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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

cif

Crystallographic Information File (CIF) https://doi.org/10.1107/S1600536801016130/wn6055sup1.cif
Contains datablocks I, global

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S1600536801016130/wn6055Isup2.hkl
Contains datablock I

CCDC reference: 176000

Key indicators

  • Single-crystal X-ray study
  • T = 293 K
  • Mean [sigma](C-C) = 0.006 Å
  • R factor = 0.062
  • wR factor = 0.151
  • Data-to-parameter ratio = 19.4

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ADDSYM reports no extra symmetry








Comment top

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.

Experimental top

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.

Computing details top

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.

Figures top
[Figure 1] Fig. 1. The molecular structure of (I) showing the atom-numbering scheme and 30% displacement ellipsoids. Hydrogen bonds are shown as dashed and H atoms are drawn as spheres of arbitrary radii.
(I) top
Crystal data top
C12H17N3O22+·2Cl·2H2OZ = 2
Mr = 342.22F(000) = 360
Triclinic, P1Dx = 1.420 Mg m3
a = 7.324 (6) ÅMo Kα radiation, λ = 0.71073 Å
b = 7.342 (9) ÅCell parameters from 38 reflections
c = 15.559 (10) Åθ = 5.2–12.5°
α = 77.95 (1)°µ = 0.42 mm1
β = 86.43 (1)°T = 293 K
γ = 78.09 (1)°Block, pale orange
V = 800.4 (13) Å30.34 × 0.22 × 0.12 mm
Data collection top
Bruker P4
diffractometer
Rint = 0.069
Radiation source: fine-focus sealed tubeθmax = 27.5°, θmin = 1.3°
Graphite monochromatorh = 19
ω scansk = 99
4551 measured reflectionsl = 2020
3686 independent reflections3 standard reflections every 100 reflections
1858 reflections with I > 2σ(I) intensity decay: <1%
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)] = 0.062Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.151H 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 parametersΔρmax = 0.28 e Å3
0 restraintsΔρmin = 0.36 e Å3
Crystal data top
C12H17N3O22+·2Cl·2H2Oγ = 78.09 (1)°
Mr = 342.22V = 800.4 (13) Å3
Triclinic, P1Z = 2
a = 7.324 (6) ÅMo Kα radiation
b = 7.342 (9) ŵ = 0.42 mm1
c = 15.559 (10) ÅT = 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 reflections3 standard reflections every 100 reflections
3686 independent reflections intensity decay: <1%
1858 reflections with I > 2σ(I)
Refinement top
R[F2 > 2σ(F2)] = 0.0620 restraints
wR(F2) = 0.151H atoms treated by a mixture of independent and constrained refinement
S = 1.00Δρmax = 0.28 e Å3
3686 reflectionsΔρmin = 0.36 e Å3
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
xyzUiso*/Ueq
Cl10.06415 (17)0.50904 (15)0.28145 (7)0.0579 (3)
Cl20.22969 (15)1.07291 (15)0.10462 (8)0.0524 (3)
O10.2586 (4)1.1241 (4)0.35890 (17)0.0534 (8)
H10.20311.23260.33950.080*
O20.4025 (4)0.7712 (4)0.44326 (19)0.0607 (9)
H20.37840.79660.39110.073*
O30.3514 (4)0.7758 (4)0.28016 (18)0.0607 (9)
H3B0.29960.88420.23430.073*
H3A0.26460.71910.27650.073*
O40.0574 (4)0.7271 (5)0.0841 (2)0.0637 (9)
H4A0.10000.84390.07410.076*
H4B0.08100.64840.14340.076*
N10.1950 (4)0.9724 (5)0.6231 (2)0.0384 (8)
N20.3266 (4)0.6828 (4)0.8874 (2)0.0361 (7)
N30.2690 (5)0.4043 (5)0.9244 (2)0.0478 (9)
H30.18490.32650.95130.057*
C10.3708 (6)0.6475 (6)0.6231 (3)0.0528 (11)
H1A0.42790.57410.58070.079*
H1B0.27320.59040.65450.079*
