The potentially tridentate O,N,S-donor ligand, 2-hydroxy-1-naphthaldehyde 2-methylthiosemicarbazone, C13H13N3OS, has been structurally characterized and the molecule is found to exhibit a distorted planar structure with the thiosemicarbazide moiety being twisted slightly out of the plane defined by the naphthyl ring.
Supporting information
CCDC reference: 143249
The title compound was synthesized by refluxing equimolar amounts of the
2-hydroxy-1-naphthaldehyde and 2-methyl-3-thiosemicarbazide in ethanol. The
compound was collected by filtration and crystals suitable for X-ray work were
obtained by slow evaporation of an ethanolic solution of the compound.
Refinement was on F2 for all reflections. H atoms were constrained using a
riding model.
Data collection: CAD4 (Enraf-Nonius, 1988); cell refinement: SET4 in CAD4; data reduction: Xtal (Hall, 1992); program(s) used to solve structure: SHELXS86 (Sheldrick, 1990); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: PLATON (Spek, 1990); software used to prepare material for publication: SHELXL97.
Crystal data top
C13H13N3OS | F(000) = 272 |
Mr = 259.32 | Dx = 1.388 Mg m−3 |
Monoclinic, P21 | Mo Kα radiation, λ = 0.71073 Å |
a = 8.056 (1) Å | Cell parameters from 25 reflections |
b = 6.7586 (6) Å | θ = 10–14° |
c = 11.694 (3) Å | µ = 0.25 mm−1 |
β = 102.93 (1)° | T = 295 K |
V = 620.56 (19) Å3 | Needle, yellow |
Z = 2 | 0.50 × 0.50 × 0.13 mm |
Data collection top
Enraf-Nonius CAD4 diffractometer | 1067 reflections with I > 2σ(I) |
Radiation source: fine-focus sealed tube | Rint = 0.048 |
Graphite monochromator | θmax = 25.0°, θmin = 1.8° |
ω–2θ scans | h = 0→9 |
Absorption correction: ψ scan (North et al., 1968) | k = 0→8 |
Tmin = 0.732, Tmax = 0.968 | l = −13→13 |
1278 measured reflections | 3 standard reflections every 120 min |
1191 independent reflections | intensity decay: < 5% |
Refinement top
Refinement on F2 | Secondary atom site location: difference Fourier map |
Least-squares matrix: full | Hydrogen site location: inferred from neighbouring sites |
R[F2 > 2σ(F2)] = 0.041 | H-atom parameters constrained |
wR(F2) = 0.121 | Calculated w = 1/[σ2(Fo2) + (0.0918P)2 + 0.0783P] where P = (Fo2 + 2Fc2)/3 |
S = 1.04 | (Δ/σ)max < 0.001 |
1191 reflections | Δρmax = 0.29 e Å−3 |
164 parameters | Δρmin = −0.24 e Å−3 |
1 restraint | Absolute structure: Flack (1983) |
Primary atom site location: structure-invariant direct methods | Absolute structure parameter: −0.03 (16) |
Crystal data top
C13H13N3OS | V = 620.56 (19) Å3 |
Mr = 259.32 | Z = 2 |
Monoclinic, P21 | Mo Kα radiation |
a = 8.056 (1) Å | µ = 0.25 mm−1 |
b = 6.7586 (6) Å | T = 295 K |
c = 11.694 (3) Å | 0.50 × 0.50 × 0.13 mm |
β = 102.93 (1)° | |
Data collection top
Enraf-Nonius CAD4 diffractometer | 1067 reflections with I > 2σ(I) |
Absorption correction: ψ scan (North et al., 1968) | Rint = 0.048 |
Tmin = 0.732, Tmax = 0.968 | 3 standard reflections every 120 min |
1278 measured reflections | intensity decay: < 5% |
1191 independent reflections | |
Refinement top
R[F2 > 2σ(F2)] = 0.041 | H-atom parameters constrained |
wR(F2) = 0.121 | Δρmax = 0.29 e Å−3 |
S = 1.04 | Δρmin = −0.24 e Å−3 |
1191 reflections | Absolute structure: Flack (1983) |
164 parameters | Absolute structure parameter: −0.03 (16) |
1 restraint | |
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. |
Refinement. Refinement of F2 against ALL reflections. The weighted R-factor
wR and goodness of fit S are based on F2, conventional
R-factors R are based on F, with F set to zero for
negative F2. The threshold expression of F2 >
σ(F2) is used only for calculating R-factors(gt) etc.
