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The reaction between 4-(4-methyl­phenyl)­but-3-en-2-one and amino­guanidine produced an unexpected product of formula C12H15N3O, consisting of a carbox­amide moiety joined to a substituted pyrazoline ring at one of the N atoms. The pyrazoline ring adopts a flat-envelope conformation and the substituted phenyl ring is oriented almost perpendicular to the heterocycle. The carbonyl O atom has partial anionic character as a result of the transfer of π density from the two adjacent sp2 N atoms and is involved in an intermolecular hydrogen bond with the amide group.

Supporting information

cif

Crystallographic Information File (CIF) https://doi.org/10.1107/S0108270103012241/fa1020sup1.cif
Contains datablocks global, IIc

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S0108270103012241/fa1020IIcsup2.hkl
Contains datablock IIc

CCDC reference: 219562

Comment top

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 CN 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 N2C3 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 N2C3 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 CO 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.

Experimental top

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).

Refinement top

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.

Computing details top

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).

Figures top
[Figure 1] Fig. 1. Displacement ellipsoid plot of (IIc), with the labelling scheme for the non-H atoms, which are drawn as 35% probability ellipsoids.
4,5-Dihydro-3-methyl-5-(4-methylphenyl)-1H-pyrazole-1-carboxamide top
Crystal data top
C12H15N3OF(000) = 232
Mr = 217.27Dx = 1.251 Mg m3
Dm = 1.25 (1) Mg m3
Dm measured by flotation in bromoform/c-hexane
Triclinic, P1Melting point: 472 K
a = 6.080 (3) ÅMo Kα radiation, λ = 0.71073 Å
b = 6.815 (3) ÅCell parameters from 15 reflections
c = 14.314 (5) Åθ = 7–18°
α = 96.86 (4)°µ = 0.08 mm1
β = 91.28 (4)°T = 293 K
γ = 101.40 (5)°Prism, colourless
V = 576.6 (4) Å30.35 × 0.30 × 0.25 mm
Z = 2
Data collection top
Syntex P21
diffractometer
Rint = 0.000
Radiation source: fine-focus sealed tubeθmax = 25.1°, θmin = 2.9°
Graphite monochromatorh = 57
θ/2θ scansk = 58
2041 measured reflectionsl = 1716
2041 independent reflections2 standard reflections every 98 reflections
1276 reflections with I > 2σ(I) intensity decay: 2%
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.052Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.146H-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 parametersΔρmax = 0.20 e Å3
0 restraintsΔρmin = 0.20 e Å3
Crystal data top
C12H15N3Oγ = 101.40 (5)°
Mr = 217.27V = 576.6 (4) Å3
Triclinic, P1Z = 2
a = 6.080 (3) ÅMo Kα radiation
b = 6.815 (3) ŵ = 0.08 mm1
c = 14.314 (5) ÅT = 293 K
α = 96.86 (4)°0.35 × 0.30 × 0.25 mm
β = 91.28 (4)°
Data collection top
Syntex P21
diffractometer
Rint = 0.000
2041 measured reflections2 standard reflections every 98 reflections
2041 independent reflections intensity decay: 2%
1276 reflections with I > 2σ(I)
Refinement top
R[F2 > 2σ(F2)] = 0.0520 restraints
wR(F2) = 0.146H-atom parameters constrained
S = 1.02Δρmax = 0.20 e Å3
2041 reflectionsΔρmin = 0.20 e Å3
147 parameters
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
N10.3944 (3)0.5165 (3)0.38719 (12)0.0494 (5)
N20.1784 (3)0.3988 (3)0.37378 (13)0.0466 (5)
C30.1975 (4)0.2311 (3)0.32709 (15)0.0448 (6)
C40.4311 (4)0.2155 (3)0.30552 (17)0.0496 (6)
H4A0.44190.16490.23990.060*
H4B0.48810.12870.34500.060*
C50.5568 (4)0.4357 (3)0.32825 (15)0.0456 (5)
H50.69690.44290.36490.055*
C60.6038 (3)0.5390 (3)0.24107 (14)0.0417 (5)
C70.7917 (4)0.5213 (4)0.19265 (16)0.0551 (7)
H70.89400.45210.21590.066*
C80.8317 (4)0.6045 (4)0.11003 (17)0.0619 (7)
H80.96010.58950.07810.074*