H1C0.46300.65100.66370.079*
C20.2911 (5)0.8444 (5)0.5772 (2)0.0372 (9)
C30.3096 (5)0.8997 (5)0.4874 (3)0.0392 (9)
C40.2351 (5)1.0844 (6)0.4449 (3)0.0400 (9)
C50.1423 (6)1.2102 (6)0.4951 (3)0.0488 (11)
H50.09251.33500.46870.059*
C60.1240 (6)1.1511 (6)0.5834 (3)0.0470 (10)
H60.06091.23640.61690.056*
C70.1657 (5)0.9223 (6)0.7191 (2)0.0444 (10)
H7A0.16110.78840.73570.053*
H7B0.04640.99410.73500.053*
C80.3171 (5)0.9619 (6)0.7693 (2)0.0416 (10)
H8A0.43750.90260.74820.050*
H8B0.31181.09780.75810.050*
C90.3005 (5)0.8897 (5)0.8667 (2)0.0385 (9)
H9A0.39360.92910.89650.046*
H9B0.17830.94450.88780.046*
C100.4912 (6)0.5563 (6)0.8848 (3)0.0446 (10)
H100.60440.58910.87380.054*
C110.4545 (6)0.3836 (6)0.9082 (3)0.0499 (11)
H110.52950.24850.91500.060*
C120.1947 (6)0.5868 (6)0.9116 (3)0.0435 (10)
H120.06540.64690.92860.052*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
Cl10.0769 (8)0.0423 (6)0.0530 (7)0.0157 (6)0.0041 (6)0.0017 (5)
Cl20.0419 (6)0.0431 (6)0.0660 (8)0.0086 (5)0.0054 (5)0.0044 (5)
O10.066 (2)0.0489 (17)0.0379 (17)0.0006 (15)0.0023 (14)0.0036 (13)
O20.076 (2)0.0533 (18)0.0454 (18)0.0133 (16)0.0090 (16)0.0171 (14)
O30.081 (2)0.0606 (19)0.0449 (18)0.0230 (17)0.0113 (16)0.0081 (14)
O40.066 (2)0.074 (2)0.055 (2)0.0270 (17)0.0102 (16)0.0046 (16)
N10.0350 (18)0.047 (2)0.0332 (18)0.0091 (15)0.0027 (14)0.0068 (15)
N20.0331 (18)0.0386 (18)0.0354 (18)0.0036 (14)0.0015 (14)0.0081 (14)
N30.054 (2)0.042 (2)0.049 (2)0.0175 (17)0.0068 (18)0.0069 (16)
C10.061 (3)0.040 (2)0.052 (3)0.003 (2)0.012 (2)0.001 (2)
C20.037 (2)0.039 (2)0.037 (2)0.0093 (17)0.0038 (17)0.0068 (17)
C30.039 (2)0.038 (2)0.041 (2)0.0036 (18)0.0041 (18)0.0118 (18)
C40.037 (2)0.045 (2)0.039 (2)0.0101 (18)0.0004 (18)0.0085 (18)
C50.056 (3)0.037 (2)0.049 (3)0.002 (2)0.001 (2)0.0042 (19)
C60.051 (3)0.042 (2)0.046 (3)0.003 (2)0.001 (2)0.0110 (19)
C70.038 (2)0.060 (3)0.035 (2)0.012 (2)0.0006 (18)0.0067 (19)
C80.044 (2)0.039 (2)0.043 (2)0.0149 (19)0.0036 (19)0.0045 (18)
C90.039 (2)0.036 (2)0.042 (2)0.0074 (18)0.0028 (18)0.0133 (17)
C100.034 (2)0.051 (3)0.047 (3)0.002 (2)0.0034 (19)0.012 (2)
C110.054 (3)0.045 (3)0.048 (3)0.000 (2)0.000 (2)0.013 (2)
C120.036 (2)0.051 (3)0.043 (2)0.009 (2)0.0079 (18)0.0110 (19)
Geometric parameters (Å, º) top
O1—C41.317 (4)N3—C111.349 (5)
O2—C31.332 (5)C1—C21.487 (5)
N1—C61.339 (5)C2—C31.377 (5)
N1—C21.354 (5)C3—C41.393 (5)
N1—C71.475 (5)C4—C51.379 (6)
N2—C121.303 (5)C5—C61.358 (5)
N2—C101.366 (5)C7—C81.504 (5)
N2—C91.460 (5)C8—C91.503 (5)
N3—C121.316 (5)C10—C111.322 (6)
C6—N1—C2121.4 (3)C2—C3—C4120.8 (4)
C6—N1—C7117.0 (3)O1—C4—C5125.2 (4)
C2—N1—C7121.6 (3)O1—C4—C3116.6 (4)
C12—N2—C10108.1 (3)C5—C4—C3118.2 (4)
C12—N2—C9125.4 (3)C6—C5—C4119.7 (4)
C10—N2—C9126.5 (3)N1—C6—C5121.3 (4)
C12—N3—C11108.8 (4)N1—C7—C8112.5 (3)
N1—C2—C3118.5 (3)C9—C8—C7112.7 (3)
N1—C2—C1120.4 (4)N2—C9—C8111.0 (3)
C3—C2—C1121.1 (4)C11—C10—N2107.5 (4)
O2—C3—C2117.7 (3)C10—C11—N3107.0 (4)
O2—C3—C4121.5 (4)N2—C12—N3108.6 (4)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O1—H1···Cl1i0.822.112.932 (4)176
O2—H2···O30.821.792.580 (4)162
O3—H3A···Cl10.842.333.153 (4)169
O3—H3B···Cl20.982.223.166 (3)163
O4—H4B···Cl10.992.193.151 (4)166
O4—H4A···Cl20.952.243.139 (4)158
N3—H3···O4ii0.952.032.776 (5)135
N3—H3···Cl2iii0.952.693.348 (4)127
Symmetry codes: (i) x, y+1, z; (ii) x, y+1, z+1; (iii) x, y1, z+1.

