The crystal structure of the title compound, C12H17N3O22+·2Cl-·2H2O, has been determined. The effects of protonating the ketonic oxygen with regard to bond distances within the hydroxypyridinone moiety are discussed and compared to the equivalent bond distances in the parent compounds 3-hydroxy-1,2-dimethyl-4-pyridinone hydrochloride monohydrate and hydrobromide monohydrate and 3-hydroxy-1,2-dimethyl-4-pyridinone itself.
Supporting information
CCDC reference: 176000
Key indicators
- Single-crystal X-ray study
- T = 293 K
- Mean (C-C) = 0.006 Å
- R factor = 0.062
- wR factor = 0.151
- Data-to-parameter ratio = 19.4
checkCIF results
No syntax errors found
ADDSYM reports no extra symmetry
The title compound was prepared by the so-called `protected route' (Harris,
1976; Farber et al., 1994). A solution of 30 g of maltol (Aldrich),
10.5 g sodium hydroxide, and 33.3 g benzyl chloride, dissolved in 150 ml of
70/30 (by volume) methanol/water was refluxed for 8 h. The resultant solution
was allowed to cool, then most of the methanol was removed under reduced
pressure. Water (100 ml) was added, and the product extracted into
dichloromethane (2 × 100 ml portions). The extracts were combined,
washed with 100 ml of dilute sodium hydroxide solution, then 100 ml water, and
dried over anhydrous magnesium sulfate. Evaporation of the dichlormethane
solvent left a residue of crude benzyl-protected intermediate. 20 g of this
intermediate were refluxed in ethanol (50 ml) with a threefold excess of
imidazole for 6 h. The pH of the product solution was reduced to 2 with dilute
hydrochloric acid and the resulting solution washed with diethyl ether to
recover unreacted intermediate. The pH was then raised to 7 (ammonium
hydroxide) and the benzyl derivative of the required product extracted into
dichloromethane (2 × 100 ml portions). The dichloromethane was removed
from the combined extracts under reduced pressure prior to the removal of the
protecting group. This was achieved by hydrogenolysis of a solution of the
benzyl derivative, in 100 ml of ethanol containing hydrogen chloride (2%),
using a palladium (10%)-activated charcoal catalyst. The resulting solution
was filtered, the ethanol reduced under reduced pressure, and the product
recrystallized from 50/50 (by volume) ethanol/water. A crystal suitable for
X-ray examination was selected from this product.
Data collection: XSCANS (Fait, 1991); cell refinement: XSCANS; data reduction: XSCANS; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXL97; software used to prepare material for publication: SHELXL97.
Crystal data top
C12H17N3O22+·2Cl−·2H2O | Z = 2 |
Mr = 342.22 | F(000) = 360 |
Triclinic, P1 | Dx = 1.420 Mg m−3 |
a = 7.324 (6) Å | Mo Kα radiation, λ = 0.71073 Å |
b = 7.342 (9) Å | Cell parameters from 38 reflections |
c = 15.559 (10) Å | θ = 5.2–12.5° |
α = 77.95 (1)° | µ = 0.42 mm−1 |
β = 86.43 (1)° | T = 293 K |
γ = 78.09 (1)° | Block, pale orange |
V = 800.4 (13) Å3 | 0.34 × 0.22 × 0.12 mm |
Data collection top
Bruker P4 diffractometer | Rint = 0.069 |
