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Nimustine hydro­chloride [systematic name: 4-amino-5-({[N-(2-chloro­ethyl)-N-nitroso­carbamoyl]­amino}­methyl)-2-methyl­pyrimidin-1-ium chloride], C9H14ClN6O2+·Cl-, is a prodrug of CENU (chloro­ethyl­nitroso­urea) and is used as a cytostatic agent in cancer therapy. Its crystal structure was determined from laboratory X-ray powder diffraction data. The proton­ation at an N atom of the pyrimidine ring was established by solid-state NMR spectroscopy.

Supporting information

cif

Crystallographic Information File (CIF) https://doi.org/10.1107/S0108270112005252/lg3071sup1.cif
Contains datablocks global, I

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S0108270112005252/lg3071Isup2.hkl
Contains datablock I

rtv

Rietveld powder data file (CIF format) https://doi.org/10.1107/S0108270112005252/lg3071Isup3.rtv
Contains datablock I

CCDC reference: 873907

Comment top

The human brain has a special membrane, known as the blood–brain barrier (BBB), that protects it very efficiently from non-self substances. These non-self substances include the vast majority of drugs used in cancer therapy. Drug therapy of brain tumours is thus much more difficult and the range of suitable cytostatics is severely restricted. Every year, most disconcertingly, more than 800 000 new cases in which the central nervous system is afflicted with cancer are registered worldwide. The majority of these cases are concerned with brain tumours, as shown by the latest study by the Robert Koch Institute (Husmann et al., 2010).

A study carried out by Skipper et al. (1961) drew attention to research on the drug class of nitrosoureas. Of all tested cytostatics, a measurable efficiency against brain tumours could only be observed for 1-methyl-1-nitrosourea (the only representative of the nitrosoureas in the aforementioned study). Since then, a range of nitrosourea derivatives have been synthesized and extensively examined (Johnston et al., 1966). Some of them, for example carmustine (or BiCNU or BCNU, from bis-chloroethylnitrosourea) and lomustine (or CeeNU or CCNU, from chloroethylcyclonitrosourea), showed a very high efficacy against tumours and were able to cross the BBB. However, their low solubility in water complicated their application (Kanamaru et al., 1980). In 1972, the Central Research Laboratory, Sankyo Co. Ltd, Tokyo, synthesized further nitrosourea derivatives, including the title nimustine hydrochloride [4-amino-5-({[N-(2-chloroethyl)-N-nitrosocarbamoyl]amino}methyl)-2-methylpyrimidin-1-ium chloride], (I), which represented an improvement, as this derivative is soluble in water and at the same time overcomes the BBB (Nakao et al., 1972). Nimustine hydrochloride is currently marketed under the trade name Nidran (or ACNU, from aminopyrimidinechloroethylnitrosourea). Presently, (I) belongs to the group of standard drugs in the fight against brain tumours, where contemporary therapeutic schemes also include additional radiation and surgical removal of the tumour (Kamiryo et al., 2004).

The exact mechanism of action is currently still under investigation. However, the preliminary findings indicate that DNA is directly attacked by nimustine by alkylation of the guanine blocks at the O6 position to yield O6-(2-chloroethyl)guanine. This alkylation massively affects the function of DNA, because in contrast with guanine, O6-(2-chloroethyl)guanine prefers to build up base pairs with thymine instead of cytosine. The information stored in DNA is altered and thereby successful replication and transcription are prevented. However, the possibility of repairing the alkylated guanine blocks using the body's own enzyme O6-alkylguanine-DNA alkyltransferase still exists. If this process does not happen, or not fast enough, the affected DNA strands may be damaged almost irreversibly. The O6-(2-chloroethyl)guanine formed is unstable and can react via the intramolecularly formed intermediate N1-O6-ethanoguanine with the complementary DNA strand to form 1-(3-cytosinyl)-2-(1-guanosinyl)ethane. As a consequence, both DNA strands are covalently cross-linked. The resulting double-strand breaks are considerably more difficult to repair, thus usually leading to cell death. However, the body's own mechanisms able to repair even these double-strand breaks are also known. These mechanisms are currently under investigation in the hope that, with the knowledge thus accumulated, the efficiency of agents such as nimustine hydrochloride can be increased (Kobayashi et al., 1994; Margison & Santibáñez-Koref, 2002; Batista et al., 2007; Kondo et al., 2010). The expectation is that the elucidation of the exact crystal structure of nimustine hydrochloride, determined from X-ray powder diffraction and solid-state NMR and reported here, will provide additional momentum to the investigation of the mode of action of nitrosourea derivatives as cytostatics and the body's response to them, as well as to the development of new prodrug candidates.