and is not relevant to the choice of reflections for refinement.
R-factors based on F2 are statistically about twice as large
as those based on F, and R- factors based on ALL data will be
even larger. |
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top | x | y | z | Uiso*/Ueq | |
C1 | −0.7419 (4) | −0.6739 (7) | −0.1715 (3) | 0.0358 (7) | |
C2 | −0.6693 (4) | −0.8398 (6) | −0.2108 (3) | 0.0397 (8) | |
C3 | −0.6255 (5) | −1.0077 (6) | −0.1409 (4) | 0.0468 (9) | |
H3 | −0.5803 | −1.1178 | −0.1708 | 0.056* | |
C4 | −0.6487 (5) | −1.0105 (7) | −0.0301 (4) | 0.0501 (10) | |
H4 | −0.6198 | −1.1234 | 0.0154 | 0.060* | |
C5 | −0.7164 (4) | −0.8442 (7) | 0.0182 (3) | 0.0439 (9) | |
C6 | −0.7310 (5) | −0.8447 (10) | 0.1368 (3) | 0.0598 (13) | |
H6 | −0.6987 | −0.9561 | 0.1831 | 0.072* | |
C7 | −0.7915 (5) | −0.6844 (12) | 0.1826 (3) | 0.0694 (15) | |
H7 | −0.7967 | −0.6843 | 0.2612 | 0.083* | |
C8 | −0.8469 (5) | −0.5174 (9) | 0.1130 (4) | 0.0638 (14) | |
H8 | −0.8920 | −0.4096 | 0.1452 | 0.077* | |
C9 | −0.8347 (5) | −0.5124 (8) | −0.0024 (3) | 0.0493 (10) | |
H9 | −0.8710 | −0.4008 | −0.0476 | 0.059* | |
C10 | −0.7671 (4) | −0.6761 (7) | −0.0530 (3) | 0.0382 (8) | |
C11 | −0.7930 (4) | −0.5054 (6) | −0.2464 (3) | 0.0374 (8) | |
H11 | −0.8649 | −0.4107 | −0.2259 | 0.045* | |
C12 | −0.9362 (5) | −0.2061 (7) | −0.4052 (3) | 0.0490 (10) | |
H12A | −0.9698 | −0.2395 | −0.3338 | 0.073* | |
H12B | −1.0308 | −0.2253 | −0.4706 | 0.073* | |
H12C | −0.9009 | −0.0703 | −0.4023 | 0.073* | |
C13 | −0.7210 (4) | −0.3187 (6) | −0.5125 (3) | 0.0406 (8) | |
N1 | −0.7393 (3) | −0.4850 (5) | −0.3420 (2) | 0.0363 (7) | |
N2 | −0.7951 (4) | −0.3331 (5) | −0.4187 (2) | 0.0388 (7) | |
N3 | −0.5897 (4) | −0.4384 (6) | −0.5126 (3) | 0.0572 (10) | |
H3A | −0.5557 | −0.5193 | −0.4554 | 0.069* | |
H3B | −0.5389 | −0.4347 | −0.5699 | 0.069* | |
O1 | −0.6391 (4) | −0.8520 (4) | −0.3196 (2) | 0.0506 (7) | |
H1 | −0.6686 | −0.7487 | −0.3553 | 0.061* | |
S1 | −0.79038 (12) | −0.16331 (19) | −0.62414 (7) | 0.0524 (3) | |
Atomic displacement parameters (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
C1 | 0.0352 (15) | 0.0387 (18) | 0.0357 (16) | −0.0064 (18) | 0.0128 (12) | 0.0023 (18) |