Radiation source: fine-focus sealed tube | θmax = 27.5°, θmin = 1.3° |
Graphite monochromator | h = −1→9 |
ω scans | k = −9→9 |
4551 measured reflections | l = −20→20 |
3686 independent reflections | 3 standard reflections every 100 reflections |
1858 reflections with I > 2σ(I) | intensity decay: <1% |
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)] = 0.062 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.151 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.00 | w = 1/[σ2(Fo2) + (0.0467P)2 + 0.4761P] where P = (Fo2 + 2Fc2)/3 |
3686 reflections | (Δ/σ)max = 0.001 |
190 parameters | Δρmax = 0.28 e Å−3 |
0 restraints | Δρmin = −0.36 e Å−3 |
Crystal data top
C12H17N3O22+·2Cl−·2H2O | γ = 78.09 (1)° |
Mr = 342.22 | V = 800.4 (13) Å3 |
Triclinic, P1 | Z = 2 |
a = 7.324 (6) Å | Mo Kα radiation |
b = 7.342 (9) Å | µ = 0.42 mm−1 |
c = 15.559 (10) Å | T = 293 K |
α = 77.95 (1)° | 0.34 × 0.22 × 0.12 mm |
β = 86.43 (1)° | |
Data collection top
Bruker P4 diffractometer | Rint = 0.069 |
4551 measured reflections | 3 standard reflections every 100 reflections |
3686 independent reflections | intensity decay: <1% |
1858 reflections with I > 2σ(I) | |
Refinement top
R[F2 > 2σ(F2)] = 0.062 | 0 restraints |
wR(F2) = 0.151 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.00 | Δρmax = 0.28 e Å−3 |
3686 reflections | Δρmin = −0.36 e Å−3 |
190 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. |
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 | |
Cl1 | 0.06415 (17) | 0.50904 (15) | 0.28145 (7) | 0.0579 (3) | |
Cl2 | 0.22969 (15) | 1.07291 (15) | 0.10462 (8) | 0.0524 (3) | |
O1 | 0.2586 (4) | 1.1241 (4) | 0.35890 (17) | 0.0534 (8) | |
H1 | 0.2031 | 1.2326 | 0.3395 | 0.080* | |
O2 | 0.4025 (4) | 0.7712 (4) | 0.44326 (19) | 0.0607 (9) | |
H2 | 0.3784 | 0.7966 | 0.3911 | 0.073* | |
O3 | 0.3514 (4) | 0.7758 (4) | 0.28016 (18) | 0.0607 (9) | |
H3B | 0.2996 | 0.8842 | 0.2343 | 0.073* | |
H3A | 0.2646 | 0.7191 | 0.2765 | 0.073* | |
O4 | 0.0574 (4) | 0.7271 (5) | 0.0841 (2) | 0.0637 (9) | |
H4A | 0.1000 | 0.8439 | 0.0741 | 0.076* | |
H4B | 0.0810 | 0.6484 | 0.1434 | 0.076* | |
N1 | 0.1950 (4) | 0.9724 (5) | 0.6231 (2) | 0.0384 (8) | |
N2 | 0.3266 (4) | 0.6828 (4) | 0.8874 (2) | 0.0361 (7) | |
N3 | 0.2690 (5) | 0.4043 (5) | 0.9244 (2) | 0.0478 (9) | |
H3 | 0.1849 | 0.3265 | 0.9513 | 0.057* | |
C1 | 0.3708 (6) | 0.6475 (6) | 0.6231 (3) | 0.0528 (11) | |
H1A | 0.4279 | 0.5741 | 0.5807 | 0.079* | |
H1B | 0.2732 | 0.5904 | 0.6545 | 0.079* | |
H1C | 0.4630 | 0.6510 | 0.6637 | 0.079* | |
C2 | 0.2911 (5) | 0.8444 (5) | 0.5772 (2) | 0.0372 (9) | |
C3 | 0.3096 (5) | 0.8997 (5) | 0.4874 (3) | 0.0392 (9) | |
C4 | 0.2351 (5) | 1.0844 (6) | 0.4449 (3) | 0.0400 (9) | |
C5 | 0.1423 (6) | 1.2102 (6) | 0.4951 (3) | 0.0488 (11) | |
H5 | 0.0925 | 1.3350 | 0.4687 | 0.059* | |
C6 | 0.1240 (6) | 1.1511 (6) | 0.5834 (3) | 0.0470 (10) | |
H6 | 0.0609 | 1.2364 | 0.6169 | 0.056* | |
C7 | 0.1657 (5) | 0.9223 (6) | 0.7191 (2) | 0.0444 (10) | |
H7A | 0.1611 | 0.7884 | 0.7357 | 0.053* | |
H7B | 0.0464 | 0.9941 | 0.7350 | 0.053* | |