As a first step, thermal gravimetry (TG) experiments were carried out to determine whether the sample of (I) contained solvent or water molecules. TG showed no mass loss or gain up to 426 K, which proves that the investigated sample of (I) contains no solvent or water molecules in the lattice. Weight loss started at 428 K. Additionally, differential scanning calorimetry (DSC) was carried out, which showed a sharp exothermic signal at 428 K resulting from decomposition.

Four possible positions of protonation are available in the molecule of (I) (N1, N3, N8 and N41). H-atom positions are generally difficult to determine from X-ray powder diffraction, although there have been cases when they have been determined successfully (Schmidt et al., 2011), even from laboratory powder data (Bekö et al., 2010). In this instance, the position of protonation could be determined by solid-state NMR spectroscopy using cross-polarization magic-angle spinning (CPMAS). In the 15N CP MAS spectrum, only the hydrogen-carrying N atoms could be detected. Three 15N peaks were observed with respect to liquid ammonia, which were assigned based on their chemical shifts to the –NH2 (N41, 91.55 p.p.m.), –NH (N8, 102.98 p.p.m.) and aromatic NH+ (N1 or N3, 172.79 p.p.m.) moieties. The corresponding values calculated with respect to nitromethane are -288.68, -277.25 and -207.44 p.p.m., considering that the chemical shift of liquid ammonia is -380.23 p.p.m. with respect to nitromethane. In the literature both reference compounds are used. By comparing the 15N chemical shift values with those obtained by Städeli & von Philipsborn (1980) for aminopyrimidines in different protonation states in solution, it can be unambiguously concluded that the chemical shift value of -207.44 p.p.m. for the aromatic N atom certainly indicates a protonated positively charged state. However, this measurement did not allow a decision to be reached on whether the protonation had occurred at N1 or N3. Solution NMR studies on pyridine and pyrimidine derivatives show that protonation of the ring N atom strongly affects the 13C chemical shifts of the adjacent C atoms (Riand et al., 1977; Liu et al., 1991). Thus, it seemed reasonable to use 13C NMR for the determination of the protonation site on the pyrimidine ring. Due to the low natural abundance of 13C isotopes, no correlation experiments could be performed in the solid state. Therefore, resonance assignments were made based on the 13C solution NMR spectrum recorded in d6-DMSO, since the two spectra (solid state and solution) showed very similar spectroscopic patterns and chemical shifts (see Table 2). The 13C signals in d6-DMSO were assigned using heteronuclear single-quantum correlation (HSQC) and heteronuclear multiple-bond correlation (HMBC) experiments.

Through a comparison of the 13C chemical shifts of neutral (in d6-DMSO) and monoprotonated (in TFA) pyrimidine derivatives, Riand et al. (1974) were able to show that the C atoms adjacent to protonated N atoms become more shielded and thus their signals undergo upfield shifts compared with the neutral molecule. These upfield shifts are larger for a C atom attached to H than for one attached to a methyl group. Riand et al. (1974) also determined that, in the case of 4-aminopyrimidines, monoprotonation occurs almost completely on atom N1 para to the amino group. Protonation of N1 in the case of 2-methyl-4-aminopyrimidine has the strongest effect on C6, for which the chemical shift changes from 154.75 to 144.8 p.p.m. The signal of the methyl group at position 2 also undergoes an upfield shift from 25.57 to 21.4 p.p.m. A similar ~10 p.p.m. upfield shift of the C6 resonance was observed for 4-amino-5-methylpyrimidine (from 153.5 to 142.2 p.p.m.) due to protonation at N1. Consequently, the chemical shift of C6 could also be an indicator for the protonation state of N1 in the case of nimustine hydrochloride and its value at 141.8 p.p.m. strongly suggests that N1 is protonated. A prediction of the 13C chemical shifts of the neutral and differently protonated nimustine molecules using the CHEMDRAW Ultra 12.0 software from CambridgeSoft Corporation (Cousins, 2011) provided further substantiation for this finding. Since the software was not able to perform calculations with protonated N atoms, we used the N-methylated form to create the positive charge. The effect of an N-methyl substituent on the 15N, 13C and 1H chemical shifts is very similar to that of an H atom. The results are summarized in the Table 2. The chemical shifts obtained for the N1-methylated derivative show the best agreement with the solid-state NMR data, which again indicates that (I) is protonated at N1.