C2 | 0.0390 (17) | 0.042 (2) | 0.0419 (18) | −0.0033 (18) | 0.0169 (14) | 0.0050 (19) |
C3 | 0.0443 (19) | 0.039 (2) | 0.059 (2) | 0.0019 (17) | 0.0149 (16) | 0.0050 (19) |
C4 | 0.044 (2) | 0.045 (2) | 0.060 (2) | −0.0005 (19) | 0.0106 (17) | 0.023 (2) |
C5 | 0.0362 (17) | 0.056 (2) | 0.0404 (18) | −0.0081 (19) | 0.0102 (14) | 0.015 (2) |
C6 | 0.051 (2) | 0.088 (4) | 0.043 (2) | −0.012 (3) | 0.0141 (17) | 0.025 (3) |
C7 | 0.059 (2) | 0.120 (5) | 0.0352 (19) | −0.019 (3) | 0.0217 (17) | 0.006 (3) |
C8 | 0.059 (3) | 0.093 (4) | 0.047 (2) | −0.004 (3) | 0.028 (2) | −0.013 (3) |
C9 | 0.048 (2) | 0.063 (3) | 0.0388 (19) | 0.002 (2) | 0.0150 (16) | 0.001 (2) |
C10 | 0.0314 (15) | 0.049 (2) | 0.0367 (16) | −0.0090 (18) | 0.0125 (12) | 0.003 (2) |
C11 | 0.0418 (18) | 0.0346 (18) | 0.0390 (18) | −0.0008 (17) | 0.0157 (14) | 0.0001 (16) |
C12 | 0.050 (2) | 0.048 (3) | 0.055 (2) | 0.0113 (18) | 0.0252 (16) | 0.0098 (18) |
C13 | 0.0415 (18) | 0.041 (2) | 0.0422 (18) | −0.0044 (17) | 0.0144 (14) | 0.0059 (17) |
N1 | 0.0408 (15) | 0.0374 (17) | 0.0340 (15) | 0.0010 (14) | 0.0152 (12) | 0.0087 (14) |
N2 | 0.0420 (14) | 0.0402 (17) | 0.0394 (14) | 0.0051 (14) | 0.0202 (12) | 0.0101 (14) |
N3 | 0.063 (2) | 0.063 (2) | 0.058 (2) | 0.0192 (19) | 0.0405 (16) | 0.0237 (19) |
O1 | 0.0673 (17) | 0.0449 (17) | 0.0489 (14) | 0.0061 (15) | 0.0324 (14) | 0.0019 (14) |
S1 | 0.0628 (6) | 0.0576 (6) | 0.0407 (5) | 0.0088 (6) | 0.0194 (4) | 0.0179 (5) |
Geometric parameters (Å, º) top
C1—C2 | 1.389 (6) | C7—C8 | 1.404 (9) |
C1—C11 | 1.440 (5) | C8—C9 | 1.375 (6) |
C1—C10 | 1.445 (4) | C9—C10 | 1.420 (6) |
C2—O1 | 1.351 (4) | C11—N1 | 1.293 (5) |
C2—C3 | 1.397 (5) | C12—N2 | 1.461 (5) |
C3—C4 | 1.350 (6) | C13—N3 | 1.332 (5) |
C4—C5 | 1.421 (6) | C13—N2 | 1.365 (5) |
C5—C10 | 1.413 (6) | C13—S1 | 1.671 (4) |
C5—C6 | 1.417 (5) | N1—N2 | 1.371 (4) |
C6—C7 | 1.348 (9) | | |
| | | |
C2—C1—C11 | 121.4 (3) | C9—C8—C7 | 120.3 (5) |
C2—C1—C10 | 118.0 (4) | C8—C9—C10 | 120.5 (5) |
C11—C1—C10 | 120.6 (4) | C5—C10—C9 | 117.9 (3) |
O1—C2—C1 | 122.7 (3) | C5—C10—C1 | 119.3 (4) |
O1—C2—C3 | 115.2 (4) | C9—C10—C1 | 122.8 (4) |
C1—C2—C3 | 122.1 (3) | N1—C11—C1 | 120.3 (3) |
C4—C3—C2 | 120.1 (4) | N3—C13—N2 | 116.6 (3) |
C3—C4—C5 | 121.3 (4) | N3—C13—S1 | 120.5 (3) |
