146 | H-atom parameters constrained |
S = 1.02 | Δρmax = 0.20 e Å−3 |
2041 reflections | Δρmin = −0.20 e Å−3 |
147 parameters |
x | y | z | Uiso*/Ueq | ||
N1 | 0.3944 (3) | 0.5165 (3) | 0.38719 (12) | 0.0494 (5) | |
N2 | 0.1784 (3) | 0.3988 (3) | 0.37378 (13) | 0.0466 (5) | |
C3 | 0.1975 (4) | 0.2311 (3) | 0.32709 (15) | 0.0448 (6) | |
C4 | 0.4311 (4) | 0.2155 (3) | 0.30552 (17) | 0.0496 (6) | |
H4A | 0.4419 | 0.1649 | 0.2399 | 0.060* | |
H4B | 0.4881 | 0.1287 | 0.3450 | 0.060* | |
C5 | 0.5568 (4) | 0.4357 (3) | 0.32825 (15) | 0.0456 (5) | |
H5 | 0.6969 | 0.4429 | 0.3649 | 0.055* | |
C6 | 0.6038 (3) | 0.5390 (3) | 0.24107 (14) | 0.0417 (5) | |
C7 | 0.7917 (4) | 0.5213 (4) | 0.19265 (16) | 0.0551 (7) | |
H7 | 0.8940 | 0.4521 | 0.2159 | 0.066* | |
C8 | 0.8317 (4) | 0.6045 (4) | 0.11003 (17) | 0.0619 (7) | |
H8 | 0.9601 | 0.5895 | 0.0781 | 0.074* | |
C9 | 0.6852 (4) | 0.7093 (4) | 0.07387 (17) | 0.0557 (7) | |
C10 | 0.5003 (4) | 0.7300 (4) | 0.12350 (18) | 0.0613 (7) | |
H10 | 0.3996 | 0.8017 | 0.1009 | 0.074* | |
C11 | 0.4593 (4) | 0.6475 (4) | 0.20621 (17) | 0.0547 (6) | |
H11 | 0.3326 | 0.6652 | 0.2388 | 0.066* | |
C12 | 0.0017 (4) | 0.0659 (4) | 0.3003 (2) | 0.0669 (8) | |
H12A | −0.1290 | 0.1006 | 0.3291 | 0.100* | |
H12B | 0.0293 | −0.0558 | 0.3215 | 0.100* | |
H12C | −0.0227 | 0.0457 | 0.2331 | 0.100* | |
C13 | 0.7255 (6) | 0.7966 (5) | −0.01765 (19) | 0.0856 (9) | |
H13A | 0.6015 | 0.7394 | −0.0617 | 0.128* | |
H13B | 0.8613 | 0.7655 | −0.0429 | 0.128* | |
H13C | 0.7393 | 0.9403 | −0.0066 | 0.128* | |
C14 | 0.4323 (4) | 0.7092 (3) | 0.43160 (15) | 0.0477 (6) | |
O1 | 0.6256 (3) | 0.8170 (3) | 0.43746 (12) | 0.0690 (6) | |
N3 | 0.2556 (3) | 0.7725 (3) | 0.46913 (13) | 0.0621 (6) | |
H3A | 0.2718 | 0.8921 | 0.4989 | 0.074* | |
H3B | 0.1255 | 0.6936 | 0.4635 | 0.074* |
U11 | U22 | U33 | U12 | U13 | U23 | |
N1 | 0.0549 (12) | 0.0404 (11) | 0.0478 (11) | 0.0004 (9) | 0.0087 (9) | −0.0008 (9) |
N2 | 0.0495 (11) | 0.0393 (11) | 0.0485 (11) | 0.0018 (8) | 0.0029 (8) | 0.0075 (9) |
C3 | 0.0518 (13) | 0.0353 (12) | 0.0473 (13) | 0.0084 (10) | −0.0023 (10) | 0.0068 (10) |
C4 | 0.0585 (15) | 0.0391 (13) | 0.0525 (14) | 0.0116 (11) | 0.0030 (11) | 0.0080 (10) |
C5 | 0.0491 (13) | 0.0437 (13) | 0.0435 (12) | 0.0071 (10) | −0.0016 (10) | 0.0083 (10) |
C6 | 0.0448 (12) | 0.0357 (12) | 0.0425 (12) | 0.0045 (9) | 0.0005 (10) | 0.0021 (9) |
C7 | 0.0548 (15) | 0.0583 (16) | 0.0566 (15) | 0.0178 (12) | 0.0042 (12) | 0.0137 (12) |
C8 | 0.0603 (16) | 0.0687 (18) | 0.0562 (15) | 0.0091 (13) | 0.0155 (12) | 0.0107 (13) |
C9 | 0.0708 (17) | 0.0436 (14) | 0.0473 (14) | −0.0042 (12) | −0.0048 (12) | 0.0113 (11) |
C10 | 0.0689 (17) | 0.0545 (16) | 0.0661 (17) | 0.0183 (13) | −0.0040 (14) | 0.0212 (13) |
C11 | 0.0592 (15) | 0.0540 (15) | 0.0561 (15) | 0.0188 (12) | 0.0064 (11) | 0.0149 (12) |
C12 | 0.0618 (16) | 0.0434 (15) | 0.089 (2) | 0.0008 (12) | −0.0022 (14) | 0.0003 (14) |