For the crystal structure determination of nimustine hydrochloride from laboratory X-ray powder diffraction data, the diffractogram was recorded in transmission mode on a Stoe STADI-P diffractometer with a Ge(111) monochromator and a linear position-sensitive detector using Cu Kα1 radiation at 293 K from 2.0 to 79.99° in 2θ. The sample was measured for 52 h in a 0.7 mm capillary in a 2:1 ratio with amorphous SiO2 to minimize preferred orientation, since (I) crystallizes in small tablet-like crystals, as shown in Fig. 1. The Stoe software WinXPOW (Stoe & Cie, 2004) was used for data acquisition.

For indexing and structure solution, the powder pattern was truncated to a real-space resolution of approximately 3.4 Å, which for Cu Kα1 radiation corresponds to the range 3.0–26.5° in 2θ. The background was subtracted with a Bayesian high-pass filter (David & Sivia, 2001). The powder pattern could be indexed without ambiguity with the program DICVOL91 (Boultif & Louër, 1991), resulting in a monoclinic unit cell with V = 1370 Å3. A comparison of the unit-cell volume with Hofmann's volume increments (Hofmann, 2002) led to the estimation that Z = 4. Subsequently, a Pawley refinement (Pawley, 1981) was carried out to extract the integrated intensities and their correlations. The Pawley fit converged with a Pawley χ2 value of 2.29. From the Pawley refinement, the space group was determined to be P21/c using Bayesian statistical analysis (Markvardsen et al., 2001). The crystal structure was solved from the powder pattern in direct space with simulated annealing using the program DASH 3.1 (David et al., 2006). The H atoms were included. The starting molecular geometry was taken from the single-crystal structure of 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea, known as semustine (or MeCCNU, from methylchloroethylcyclonitrosourea) [Cambridge Structural Database (CSD; Version 5.32, updated November 2011; Allen, 2002) refcode CEMCNU10; Smith & Camerman, 1978], replacing the 4-methylcyclohexyl group with a 4-amino-2-methylpyrimidin-1-ium-5-yl group, which was constructed with the following bond lengths: C—H = 1.089, C—C alkyl = 1.530, C—C aromatic = 1.384, C—N aromatic = 1.338, C—N amine = 1.468 and N—H amine = 1.015 Å, using the program Mercury (Macrae et al., 2008). Two models were constructed, one with the protonation at N1 and one with it at the N3 position.

The nimustine molecule has seven flexible torsion angles, which were left free during the simulated annealing (rotations around single bonds, except for C—NH2 and C—CH3). In 50 simulated annealing runs, the crystal structure was found approximately ten times for both models. Both models resulted in the same chloride anion position, close to the N1 position, with N1···Cl distances typical for an N—H···Cl hydrogen bond [Reference?]. This confirmed N1 to be protonated, as shown by the NMR experiments, and gave the final indication for further development of this model.

The nimustine molecules in (I) show a zigzag arrangement along the crystallographic c axis. They are bridged by chloride anions via hydrogen bonds formed to the primary amine substituent of the pyrimidine, the secondary amine group of the urea and the protonated N atom of the pyrimidine fragment, leading to a chain-like motif along the crystallographic b axis. The three NH groups form a channel around the chloride anions along the a axis (Fig. 2). Each nimustine molecule is connected to two different chloride anions (Table 1 and Fig. 3). All hydrogen bonds are in the accepted range, as can be seen in Table 1.