C90.6852 (4)0.7093 (4)0.07387 (17)0.0557 (7)
C100.5003 (4)0.7300 (4)0.12350 (18)0.0613 (7)
H100.39960.80170.10090.074*
C110.4593 (4)0.6475 (4)0.20621 (17)0.0547 (6)
H110.33260.66520.23880.066*
C120.0017 (4)0.0659 (4)0.3003 (2)0.0669 (8)
H12A0.12900.10060.32910.100*
H12B0.02930.05580.32150.100*
H12C0.02270.04570.23310.100*
C130.7255 (6)0.7966 (5)0.01765 (19)0.0856 (9)
H13A0.60150.73940.06170.128*
H13B0.86130.76550.04290.128*
H13C0.73930.94030.00660.128*
C140.4323 (4)0.7092 (3)0.43160 (15)0.0477 (6)
O10.6256 (3)0.8170 (3)0.43746 (12)0.0690 (6)
N30.2556 (3)0.7725 (3)0.46913 (13)0.0621 (6)
H3A0.27180.89210.49890.074*
H3B0.12550.69360.46350.074*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
N10.0549 (12)0.0404 (11)0.0478 (11)0.0004 (9)0.0087 (9)0.0008 (9)
N20.0495 (11)0.0393 (11)0.0485 (11)0.0018 (8)0.0029 (8)0.0075 (9)
C30.0518 (13)0.0353 (12)0.0473 (13)0.0084 (10)0.0023 (10)0.0068 (10)
C40.0585 (15)0.0391 (13)0.0525 (14)0.0116 (11)0.0030 (11)0.0080 (10)
C50.0491 (13)0.0437 (13)0.0435 (12)0.0071 (10)0.0016 (10)0.0083 (10)
C60.0448 (12)0.0357 (12)0.0425 (12)0.0045 (9)0.0005 (10)0.0021 (9)
C70.0548 (15)0.0583 (16)0.0566 (15)0.0178 (12)0.0042 (12)0.0137 (12)
C80.0603 (16)0.0687 (18)0.0562 (15)0.0091 (13)0.0155 (12)0.0107 (13)
C90.0708 (17)0.0436 (14)0.0473 (14)0.0042 (12)0.0048 (12)0.0113 (11)
C100.0689 (17)0.0545 (16)0.0661 (17)0.0183 (13)0.0040 (14)0.0212 (13)
C110.0592 (15)0.0540 (15)0.0561 (15)0.0188 (12)0.0064 (11)0.0149 (12)
C120.0618 (16)0.0434 (15)0.089 (2)0.0008 (12)0.0022 (14)0.0003 (14)
C130.116 (3)0.074 (2)0.0612 (18)0.0066 (18)0.0034 (17)0.0275 (15)
C140.0640 (15)0.0386 (13)0.0364 (12)0.0007 (11)0.0022 (11)0.0044 (10)
O10.0800 (13)0.0520 (11)0.0651 (11)0.0075 (9)0.0075 (9)0.0008 (9)
N30.0715 (15)0.0450 (12)0.0636 (14)0.0037 (10)0.0126 (11)0.0061 (10)
Geometric parameters (Å, º) top
N1—C141.363 (3)C8—H80.9300
N1—N21.393 (3)C9—C101.365 (3)
N1—C51.460 (3)C9—C131.508 (3)
N2—C31.281 (3)C10—C111.377 (3)
C3—C121.476 (3)C10—H100.9300
C3—C41.482 (3)C11—H110.9300
C4—C51.536 (3)C12—H12A0.9600
C4—H4A0.9700C12—H12B0.9600
C4—H4B0.9700C12—H12C0.9600
C5—C61.510 (3)C13—H13A0.9600
C5—H50.9800C13—H13B0.9600
C6—C71.367 (3)C13—H13C0.9600
C6—C111.376 (3)C14—O11.252 (3)
C7—C81.378 (3)C14—N31.335 (3)
C7—H70.9300N3—H3A0.8600
C8—C91.375 (3)N3—H3B0.8600
C14—N1—N2121.44 (19)C10—C9—C8117.5 (2)
C14—N1—C5123.52 (19)C10—C9—C13121.1 (2)
N2—N1—C5112.97 (17)C8—C9—C13121.4 (3)
C3—N2—N1106.45 (18)C9—C10—C11121.6 (2)
N2—C3—C12122.0 (2)C9—C10—H10119.2
N2—C3—C4114.5 (2)C11—C10—H10119.2
C12—C3—C4123.4 (2)C6—C11—C10120.6 (2)
C3—C4—C5102.04 (18)C6—C11—H11119.7
C3—C4—H4A111.4C10—C11—H11119.7
C5—C4—H4A111.4C3—C12—H12A109.5
C3—C4—H4B111.4C3—C12—H12B109.5
C5—C4—H4B111.4H12A—C12—H12B109.5
H4A—C4—H4B109.2C3—C12—H12C109.5
N1—C5—C6113.05 (18)H12A—C12—H12C109.5
N1—C5—C499.65 (17)H12B—C12—H12C109.5
C6—C5—C4112.64 (18)C9—C13—H13A109.5
N1—C5—H5110.4C9—C13—H13B109.5
C6—C5—H5110.4H13A—C13—H13B109.5
C4—C5—H5110.4C9—C13—H13C109.5
C7—C6—C11117.9 (2)H13A—C13—H13C109.5
C7—C6—C5120.0 (2)H13B—C13—H13C109.5
C11—C6—C5122.1 (2)O1—C14—N3122.9 (2)
C6—C7—C8121.1 (2)O1—C14—N1120.5 (2)
C6—C7—H7119.5N3—C14—N1116.6 (2)
C8—C7—H7119.5C14—N3—H3A120.0
C9—C8—C7121.2 (2)C14—N3—H3B120.0
C9—C8—H8119.4H3A—N3—H3B120.0
C7—C8—H8119.4
C14—N1—N2—C3177.32 (19)C4—C5—C6—C1192.4 (3)
C5—N1—N2—C313.1 (2)C11—C6—C7—C81.9 (3)
N1—N2—C3—C12179.3 (2)C5—C6—C7—C8176.3 (2)
N1—N2—C3—C41.3 (2)C6—C7—C8—C90.5 (4)
N2—C3—C4—C513.7 (3)C7—C8—C9—C100.9 (4)
C12—C3—C4—C5168.3 (2)C7—C8—C9—C13178.6 (2)
C14—N1—C5—C664.5 (3)C8—C9—C10—C110.8 (4)
N2—N1—C5—C699.4 (2)C13—C9—C10—C11178.7 (2)
C14—N1—C5—C4175.76 (19)C7—C6—C11—C101.9 (3)
N2—N1—C5—C420.4 (2)C5—C6—C11—C10176.2 (2)
C3—C4—C5—N118.7 (2)C9—C10—C11—C60.6 (4)
C3—C4—C5—C6101.3 (2)N2—N1—C14—O1175.2 (2)
N1—C5—C6—C7162.26 (19)C5—N1—C14—O112.7 (3)
C4—C5—C6—C785.7 (2)N2—N1—C14—N36.1 (3)
N1—C5—C6—C1119.7 (3)C5—N1—C14—N3168.55 (19)