C13 | 0.116 (3) | 0.074 (2) | 0.0612 (18) | −0.0066 (18) | 0.0034 (17) | 0.0275 (15) |
C14 | 0.0640 (15) | 0.0386 (13) | 0.0364 (12) | 0.0007 (11) | 0.0022 (11) | 0.0044 (10) |
O1 | 0.0800 (13) | 0.0520 (11) | 0.0651 (11) | −0.0075 (9) | 0.0075 (9) | 0.0008 (9) |
N3 | 0.0715 (15) | 0.0450 (12) | 0.0636 (14) | 0.0037 (10) | 0.0126 (11) | −0.0061 (10) |
N1—C14 | 1.363 (3) | C8—H8 | 0.9300 |
N1—N2 | 1.393 (3) | C9—C10 | 1.365 (3) |
N1—C5 | 1.460 (3) | C9—C13 | 1.508 (3) |
N2—C3 | 1.281 (3) | C10—C11 | 1.377 (3) |
C3—C12 | 1.476 (3) | C10—H10 | 0.9300 |
C3—C4 | 1.482 (3) | C11—H11 | 0.9300 |
C4—C5 | 1.536 (3) | C12—H12A | 0.9600 |
C4—H4A | 0.9700 | C12—H12B | 0.9600 |
C4—H4B | 0.9700 | C12—H12C | 0.9600 |
C5—C6 | 1.510 (3) | C13—H13A | 0.9600 |
C5—H5 | 0.9800 | C13—H13B | 0.9600 |
C6—C7 | 1.367 (3) | C13—H13C | 0.9600 |
C6—C11 | 1.376 (3) | C14—O1 | 1.252 (3) |
C7—C8 | 1.378 (3) | C14—N3 | 1.335 (3) |
C7—H7 | 0.9300 | N3—H3A | 0.8600 |
C8—C9 | 1.375 (3) | N3—H3B | 0.8600 |
C14—N1—N2 | 121.44 (19) | C10—C9—C8 | 117.5 (2) |
C14—N1—C5 | 123.52 (19) | C10—C9—C13 | 121.1 (2) |
N2—N1—C5 | 112.97 (17) | C8—C9—C13 | 121.4 (3) |
C3—N2—N1 | 106.45 (18) | C9—C10—C11 | 121.6 (2) |
N2—C3—C12 | 122.0 (2) | C9—C10—H10 | 119.2 |
N2—C3—C4 | 114.5 (2) | C11—C10—H10 | 119.2 |
C12—C3—C4 | 123.4 (2) | C6—C11—C10 | 120.6 (2) |
C3—C4—C5 | 102.04 (18) | C6—C11—H11 | 119.7 |
C3—C4—H4A | 111.4 | C10—C11—H11 | 119.7 |
C5—C4—H4A | 111.4 | C3—C12—H12A | 109.5 |
C3—C4—H4B | 111.4 | C3—C12—H12B | 109.5 |
C5—C4—H4B | 111.4 | H12A—C12—H12B | 109.5 |
H4A—C4—H4B | 109.2 | C3—C12—H12C | 109.5 |
N1—C5—C6 | 113.05 (18) | H12A—C12—H12C | 109.5 |
N1—C5—C4 | 99.65 (17) | H12B—C12—H12C | 109.5 |
C6—C5—C4 | 112.64 (18) | C9—C13—H13A | 109.5 |
N1—C5—H5 | 110.4 | C9—C13—H13B | 109.5 |
C6—C5—H5 | 110.4 | H13A—C13—H13B | 109.5 |
C4—C5—H5 | 110.4 | C9—C13—H13C | 109.5 |
C7—C6—C11 | 117.9 (2) | H13A—C13—H13C | 109.5 |
C7—C6—C5 | 120.0 (2) | H13B—C13—H13C | 109.5 |
C11—C6—C5 | 122.1 (2) | O1—C14—N3 | 122.9 (2) |
C6—C7—C8 | 121.1 (2) | O1—C14—N1 | 120.5 (2) |
C6—C7—H7 | 119.5 | N3—C14—N1 | 116.6 (2) |
C8—C7—H7 | 119.5 | C14—N3—H3A | 120.0 |
C9—C8—C7 | 121.2 (2) | C14—N3—H3B | 120.0 |
C9—C8—H8 | 119.4 | H3A—N3—H3B | 120.0 |
C7—C8—H8 | 119.4 | ||
C14—N1—N2—C3 | 177.32 (19) | C4—C5—C6—C11 | 92.4 (3) |
C5—N1—N2—C3 | 13.1 (2) | C11—C6—C7—C8 | −1.9 (3) |
N1—N2—C3—C12 | 179.3 (2) | C5—C6—C7—C8 | 176.3 (2) |
N1—N2—C3—C4 | 1.3 (2) | C6—C7—C8—C9 | 0.5 (4) |
N2—C3—C4—C5 | −13.7 (3) | C7—C8—C9—C10 | 0.9 (4) |
C12—C3—C4—C5 | 168.3 (2) | C7—C8—C9—C13 | −178.6 (2) |
C14—N1—C5—C6 | −64.5 (3) | C8—C9—C10—C11 | −0.8 (4) |
N2—N1—C5—C6 | 99.4 (2) | C13—C9—C10—C11 | 178.7 (2) |
C14—N1—C5—C4 | 175.76 (19) | C7—C6—C11—C10 | 1.9 (3) |
N2—N1—C5—C4 | −20.4 (2) | C5—C6—C11—C10 | −176.2 (2) |
C3—C4—C5—N1 | 18.7 (2) | C9—C10—C11—C6 | −0.6 (4) |
C3—C4—C5—C6 | −101.3 (2) | N2—N1—C14—O1 | −175.2 (2) |