C8 | 0.3171 (5) | 0.9619 (6) | 0.7693 (2) | 0.0416 (10) | |
H8A | 0.4375 | 0.9026 | 0.7482 | 0.050* | |
H8B | 0.3118 | 1.0978 | 0.7581 | 0.050* | |
C9 | 0.3005 (5) | 0.8897 (5) | 0.8667 (2) | 0.0385 (9) | |
H9A | 0.3936 | 0.9291 | 0.8965 | 0.046* | |
H9B | 0.1783 | 0.9445 | 0.8878 | 0.046* | |
C10 | 0.4912 (6) | 0.5563 (6) | 0.8848 (3) | 0.0446 (10) | |
H10 | 0.6044 | 0.5891 | 0.8738 | 0.054* | |
C11 | 0.4545 (6) | 0.3836 (6) | 0.9082 (3) | 0.0499 (11) | |
H11 | 0.5295 | 0.2485 | 0.9150 | 0.060* | |
C12 | 0.1947 (6) | 0.5868 (6) | 0.9116 (3) | 0.0435 (10) | |
H12 | 0.0654 | 0.6469 | 0.9286 | 0.052* | |
Atomic displacement parameters (Å2) top | U11 | U22 | U33 | U12 | U13 | U23 |
Cl1 | 0.0769 (8) | 0.0423 (6) | 0.0530 (7) | −0.0157 (6) | −0.0041 (6) | −0.0017 (5) |
Cl2 | 0.0419 (6) | 0.0431 (6) | 0.0660 (8) | −0.0086 (5) | −0.0054 (5) | 0.0044 (5) |
O1 | 0.066 (2) | 0.0489 (17) | 0.0379 (17) | 0.0006 (15) | 0.0023 (14) | −0.0036 (13) |
O2 | 0.076 (2) | 0.0533 (18) | 0.0454 (18) | 0.0133 (16) | −0.0090 (16) | −0.0171 (14) |
O3 | 0.081 (2) | 0.0606 (19) | 0.0449 (18) | −0.0230 (17) | −0.0113 (16) | −0.0081 (14) |
O4 | 0.066 (2) | 0.074 (2) | 0.055 (2) | −0.0270 (17) | −0.0102 (16) | −0.0046 (16) |
N1 | 0.0350 (18) | 0.047 (2) | 0.0332 (18) | −0.0091 (15) | −0.0027 (14) | −0.0068 (15) |
N2 | 0.0331 (18) | 0.0386 (18) | 0.0354 (18) | −0.0036 (14) | −0.0015 (14) | −0.0081 (14) |
N3 | 0.054 (2) | 0.042 (2) | 0.049 (2) | −0.0175 (17) | 0.0068 (18) | −0.0069 (16) |
C1 | 0.061 (3) | 0.040 (2) | 0.052 (3) | −0.003 (2) | −0.012 (2) | −0.001 (2) |
C2 | 0.037 (2) | 0.039 (2) | 0.037 (2) | −0.0093 (17) | −0.0038 (17) | −0.0068 (17) |
C3 | 0.039 (2) | 0.038 (2) | 0.041 (2) | −0.0036 (18) | −0.0041 (18) | −0.0118 (18) |
C4 | 0.037 (2) | 0.045 (2) | 0.039 (2) | −0.0101 (18) | 0.0004 (18) | −0.0085 (18) |
C5 | 0.056 (3) | 0.037 (2) | 0.049 (3) | −0.002 (2) | −0.001 (2) | −0.0042 (19) |
C6 | 0.051 (3) | 0.042 (2) | 0.046 (3) | −0.003 (2) | −0.001 (2) | −0.0110 (19) |
C7 | 0.038 (2) | 0.060 (3) | 0.035 (2) | −0.012 (2) | −0.0006 (18) | −0.0067 (19) |
C8 | 0.044 (2) | 0.039 (2) | 0.043 (2) | −0.0149 (19) | −0.0036 (19) | −0.0045 (18) |
C9 | 0.039 (2) | 0.036 (2) | 0.042 (2) | −0.0074 (18) | −0.0028 (18) | −0.0133 (17) |
C10 | 0.034 (2) | 0.051 (3) | 0.047 (3) | −0.002 (2) | −0.0034 (19) | −0.012 (2) |
C11 | 0.054 (3) | 0.045 (3) | 0.048 (3) | 0.000 (2) | 0.000 (2) | −0.013 (2) |
C12 | 0.036 (2) | 0.051 (3) | 0.043 (2) | −0.009 (2) | 0.0079 (18) | −0.0110 (19) |
Geometric parameters (Å, º) top
O1—C4 | 1.317 (4) | N3—C11 | 1.349 (5) |
O2—C3 | 1.332 (5) | C1—C2 | 1.487 (5) |
N1—C6 | 1.339 (5) | C2—C3 | 1.377 (5) |
N1—C2 | 1.354 (5) | C3—C4 | 1.393 (5) |
N1—C7 | 1.475 (5) | C4—C5 | 1.379 (6) |
N2—C12 | 1.303 (5) | C5—C6 | 1.358 (5) |
N2—C10 | 1.366 (5) | C7—C8 | 1.504 (5) |
N2—C9 | 1.460 (5) | C8—C9 | 1.503 (5) |
N3—C12 | 1.316 (5) | C10—C11 | 1.322 (6) |
| | | |
C6—N1—C2 | 121.4 (3) | C2—C3—C4 | 120.8 (4) |
C6—N1—C7 | 117.0 (3) | O1—C4—C5 | 125.2 (4) |
C2—N1—C7 | 121.6 (3) | O1—C4—C3 | 116.6 (4) |