C10—C5—C6 | 120.1 (4) | N2—C13—S1 | 122.9 (3) |
C10—C5—C4 | 119.2 (3) | C11—N1—N2 | 121.4 (3) |
C6—C5—C4 | 120.7 (4) | C13—N2—N1 | 116.2 (3) |
C7—C6—C5 | 120.2 (5) | C13—N2—C12 | 122.4 (3) |
C6—C7—C8 | 120.8 (4) | N1—N2—C12 | 121.2 (3) |
| | | |
C11—C1—C2—O1 | 1.4 (5) | C4—C5—C10—C1 | −2.7 (5) |
C10—C1—C2—O1 | −179.4 (3) | C8—C9—C10—C5 | 1.2 (6) |
C11—C1—C2—C3 | −177.3 (3) | C8—C9—C10—C1 | −176.1 (3) |
C10—C1—C2—C3 | 1.8 (5) | C2—C1—C10—C5 | 0.5 (5) |
O1—C2—C3—C4 | 179.3 (3) | C11—C1—C10—C5 | 179.7 (3) |
C1—C2—C3—C4 | −1.9 (5) | C2—C1—C10—C9 | 177.8 (3) |
C2—C3—C4—C5 | −0.4 (6) | C11—C1—C10—C9 | −3.0 (5) |
C3—C4—C5—C10 | 2.7 (5) | C2—C1—C11—N1 | −15.4 (5) |
C3—C4—C5—C6 | −176.3 (4) | C10—C1—C11—N1 | 165.5 (3) |
C10—C5—C6—C7 | −0.7 (6) | C1—C11—N1—N2 | 175.6 (3) |
C4—C5—C6—C7 | 178.4 (4) | N3—C13—N2—N1 | −7.5 (5) |
C5—C6—C7—C8 | 2.4 (7) | S1—C13—N2—N1 | 171.5 (3) |
C6—C7—C8—C9 | −2.2 (7) | N3—C13—N2—C12 | 177.8 (4) |
C7—C8—C9—C10 | 0.4 (6) | S1—C13—N2—C12 | −3.2 (5) |
C6—C5—C10—C9 | −1.1 (5) | C11—N1—N2—C13 | 175.7 (3) |
C4—C5—C10—C9 | 179.9 (3) | C11—N1—N2—C12 | −9.5 (5) |
C6—C5—C10—C1 | 176.4 (3) | | |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
N3—H3A···S1i | 0.86 | 2.90 | 3.472 (3) | 125 |
N3—H3B···O1ii | 0.86 | 2.21 | 3.033 (4) | 162 |
O1—H1···N1 | 0.82 | 1.89 | 2.603 (4) | 145 |
Symmetry codes: (i) −x−1, y−1/2, −z−1; (ii) −x−1, y+1/2, −z−1. |
Experimental details
Crystal data |
Chemical formula | C13H13N3OS |
Mr | 259.32 |
Crystal system, space group | Monoclinic, P21 |
Temperature (K) | 295 |
a, b, c (Å) | 8.056 (1), 6.7586 (6), 11.694 (3) |
β (°) | 102.93 (1) |
V (Å3) | 620.56 (19) |
Z | 2 |
Radiation type | Mo Kα |
µ (mm−1) | 0.25 |
Crystal size (mm) | 0.50 × 0.50 × 0.13 |
|
Data collection |
Diffractometer | Enraf-Nonius CAD4 diffractometer |
Absorption correction | ψ scan (North et al., 1968) |
Tmin, Tmax | 0.732, 0.968 |
No. of measured, independent and observed [I > 2σ(I)] reflections | 1278, 1191, 1067 |
Rint | 0.048 |
(sin θ/λ)max (Å−1) | 0.594 |
|
Refinement |
R[F2 > 2σ(F2)], wR(F2), S | 0.041, 0.121, 1.04 |
No. of reflections | 1191 |
No. of parameters | 164 |
No. of restraints | 1 |
H-atom treatment | H-atom parameters constrained |