N1—C5—C6—C7 | 162.26 (19) | C5—N1—C14—O1 | −12.7 (3) |
C4—C5—C6—C7 | −85.7 (2) | N2—N1—C14—N3 | 6.1 (3) |
N1—C5—C6—C11 | −19.7 (3) | C5—N1—C14—N3 | 168.55 (19) |
Experimental details
Crystal data | |
Chemical formula | C12H15N3O |
Mr | 217.27 |
Crystal system, space group | Triclinic, P1 |
Temperature (K) | 293 |
a, b, c (Å) | 6.080 (3), 6.815 (3), 14.314 (5) |
α, β, γ (°) | 96.86 (4), 91.28 (4), 101.40 (5) |
V (Å3) | 576.6 (4) |
Z | 2 |
Radiation type | Mo Kα |
µ (mm−1) | 0.08 |
Crystal size (mm) | 0.35 × 0.30 × 0.25 |
Data collection | |
Diffractometer | Syntex P21 diffractometer |
Absorption correction | – |
No. of measured, independent and observed [I > 2σ(I)] reflections | 2041, 2041, 1276 |
Rint | 0.000 |
(sin θ/λ)max (Å−1) | 0.596 |
Refinement | |
R[F2 > 2σ(F2)], wR(F2), S | 0.052, 0.146, 1.02 |
No. of reflections | 2041 |
No. of parameters | 147 |
H-atom treatment | H-atom parameters constrained |
Δρmax, Δρmin (e Å−3) | 0.20, −0.20 |
Computer programs: Syntex P21 diffractometer software, XP21 (Pavelčík, 1987), SHELXS97 (Sheldrick, 1990), SHELXL97 (Sheldrick, 1997), ORTEPII (Johnson, 1976).
N1—C14 | 1.363 (3) | C4—C5 | 1.536 (3) |
N1—N2 | 1.393 (3) | C5—C6 | 1.510 (3) |
N1—C5 | 1.460 (3) | C14—O1 | 1.252 (3) |
N2—C3 | 1.281 (3) | C14—N3 | 1.335 (3) |
C3—C4 | 1.482 (3) | ||
C14—N1—N2 | 121.44 (19) | N1—C5—C6 | 113.05 (18) |
C14—N1—C5 | 123.52 (19) | N1—C5—C4 | 99.65 (17) |
N2—N1—C5 | 112.97 (17) | C6—C5—C4 | 112.64 (18) |
C3—N2—N1 | 106.45 (18) | O1—C14—N3 | 122.9 (2) |
N2—C3—C4 | 114.5 (2) | O1—C14—N1 | 120.5 (2) |
C3—C4—C5 | 102.04 (18) | N3—C14—N1 | 116.6 (2) |
C14—N1—N2—C3 | 177.32 (19) | C3—C4—C5—N1 | 18.7 (2) |
C5—N1—N2—C3 | 13.1 (2) | N1—C5—C6—C11 | −19.7 (3) |
N1—N2—C3—C4 | 1.3 (2) | N2—N1—C14—O1 | −175.2 (2) |
N2—C3—C4—C5 | −13.7 (3) | N2—N1—C14—N3 | 6.1 (3) |
In the search for new inhibitors of nitric oxide (NO) synthase, we have found that cyclocondensation of 4-(2-hydroxyphenyl)but-3-en-2-one with aminoguanidine affords 4,5-dihydro-5-(2-hydroxyphenyl)-3-methyl-1H-pyrazole-1-carboximidamide (Ia) as the sole product. In contrast, analogous heterocyclization of both 4-phenyl and 4-(4-methylphenyl)but-3-en-2-one gave rise to two products, of which the corresponding amidines (Ib) and (Ic) were easily identified. In the latter two cases, the compounds isolated were established to be 5-aryl-4,5-dihydro-3-methyl-1H-pyrazole-1-carboxamides (IIb) and (IIc), which probably arose from the target amidines (Ib) and (Ic) by hydrolysis (Světlík & Sallai, 2002). However, since the NMR spectra of the resultant heterocycles are almost identical, it was desirable to determine the structure of the carboxamides. A further purpose of this structure determination was to establish the spatial distribution of the pharmacophoric groups for subsequent use in an analysis of structure–activity relationships. In this communication, we report the structure of (IIc).