Related literature top

For related literature, see: Accelrys (2003); Allen (2002); Batista et al. (2007); Bekö et al. (2010); Boultif & Louër (1991); Bruno et al. (2004); Cousins (2011); David & Sivia (2001); David et al. (2006); Hofmann (2002); Husmann et al. (2010); Johnston et al. (1966); Kamiryo et al. (2004); Kanamaru et al. (1980); Kobayashi et al. (1994); Kondo et al. (2010); Liu et al. (1991); Macrae et al. (2008); Margison & Santibáñez-Koref (2002); Markvardsen et al. (2001); Mayo et al. (1990); Nakao et al. (1972); Pawley (1981); Riand et al. (1974, 1977); Schmidt et al. (2011); Sheldrick (2008); Skipper et al. (1961); Smith & Camerman (1978); Städeli & von Philipsborn (1980); Stoe & Cie (2004).

Experimental top

Nimustine hydrochloride, (I), was purchased from Sigma–Aldrich (>98% purity) and used as received. The TG measurement was performed on a TGA 92 (SETARAM) device. About 10–15 mg of the sample was filled into corundum crucibles and measured from room temperature to 473 K at a rate of 3 K min-1 under a nitrogen atmosphere. The DSC measurement was performed on a DSC 131 (SETARAM) device in a similar fashion as for the TG measurement. For the solid-state NMR measurements, 80 mg of crystalline (I) with a natural 15N and 13C isotope abundance was used. The compound was packed in a 4 mm zirconia rotor. The measurements were performed in a Bruker 850 MHz instrument at 10 kHz spinning speed at 290 K and referenced against liquid ammonia. The 13C NMR spectrum was measured on a Bruker Avance 400 device in tubes filled with d6-DMSO (reference) and 15–20 mg of (I). The scanning electron microscopy image in Fig. 1 was recorded using an Amray 1919 ECO scanning electron microscope at 20 kV and a low vacuum of 7 Pa. The elemental analysis (CHNS) was carried out on an Elementar (vario MICRO cube) elemental analyser. About 1–4 mg of the sample was placed in a tin vessel and measured at 1423 K under a helium atmosphere with addition of oxygen during the measurement. Elemental analysis calculated for C9H14Cl2N6O2 (%): C 34.97, H 4.56, N 27.18; found: C 34.98, H 4.54, N 27.17.

Refinement top

The whole powder pattern out to 1.20 Å resolution was used for the Rietveld refinement. A total of 86 parameters were refined, namely the background (fitted using Chebyshev polynomials with 20 refinable coefficients), zero-point error, scale parameter, atomic coordinates (refined with restraints), anisotropic peak broadening, lattice parameters, a scale factor and a common isotropic displacement parameter for the C, N and O atoms. The isotropic displacement parameter of the H atoms was constrained at 1.2 times the global isotropic displacement parameter. For the two Cl atoms, individual isotropic displacement parameters were assigned. 42 suitable chemical restraints from Mogul (Bruno et al., 2004) were added (see Table 3), 18 for bond lengths, 23 for bond angles and one for the planarity of the 4-amino-2-methylpyrimidin-1-ium-5-yl group, including the aromatic C and N, the amino N and the methyl and alkyl C atoms. Finally, the H-atom positions were adjusted using the DREIDING/X6 force field (Mayo et al., 1990) within the program package Cerius2 (Accelrys, 2003). During the optimization, the coordinates of all other atoms and the lattice parameters were fixed. In the case of the methyl group attached to C2 at the pyrimidine ring, the H atoms had to be moved to a more suitable orientation with respect to the amine N1—H1 group. Bond lengths were set manually according to mean values from the CSD (aromatic C—H = 0.950 Å, methyl C—H = 0.969 Å, alkyl C—H = 0.985 Å, primary amine N—H = 0.865 Å and secondary amine N—H = 0.898 Å). The difference electron density was calculated using SHELXTL (Sheldrick, 2008). The highest residual electron density (0.41 e Å-3) is located close to the position of the chloride anion. However, a refinement of split-atom positions for Cl1 did not improve the fit. The final Rietveld plot for (I) is shown in Fig. 4.