Δρmax, Δρmin (e Å−3) | 0.29, −0.24 |
Absolute structure | Flack (1983) |
Absolute structure parameter | −0.03 (16) |
Selected geometric parameters (Å, º) topC1—C2 | 1.389 (6) | C7—C8 | 1.404 (9) |
C1—C11 | 1.440 (5) | C8—C9 | 1.375 (6) |
C1—C10 | 1.445 (4) | C9—C10 | 1.420 (6) |
C2—O1 | 1.351 (4) | C11—N1 | 1.293 (5) |
C2—C3 | 1.397 (5) | C12—N2 | 1.461 (5) |
C3—C4 | 1.350 (6) | C13—N3 | 1.332 (5) |
C4—C5 | 1.421 (6) | C13—N2 | 1.365 (5) |
C5—C10 | 1.413 (6) | C13—S1 | 1.671 (4) |
C5—C6 | 1.417 (5) | N1—N2 | 1.371 (4) |
C6—C7 | 1.348 (9) | | |
| | | |
C2—C1—C11 | 121.4 (3) | C9—C8—C7 | 120.3 (5) |
C2—C1—C10 | 118.0 (4) | C8—C9—C10 | 120.5 (5) |
C11—C1—C10 | 120.6 (4) | C5—C10—C9 | 117.9 (3) |
O1—C2—C1 | 122.7 (3) | C5—C10—C1 | 119.3 (4) |
O1—C2—C3 | 115.2 (4) | C9—C10—C1 | 122.8 (4) |
C1—C2—C3 | 122.1 (3) | N1—C11—C1 | 120.3 (3) |
C4—C3—C2 | 120.1 (4) | N3—C13—N2 | 116.6 (3) |
C3—C4—C5 | 121.3 (4) | N3—C13—S1 | 120.5 (3) |
C10—C5—C6 | 120.1 (4) | N2—C13—S1 | 122.9 (3) |
C10—C5—C4 | 119.2 (3) | C11—N1—N2 | 121.4 (3) |
C6—C5—C4 | 120.7 (4) | C13—N2—N1 | 116.2 (3) |
C7—C6—C5 | 120.2 (5) | C13—N2—C12 | 122.4 (3) |
C6—C7—C8 | 120.8 (4) | N1—N2—C12 | 121.2 (3) |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
N3—H3A···S1i | 0.86 | 2.90 | 3.472 (3) | 125.3 |
N3—H3B···O1ii | 0.86 | 2.21 | 3.033 (4) | 161.5 |
O1—H1···N1 | 0.82 | 1.89 | 2.603 (4) | 145.1 |
Symmetry codes: (i) −x−1, y−1/2, −z−1; (ii) −x−1, y+1/2, −z−1. |
Ligands of the aroylhydrazone class have shown much promise as potential chelators for treatment of iron overload disease and perhaps cancer (Johnson et al., 1982; Baker et al., 1992; Richardson et al., 1995; Richardson & Milnes, 1997). Our previous investigations have demonstrated that 2-hydroxy-1-naphthaldehyde isonicotinoyl hydrazone (II) and several other aroylhydrazone chelators possess anti-tumour activity due to their ability to bind intracellular iron (Richardson et al., 1995; Richardson & Milnes, 1997; Darnell & Richardson, 1999; Richardson & Bernhardt, 1999). From these studies we have been able to identify structural components of the hydrazones which infer anti-neoplastic activity, namely the salicylaldehyde and 2-hydroxy-1-naphthaldehyde moieties (Richardson et al., 1995).