Experimental details

Crystal data
Chemical formulaC12H15N3O
Mr217.27
Crystal system, space groupTriclinic, 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)
V3)576.6 (4)
Z2
Radiation typeMo Kα
µ (mm1)0.08
Crystal size (mm)0.35 × 0.30 × 0.25
Data collection
DiffractometerSyntex P21
diffractometer
Absorption correction
No. of measured, independent and
observed [I > 2σ(I)] reflections
2041, 2041, 1276
Rint0.000
(sin θ/λ)max1)0.596
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.052, 0.146, 1.02
No. of reflections2041
No. of parameters147
H-atom treatmentH-atom parameters constrained
Δρmax, Δρmin (e Å3)0.20, 0.20

Computer programs: Syntex P21 diffractometer software, XP21 (Pavelčík, 1987), SHELXS97 (Sheldrick, 1990), SHELXL97 (Sheldrick, 1997), ORTEPII (Johnson, 1976).

Selected geometric parameters (Å, º) top
N1—C141.363 (3)C4—C51.536 (3)
N1—N21.393 (3)C5—C61.510 (3)
N1—C51.460 (3)C14—O11.252 (3)
N2—C31.281 (3)C14—N31.335 (3)
C3—C41.482 (3)
C14—N1—N2121.44 (19)N1—C5—C6113.05 (18)
C14—N1—C5123.52 (19)N1—C5—C499.65 (17)
N2—N1—C5112.97 (17)C6—C5—C4112.64 (18)
C3—N2—N1106.45 (18)O1—C14—N3122.9 (2)
N2—C3—C4114.5 (2)O1—C14—N1120.5 (2)
C3—C4—C5102.04 (18)N3—C14—N1116.6 (2)
C14—N1—N2—C3177.32 (19)C3—C4—C5—N118.7 (2)
C5—N1—N2—C313.1 (2)N1—C5—C6—C1119.7 (3)
N1—N2—C3—C41.3 (2)N2—N1—C14—O1175.2 (2)
N2—C3—C4—C513.7 (3)N2—N1—C14—N36.1 (3)
 

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