Computing details top

Data collection: WINXPOW (Stoe & Cie, 2004); cell refinement: TOPAS Academic (Coelho, 2007); data reduction: DASH (David et al., 2006); program(s) used to solve structure: DASH (David et al., 2006); program(s) used to refine structure: TOPAS Academic (Coelho, 2007); molecular graphics: Mercury (Macrae et al., 2008); software used to prepare material for publication: publCIF (Westrip, 2010).

Figures top
[Figure 1] Fig. 1. A scanning electron microscopy image of nimustine hydrochloride, (I), showing the tablet-shaped habit of the crystals.
[Figure 2] Fig. 2. A packing diagram for (I), showing the zigzag arrangement and double-layer packing motif along the crystallographic c axis. Hydrogen bonds are represented by dashed lines.
[Figure 3] Fig. 3. Hydrogen bonds to the neighbouring molecules of (I). In order to illustrate the most important hydrogen bonds, only the Cl atoms symmetry-equivalent to Cl1 are shown. Hydrogen bonds are represented by dashed lines. All H atoms not taking part in hydrogen bonds have been omitted for clarity. [Symmetry codes: (i) -x, y + 1/2, -z + 1/2; (ii) -x, y - 1/2, -z + 1/2.]
[Figure 4] Fig. 4. The final Rietveld plot, showing the observed (black points), calculated (upper solid line) and difference (lower solid line) profiles, and tick marks (vertical lines) for (I). The change of scale at 37° in 2θ is a factor of five.
4-amino-5-({[N-(2-chloroethyl)-N-nitrosocarbamoyl]amino}methyl)- 2-methylpyrimidin-1-ium chloride top
Crystal data top
C9H14ClN6O2+·ClF(000) = 640.0
Mr = 309.16standard setting
Monoclinic, P21/cDx = 1.495 Mg m3
Hall symbol: -P 2ybcCu Kα1 radiation, λ = 1.54056 Å
a = 5.25191 (12) ŵ = 4.35 mm1
b = 12.2401 (3) ÅT = 293 K
c = 21.4088 (5) ÅParticle morphology: tablet
β = 93.2353 (7)°white
V = 1374.05 (6) Å3cylinder, 10 × 0.7 mm
Z = 4
Data collection top
Stoe STADI-P with a linear position-sensitive detector
diffractometer
Data collection mode: transmission
Radiation source: X-ray tubeScan method: step
Primary focusing, Ge 111 monochromator2θmin = 2.0°, 2θmax = 79.99°, 2θstep = 0.01°
Specimen mounting: 0.7mm glass capillary
Refinement top
Refinement on InetProfile function: modified Thompson–Cox–Hastings pseudo-Voigt [Young, R. A. (1993). The Rietveld Method, pp. 115–118. New York: Oxford University Press Inc.]
Least-squares matrix: full with fixed elements per cycle86 parameters
Rp = 0.08742 restraints
Rwp = 0.0840 constraints
Rexp = 0.061H-atom parameters not refined