Experimental details

Crystal data
Chemical formulaC12H17N3O22+·2Cl·2H2O
Mr342.22
Crystal system, space groupTriclinic, 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)
V3)800.4 (13)
Z2
Radiation typeMo Kα
µ (mm1)0.42
Crystal size (mm)0.34 × 0.22 × 0.12
Data collection
DiffractometerBruker P4
diffractometer
Absorption correction
No. of measured, independent and
observed [I > 2σ(I)] reflections
4551, 3686, 1858
Rint0.069
(sin θ/λ)max1)0.650
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.062, 0.151, 1.00
No. of reflections3686
No. of parameters190
H-atom treatmentH atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å3)0.28, 0.36

Computer programs: XSCANS (Fait, 1991), XSCANS, SHELXS97 (Sheldrick, 1997), SHELXL97 (Sheldrick, 1997), SHELXL97.

Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O1—H1···Cl1i0.822.112.932 (4)176.4
O2—H2···O30.821.792.580 (4)162.4
O3—H3A···Cl10.842.333.153 (4)168.5
O3—H3B···Cl20.982.223.166 (3)162.7
O4—H4B···Cl10.992.193.151 (4)166.0
O4—H4A···Cl20.952.243.139 (4)157.9
N3—H3···O4ii0.952.032.776 (5)134.9
N3—H3···Cl2iii0.952.693.348 (4)126.8
Symmetry codes: (i) x, y+1, z; (ii) x, y+1, z+1; (iii) x, y1, 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—O1C3—O2ΔaC3—C4C5—C6N1—C7
(I)1.315 (5)1.330 (5)0.0151.393 (5)1.358 (6)1.474 (5)
L1.HCl1.338 (3)1.342 (3)0.0041.408 (4)1.347 (5)1.484 (3)
L1.HBr1.328 (5)1.343 (5)0.0151.385 (6)1.349 (7)1.479 (7)
L11.278 (3)1.363 (3)0.0851.431 (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.
 

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