Another related group of chelators known as the thiosemicarbazones also show high anti-tumour activity due to their ability to inhibit ribonucleotide reductase (Cory et al., 1995; Liu et al., 1995). Considering this, we have designed and synthesized a new group of ligands by condensation of salicylaldehyde and 2-hydroxy-1-naphthaldehyde with a range of thiosemicarbazides. The parent compound of this new series of chelators is 2-hydroxy-1-naphthaldehyde thiosemicarbazone (III). Substitution of a methyl group at the 2-position of (III) to give (I) results in a marked decrease in anti-proliferative activity and a decrease in iron chelation efficacy (Lovejoy et al. 1999). These data may suggest that this latter subsititution diminishes the metal ion binding capability of these chelators. Studies assessing the biological activity of this new class of compounds are underway and will be reported elsewhere (Lovejoy et al., 1999). In the present communication we report the X-ray crystal structure of 2'-hydroxy-1'-naphthaldehyde-2-methyl-3-thiosemicarbazone, (I).
A view of (I) is shown in Figure 1. The bond lengths are typical of a compound of ths type (Table 1), and the angles are all close to 120°. The greatest deviation from an ideal trigonal planar geometry is at N2 where steric repulsion between the N-methyl group and S1 contract the C13—N2—N1 angle to 116.1 (3)°. The naphthyl ring is planar, with atoms C1—C10 all lying within 0.05 Å of the least-squares plane of the ring system. The atoms deviating the most from the napthyl ring system in the molecule are C12 [0.428 (3) Å], C13 [-0.671 (7) Å], N3 [-1.288 (7) Å] and S1 [-0.452 (8) Å], which is also seen in the C11—N1—N2—C12 torsion angle of 9.7 (5)°. The conformation of the molecule finds S1 anti to N1. Generally, it has been found that ligands of the salicylaldehyde thiosemicarbazone class [such as (IV)] act as meridionally coordinating, tridentate S,N,O-donors, so there needs to be a ca 180° rotation about N2—C13 in (I) before a metal ion can be bound in this fashion. The potential donors O1 and N1 are found in a syn disposition, as a result of a strong intramolecular hydrogen bond [O1—H1···N1 1.89 Å, O1···N1 2.603 (4) Å].
The presence of the N-methyl group in (I) also has other consequences for the coordination chemistry of this potentially tridentate ligand. In the structures of unsubstituted thiosemicarbazones such as (IV), the aldimine and phenolic protons (attached at positions corresponding to O1 and N2 in the present structure) can be removed upon coordination of the S, N and O-donors. However, it is not essential that either the aldimine or the phenolic protons are lost upon coordination of ligands in this class. Examples of (IV) coordinated in its neutral (Zimmer et al., 1991), mono anionic (Soriano-Garcia et al., 1985) and dianionic (Gyepes et al., 1981) forms are known. In the present case, the N-methyl group renders (I) incapable of losing more than one proton (at O1). In principle, this should not detract from the ability of (I) (or its anion) to coordinate to a metal ion, but the charge of the resulting complex will not be as variable as those found for complexes of (IV). The charge of the ligand and its resulting complexes in vivo are important for determining the biological activity of these chelators. Passage across the cell membrane is inhibited if the compound is hydrophilic, so systems close to neutrality are generally desirable if high iron chelation activity is sought (Richardson et al., 1990).
We are currently exploring the coordination chemistry and biological activity of these novel chelators.