C12—N2—C10 | 108.1 (3) | C5—C4—C3 | 118.2 (4) |
C12—N2—C9 | 125.4 (3) | C6—C5—C4 | 119.7 (4) |
C10—N2—C9 | 126.5 (3) | N1—C6—C5 | 121.3 (4) |
C12—N3—C11 | 108.8 (4) | N1—C7—C8 | 112.5 (3) |
N1—C2—C3 | 118.5 (3) | C9—C8—C7 | 112.7 (3) |
N1—C2—C1 | 120.4 (4) | N2—C9—C8 | 111.0 (3) |
C3—C2—C1 | 121.1 (4) | C11—C10—N2 | 107.5 (4) |
O2—C3—C2 | 117.7 (3) | C10—C11—N3 | 107.0 (4) |
O2—C3—C4 | 121.5 (4) | N2—C12—N3 | 108.6 (4) |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
O1—H1···Cl1i | 0.82 | 2.11 | 2.932 (4) | 176 |
O2—H2···O3 | 0.82 | 1.79 | 2.580 (4) | 162 |
O3—H3A···Cl1 | 0.84 | 2.33 | 3.153 (4) | 169 |
O3—H3B···Cl2 | 0.98 | 2.22 | 3.166 (3) | 163 |
O4—H4B···Cl1 | 0.99 | 2.19 | 3.151 (4) | 166 |
O4—H4A···Cl2 | 0.95 | 2.24 | 3.139 (4) | 158 |
N3—H3···O4ii | 0.95 | 2.03 | 2.776 (5) | 135 |
N3—H3···Cl2iii | 0.95 | 2.69 | 3.348 (4) | 127 |
Symmetry codes: (i) x, y+1, z; (ii) −x, −y+1, −z+1; (iii) x, y−1, z+1. |
Experimental details
Crystal data |
Chemical formula | C12H17N3O22+·2Cl−·2H2O |
Mr | 342.22 |
Crystal system, space group | Triclinic, P1 |
Temperature (K) | 293 |
a, b, c (Å) | 7.324 (6), 7.342 (9), 15.559 (10) |
α, β, γ (°) | 77.95 (1), 86.43 (1), 78.09 (1) |
V (Å3) | 800.4 (13) |
Z | 2 |
Radiation type | Mo Kα |
µ (mm−1) | 0.42 |
Crystal size (mm) | 0.34 × 0.22 × 0.12 |
|
Data collection |
Diffractometer | Bruker P4 diffractometer |
Absorption correction | – |
No. of measured, independent and observed [I > 2σ(I)] reflections | 4551, 3686, 1858 |
Rint | 0.069 |
(sin θ/λ)max (Å−1) | 0.650 |
|
Refinement |
R[F2 > 2σ(F2)], wR(F2), S | 0.062, 0.151, 1.00 |
No. of reflections | 3686 |
No. of parameters | 190 |
H-atom treatment | H atoms treated by a mixture of independent and constrained refinement |
Δρmax, Δρmin (e Å−3) | 0.28, −0.36 |
Hydrogen-bond geometry (Å, º) top
D—H···A | D—H | H···A | D···A | D—H···A |
O1—H1···Cl1i | 0.82 | 2.11 | 2.932 (4) | 176.4 |
O2—H2···O3 | 0.82 | 1.79 | 2.580 (4) | 162.4 |
O3—H3A···Cl1 | 0.84 | 2.33 | 3.153 (4) | 168.5 |
O3—H3B···Cl2 | 0.98 | 2.22 | 3.166 (3) | 162.7 |
O4—H4B···Cl1 | 0.99 | 2.19 | 3.151 (4) | 166.0 |
O4—H4A···Cl2 | 0.95 | 2.24 | 3.139 (4) | 157.9 |
N3—H3···O4ii | 0.95 | 2.03 | 2.776 (5) | 134.9 |
N3—H3···Cl2iii | 0.95 | 2.69 | 3.348 (4) | 126.8 |
Symmetry codes: (i) x, y+1, z; (ii) −x, −y+1, −z+1; (iii) x, y−1, z+1. |
Comparison of selected bond distances (Å) in the hydropyridinone
moiety of (I) with analogous distances in the hydrochloride and hydrobromide
of L1 and in free L1 top | C4—O1 | C3—O2 | Δa | C3—C4 | C5—C6 | N1—C7 |
(I) | 1.315 (5) | 1.330 (5) | 0.015 | 1.393 (5) | 1.358 (6) | 1.474 (5) |
L1.HCl | 1.338 (3) | 1.342 (3) | 0.004 | 1.408 (4) | 1.347 (5) | 1.484 (3) |
L1.HBr | 1.328 (5) | 1.343 (5) | 0.015 | 1.385 (6) | 1.349 (7) | 1.479 (7) |
L1 | 1.278 (3) | 1.363 (3) | 0.085 | 1.431 (4) | 1.356 (4) | 1.469 (4) |
Notes: (a) Δ is the difference between the CO bond distances to the ketonic and
hydroxylic oxygens, (C4—O1) and (C3—O2), respectively. |