The molecular structure and the atom-numbering scheme are shown in Fig. 1. As can be seen, the compound is indeed the hydrolytic product of the amidine (Ic), i.e. (IIc) consists of a substituted pyrazoline ring and a carboxamide function attached to atom N1.
As mentioned above, the main purpose of this structure determination was to establish the relative three-dimensional disposition of the putative pharmacophoric elements [phenyl ring(s) and hydrogen-bond donor and acceptor] that are responsible for binding a compound to the NO synthase (Griffith & Gross, 1996). Obviously, the disposition of these structural elements depends primarily on the conformation of the central heterocycle. The pyrazoline ring adopts a flat-envelope conformation, with atom C5 on the flap; the deviation of the out-of-plane atom from the mean plane of the remaining four atoms [r.m.s. deviation 0.005 (2) Å] is 0.329 (3) Å. The 4-methylphenyl group occupies a pseudoaxial position and, as a result, is approximately perpendicular to the mean plane of the pyrazoline ring [dihedral angle 78.8 (2)°]. The phenyl ring is rotated about the exocyclic C5—C6 bond in such a manner that the N1—C5—C6—C11 torsion angle is −19.7 (3)°.
Selected bond lengths and angles in the molecule are listed in Table 1. As expected, atom N1 is sp2 hybridized, as evidenced by the sum of the valence angles around this atom [357.9 (1)°], with the lone-pair electrons available for π bonding. It has been reported (Krishna et al., 1999) that the N—N bond length in the pyrazoline ring varies over a wide range, from 1.385 (4) to 1.234 (8) Å, where the length depends on the substituents bonded to the N atoms; accordingly, the length of the adjacent C═N bond ranges from 1.288 (4) to 1.461 (8) Å. This variation is caused by a varying degree of conjugation in the π-electron portion of the pyrazoline ring, which is sensitive to the nature of substituent(s) bonded to the atoms of the π system. The N1—N2 bond length of 1.393 (3) Å found in the present derivative further extends this range, approximating the length of a pure single bond (1.41 Å; Burke-Laing & Laing, 1976). Similarly, the corresponding N2═C3 bond [1.281 (3) Å] has the character of a pure double bond (1.27 Å). That the lone-pair electrons on atom N1 are delocalized through conjugation with the carboxamide group rather than the N2═C3 double bond is also seen in the N1—C14 bond length [1.363 (3) Å], which is intermediate between the single- and double-bond values. However, π-electron delocalization from the exocyclic amide N atom into the C14—O1 carbonyl bond is even more pronounced, as reflected in the C14—N3 bond length [1.335 (3) Å], which is ca 0.03 Å shorter than the N1—C14 bond and is comparable to the value typically found in amides (Benedetti et al., 1983). Owing to the transfer of the π density from 'both' sides of the carbonyl group, atom O1 has partial anionic character, as shown by a lengthening of the C═O bond [1.252 (3) Å] relative to that normally found for amides; as a result, atom O1 should have an increased capacity to function as a hydrogen-bond acceptor. Other bond distances and angles in the remaining parts of the molecule are close to the values generally expected.
The enhanced ability of carbonyl atom O1 as a hydrogen-bond acceptor is reflected in the crystal packing, which is dominated by a pair of hydrogen bonds that join neighboring molecules related by a center of symmetry [N3—H3···O1(1 − x, 2 − y, 1 − z); N···O = 2.898 (3), H···O = 2.05 Å and N—H···O = 169 °]. This self-complementary interaction aggregates molecules into pairs, which are loosely packed in the extended structure by van der Waals interactions with surrounding pairs.