RBragg = 0.012Weighting scheme based on measured s.u.'s w = 1/σ[Yobs]2
χ2 = 1.388(Δ/σ)max = 0.001
7600 data pointsBackground function: Bayesian high-pass filter with 20 terms
Excluded region(s): none
Crystal data top
C9H14ClN6O2+·ClV = 1374.05 (6) Å3
Mr = 309.16Z = 4
Monoclinic, P21/cCu Kα1 radiation, λ = 1.54056 Å
a = 5.25191 (12) ŵ = 4.35 mm1
b = 12.2401 (3) ÅT = 293 K
c = 21.4088 (5) Åcylinder, 10 × 0.7 mm
β = 93.2353 (7)°
Data collection top
Stoe STADI-P with a linear position-sensitive detector
diffractometer
Scan method: step
Specimen mounting: 0.7mm glass capillary2θmin = 2.0°, 2θmax = 79.99°, 2θstep = 0.01°
Data collection mode: transmission
Refinement top
Rp = 0.0877600 data points
Rwp = 0.08486 parameters
Rexp = 0.06142 restraints
RBragg = 0.012H-atom parameters not refined
χ2 = 1.388
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
N10.2496 (3)1.00900 (16)0.32387 (9)0.03447
H10.364351.063360.327030.04137
Cl10.6402 (4)1.18836 (15)0.30215 (9)0.04632
C20.2413 (3)0.93001 (14)0.36777 (7)0.03447
N30.0697 (3)0.84949 (12)0.36279 (9)0.03447
C40.1011 (3)0.84567 (13)0.31280 (7)0.03447
C50.0954 (3)0.92776 (12)0.26642 (6)0.03447
C60.0829 (3)1.00884 (17)0.27321 (8)0.03447
H60.089011.065550.243010.04137
C70.2813 (4)0.9303 (2)0.20896 (10)0.03447
H7A0.451780.909720.221980.04137
H7B0.297611.006000.193630.04137
N80.2153 (6)0.8603 (2)0.15774 (13)0.03447
H80.302480.798010.150690.04137
C90.0221 (5)0.88714 (18)0.12384 (12)0.03447
O100.0974 (7)0.9721 (2)0.12892 (17)0.03447
N110.0358 (4)0.80906 (18)0.07853 (12)0.03447
N120.1079 (6)0.7177 (2)0.07355 (17)0.03447
O130.0312 (6)0.6446 (3)0.03990 (16)0.03447
C140.2722 (5)0.8208 (4)0.04404 (13)0.03447
H14A0.363960.750540.044520.04137
H14B0.388460.874260.064900.04137
C150.1973 (5)0.8492 (4)0.02069 (13)0.03447
H15A0.093940.793360.043560.04137
H15B0.098480.917440.019120.04137
Cl160.4879 (4)0.88295 (15)0.06071 (9)0.06129
C210.4272 (5)0.9340 (2)0.42268 (12)0.03447
H21A0.398370.872510.449930.04137
H21B0.599020.930440.408550.04137
H21C0.405401.001540.445390.04137
N410.2708 (4)0.76506 (19)0.30853 (12)0.03447
H41A0.374350.759750.275800.04137
H41B0.273870.716820.337990.04137
Geometric parameters (Å, º) top
N1—H10.898C9—O101.216 (4)
N1—C21.351 (3)C9—N111.407 (3)
N1—C61.355 (2)N11—N121.350 (4)
C2—N31.336 (2)N11—C141.487 (4)
C2—C211.486 (3)N12—O131.231 (5)
N3—C41.358 (2)C14—H14A0.985
C4—C51.414 (2)C14—H14B0.985
C4—N411.330 (3)C14—C151.461 (4)
C5—C61.367 (3)C15—H15A0.985
C5—C71.527 (3)C15—H15B0.985
C6—H60.950C15—Cl161.839 (4)
C7—H7A0.986C21—H21A0.969