3-Hydroxy-4-pyridinones and several of their metal complexes are proving of considerable value and interest in relation to the control of metal levels (particularly of iron) and the introduction of metal ions (e.g. Ga, In, Gd) into the body for diagnosis or therapy (Hider & Hall, 1998). Appropriate substitution is needed to maximize effectiveness while minimizing undesirable side effects; the incorporation of acidic (–SO3H and –CO2H) or basic (nitrogen-containing) moieties confers a useful degree of hydrophilicity and the possibility of pH control (Molenda et al., 1994). The attachment of imidazole-containing moieties to the N atom of the pyridinone ring has recently been shown to be advantageous in the development of chelators for targetting lysosome iron (Lu et al., 2000). We report here the structure of such an imidazole-containing hydroxypyridinone, in a doubly protonated form in a hydrated hydrochloride salt, specifically 3-hydroxy-1-(3-imidazolylpropyl)-2-methyl-4-pyridinone dihydrochloride dihydrate, (I); this complements the published information on ligand synthesis and properties.
The pyridinone is, as expected, essentially planar. Bond distances and angles in the hydroxypyridinone moiety are the same, within experimental uncertainty, as those in the parent compounds 3-hydroxy-1,2-dimethyl-4-pyridinone hydrochloride monohydrate (Parsons, 1993) and hydrobromide monohydrate (Hider et al., 1990). This is shown in Table 2, where selected bond distances in the hydroxypyridinone moieties of these hydrohalide salts are compared with each other and with the analogous bond distances in 3-hydroxy-1,2-dimethyl-4-pyridinone (L1) itself (Clarke et al., 1992). Protonation of the ketonic oxygen, O1, results in an extension of the C4—O1 bond to a length almost that of C3—O2. Both C—O bonds are considerably shorter than the sum of the covalent radii of carbon and oxygen (1.43 Å). The double-bond character of C3—C4 is significantly reduced as a result of protonation of O1. Other bonds in the pyridinone ring, and the N—C bond connecting the 1-substituent to the pyridinone ring, are not significantly affected by protonation.
In the title compound, as in L1.HX·H2O (X = Cl or Br), the hydroxypyridinone moiety and halide ions are linked by hydrogen bonding, as shown in Fig. 1. The hydrogen-bonded chloride–water–chloride– columns lie parallel to the columns of the imidazole-hydroxypyridinone molecules; both sets of columns lie parallel to the b axis.
The imidazole ring approximates closely to planarity. Its C—N and C—C bond distances are within the ranges established from structure determinations for a large number of organic and organometallic derivatives. In particular, the interatomic distances in the imidazole ring of (I) are very similar to those in several imidazolium salts, such as 1-methyl-imidazolium hydrogen-D-tartrate (Fuller et al., 1995) and trichloromethylphosphonate (Holmes et al., 1992), and 3-ethyl-1-methylimidazolium nitrite (Wilkes & Zaworotko, 1992). Such imidazolium salts tend to have the shortest C12—N2 bonds, i.e. most double-bond character to this bond.