C7—H7B0.985C21—H21B0.969
C7—N81.449 (4)C21—H21C0.970
N8—H80.898N41—H41A0.865
N8—C91.322 (4)N41—H41B0.865
H1—N1—C2121.7O10—C9—N11120.8 (3)
H1—N1—C6117.5C9—N11—N12118.4 (2)
C2—N1—C6120.7 (2)C9—N11—C14119.7 (2)
N1—C2—N3121.4 (2)N12—N11—C14121.3 (2)
N1—C2—C21118.8 (2)N11—N12—O13116.7 (3)
N3—C2—C21119.8 (2)N11—C14—H14A109.4
C2—N3—C4120.1 (2)N11—C14—H14B110.6
N3—C4—C5119.3 (1)N11—C14—C15107.8 (3)
N3—C4—N41119.4 (2)H14A—C14—H14B106.6
C5—C4—N41121.3 (2)H14A—C14—C15108.8
C4—C5—C6118.9 (1)H14B—C14—C15113.5
C4—C5—C7122.8 (1)C14—C15—H15A114.7
C6—C5—C7118.3 (2)C14—C15—H15B106.5
N1—C6—C5119.6 (2)C14—C15—Cl16108.0 (2)
N1—C6—H6119.9H15A—C15—H15B109.2
C5—C6—H6120.5H15A—C15—Cl16111.9
C5—C7—H7A108.5H15B—C15—Cl16106.1
C5—C7—H7B109.1C2—C21—H21A109.5
C5—C7—N8115.4 (2)C2—C21—H21B109.5
H7A—C7—H7B105.7C2—C21—H21C109.5
H7A—C7—N8108.8H21A—C21—H21B109.5
H7B—C7—N8108.9H21A—C21—H21C109.5
C7—N8—H8119.2H21B—C21—H21C109.4
C7—N8—C9119.5 (2)C4—N41—H41A120.0
H8—N8—C9121.2C4—N41—H41B119.8
N8—C9—O10124.9 (3)H41A—N41—H41B120.2
N8—C9—N11114.3 (2)
H1—N1—C2—N3179.9C6—C5—C7—H7B24.6
H1—N1—C2—C210.1C6—C5—C7—N898.3 (2)
C6—N1—C2—N30.1 (3)C5—C7—N8—H8105.1
C6—N1—C2—C21179.7 (2)C5—C7—N8—C972.3 (3)
H1—N1—C6—C5179.9H7A—C7—N8—H817.1
H1—N1—C6—H60.9H7A—C7—N8—C9165.6
C2—N1—C6—C50.1 (3)H7B—C7—N8—H8131.8
C2—N1—C6—H6179.0H7B—C7—N8—C950.8
N1—C2—N3—C40.1 (3)C7—N8—C9—O106.0 (4)
C21—C2—N3—C4179.8 (2)C7—N8—C9—N11175.5 (2)
N1—C2—C21—H21A180.0H8—N8—C9—O10176.7
N1—C2—C21—H21B60.0H8—N8—C9—N111.9
N1—C2—C21—H21C60.0N8—C9—N11—N120.7 (4)
N3—C2—C21—H21A0.3N8—C9—N11—C14170.6 (3)
N3—C2—C21—H21B120.3O10—C9—N11—N12178.0 (3)
N3—C2—C21—H21C119.7O10—C9—N11—C1410.8 (4)
C2—N3—C4—C50.2 (2)C9—N11—N12—O13170.1 (3)
C2—N3—C4—N41179.9 (2)C14—N11—N12—O131.0 (4)
N3—C4—C5—C60.1 (2)C9—N11—C14—H14A131.7
N3—C4—C5—C7179.6 (2)C9—N11—C14—H14B14.6
N41—C4—C5—C6179.9 (2)C9—N11—C14—C15110.0 (3)
N41—C4—C5—C70.2 (3)N12—N11—C14—H14A39.3
N3—C4—N41—H41A176.3N12—N11—C14—H14B156.4
N3—C4—N41—H41B1.6N12—N11—C14—C1578.9 (3)
C5—C4—N41—H41A3.9N11—C14—C15—H15A62.4
C5—C4—N41—H41B178.1N11—C14—C15—H15B58.4
C4—C5—C6—N10.0 (3)N11—C14—C15—Cl16172.0 (2)
C4—C5—C6—H6179.1H14A—C14—C15—H15A56.2
C7—C5—C6—N1179.7 (2)H14A—C14—C15—H15B177.0
C7—C5—C6—H60.7H14A—C14—C15—Cl1669.4
C4—C5—C7—H7A40.4H14B—C14—C15—H15A174.6
C4—C5—C7—H7B155.1H14B—C14—C15—H15B64.5
C4—C5—C7—N882.0 (2)H14B—C14—C15—Cl1649.1
C6—C5—C7—H7A139.3
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N1—H1···Cl10.902.193.058 (3)161.5
N8—H8···Cl1ii0.902.483.22 (3)139.4
N41—H41A···Cl1ii0.872.293.22 (3)160.8

Experimental details

Crystal data
Chemical formulaC9H14ClN6O2+·Cl
Mr309.16
Crystal system, space groupMonoclinic, P21/c
Temperature (K)293
a, b, c (Å)5.25191 (12), 12.2401 (3), 21.4088 (5)
β (°) 93.2353 (7)
V3)1374.05 (6)
Z4
Radiation typeCu Kα1, λ = 1.54056 Å
µ (mm1)4.35
Specimen shape, size (mm)Cylinder, 10 × 0.7
Data collection
DiffractometerStoe STADI-P with a linear position-sensitive detector
diffractometer
Specimen mounting0.7mm glass capillary
Data collection modeTransmission
Scan methodStep
2θ values (°)2θmin = 2.0 2θmax = 79.99 2θstep = 0.01
Refinement
R factors and goodness of fitRp = 0.087, Rwp = 0.084, Rexp = 0.061, RBragg = 0.012, χ2 = 1.388
No. of data points7600
No. of parameters86
No. of restraints42
H-atom treatmentH-atom parameters not refined

Computer programs: WINXPOW (Stoe & Cie, 2004), TOPAS Academic (Coelho, 2007), DASH (David et al., 2006), Mercury (Macrae et al., 2008), publCIF (Westrip, 2010).

Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N1—H1···Cl10.902.193.058 (3)161.5
N8—H8···Cl1ii0.902.483.22 (3)139.4
N41—H41A···Cl1ii0.872.293.22 (3)160.8
Comparison of the 13C solid-state and 13C liquid NMR measurements of (I) and the predicted values top
AtomExperimental valuesPredicted values
Solid stateIn d6-DMSONeutralN1—CH3aN3—CH3a
C2121.721.324.519.923.2
C739.037.941.240.235.3
C1440.139.940.340.340.3
C1542.040.338.938.938.9
C5110.9112.1112.7108.0136.0
C6148.4141.8158.9145.6121.2
C9153.56153.9153.0153.0153.0
C2161.1160.9163.9169.6164.0
C4164.7163.5161.4164.0164.5
Note: (a) see Comment.
Restraints for bond lengths and angles, and flatten and refined values from the refinement of (I) top
BondRestraint valueRefined valueAngleRestraint valueRefined value
N1—C21.3431.351 (3)C2—N1—C6118.4120.7 (2)
N1—C61.3381.355 (2)N1—C2—N3121.6121.4 (2)
C2—N31.3131.336 (2)N1—C2—C21119.2118.8 (2)
C2—C211.4861.486 (3)N3—C2—C21119.2119.8 (2)
N3—C41.3381.358 (2)C2—N3—C4120.0120.1 (2)
C4—C51.3841.414 (2)N3—C4—C5120.0119.3 (1)
C4—N411.3351.330 (3)N3—C4—N41120.0119.4 (2)
C5—C61.3841.367 (3)C5—C4—N41120.0121.3 (2)
C5—C71.5301.527 (3)C4—C5—C6120.0118.9 (1)
C7—N81.4621.449 (4)C4—C5—C7120.0122.8 (1)
N8—C91.3241.322 (4)C6—C5—C7120.0118.3 (2)
C9—O101.2131.216 (4)N1—C6—C5120.0119.6 (2)
C9—N111.3811.407 (3)C5—C7—N8112.8115.4 (2)
N11—N121.3331.350 (4)C7—N8—C9120.6119.5 (2)
N11—C141.4811.487 (4)N8—C9—O10126.6124.9 (3)
N12—O131.2171.231 (5)N8—C9—N11114.5114.3 (2)
C14—C151.4461.461 (4)O10—C9—N11118.9120.8 (3)
C15—Cl161.8311.839 (4)C9—N11—N12118.3118.4 (2)
C9—N11—C14119.9119.7 (2)
N12—N11—C14121.8121.3 (2)
N11—N12—O13114.7116.7 (3)
N11—C14—C15108.8107.8 (3)
C14—C15—Cl16106.5108.0 (2)
Planar restraint*
N1, C2, C21, N3, C4, C41, C5, C7, C60.04.6 (2)
(*) see TOPAS manual (Coelho, 2007) for formulae.
 

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