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In the title compound, di­methyl­({5-[2-(1-methyl­amino-2-nitro­eth­enyl­amino)­ethyl­thio­methyl]-2-furyl}­methyl)­ammon­ium chloride, C13H23N4O3S+·­Cl-, protonation occurs at the di­methyl­amino N atom. The ranitidine mol­ecule adopts an eclipsed conformation. Bond lengths indicate extensive electron delocalization in the N,N'-di­methyl-2-nitro-1,1-ethenedi­amine system of the mol­ecule. The nitro and methyl­amino groups are trans across the side chain C=C double bond, while the ethyl­amino and nitro groups are cis. The Cl- ions link mol­ecules through hydrogen bonds.

Supporting information

cif

Crystallographic Information File (CIF) https://doi.org/10.1107/S010827010000785X/fg1581sup1.cif
Contains datablocks I, global

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S010827010000785X/fg1581Isup2.hkl
Contains datablock I

CCDC reference: 150368

Comment top

Ranitidine, an H2 receptor antagonist, is a high potency inhibitor of gastric acid secretion, and is used in the treatment of peptic ulcers and related gastro-intestinal disorders (Brogden et al., 1982). The crystal structure of ranitidine hydrogen oxalate (Kojić-Prodić et al., 1982) and ranitidine hydrochloride (Ishida et al., 1990) have previously been reported. Here we report the crystal structure of ranitidine hydrochloride, (I), in a different and as yet unpublished crystal form, and compare it with the published structures. \sch

The molecular structure is presented in Fig. 1. The enamine portion of the molecule can exist in two possible configurations with respect to the C15C18 double bond: E and Z arrangements, in which the methylamino and nitro substituents are cis and trans to each other, respectively. The Z configuration is adopted in this structure, as opposed to the E arrangement in the crystal structure of ranitidine hydrogen oxalate, and both forms, disordered, in the previous structure of ranitidine hydrochloride. An equimolar mixture of E/Z enamine isomers has been reported in solution (Cholerton et al., 1984); interconversion presumably is facilitated by Π-electron delocalization over the enamine system. Thus the C15C18 bond in this structure is lengthened to 1.425 (3) Å, and the single bonds C15—N14, C15—N16 and C18—N19 are shortened to 1.335 (3), 1.332 (3) and 1.349 (3) Å, respectively. Similarly, the two N—O distances in the nitro group, 1.270 (2) and 1.284 (2) Å, indicate electron delocalization, even though O20 takes part in a strong hydrogen bond and O21 is involved in a weak C—H···O interaction. The same phenomena were observed in ranitidine hydrogen oxalate, whereas in the other crystal form of ranitidine hydrohloride the disordered structure was interpreted in terms of electronically localized E and Z forms with distinct double and single bond lengths. Bond distances and angles in the rest of the molecule agree well with commonly accepted values. The least-squares plane through the nine atoms involved in the enamine moiety (C13 to O21) indicate they are planar, the r.m.s. deviation of the atoms being 0.035 (2) Å with maximum of 0.069 (2) Å for O20 and minimum of 0.001 (1) Å for C13. The ranitidine molecule, as a whole, adopts an eclipsed conformation (i.e. neither fully folded nor fully extended) similar to that of disordered ranitidine hydrochloride. Rotation of the group of atoms C13 through O21 by 114° about the C12—C13 bond results in conformational coincidence of this structure with the Z isomer in the disordered ranitidine HCl structure (Fig. 2) (primed set of atoms in Ishida et al. (1990)]. In contrast, ranitidine hydrogen oxalate was found to have a folded conformation. An open conformation is reportedly the one that is most likely to exist in solution (Sega et al., 1982; Gaggelli et al., 1988).

An intramolecular hydrogen bond from N14 to O20 (see Table 1) helps to stabilize the planarity of the 2-ethylamino-2-methylamino-1-nitroethylene moiety. Such an interaction is present in all of the ranitidine crystal structures and is the reason for E/Z configurations being favored in the solid state; in aqueous solution, with water available as a hydrogen-bond donor, rotation about the C15—C18 bond occurs readily (Cholerton et al., 1984). Rotation also occurs in other solvents: attempted crystallization of the present material in acetonitrile, the crystallization solvent used in the previous ranitidine hydrochloride structure determination, resulted in our getting crystals of that crystal form.

The furanyl ring is almost perfectly planar and forms an angle of 69.5 (1)° with the plane through the 2-ethylamino-2-methylamino-1-nitroethylene moiety atoms (C13 through O21), close to the value 63.4 (1)° in disordered ranitidine hydrochloride, and 75.2 (1)° in ranitidine hydrogen oxalate. In the crystal structure, the molecules are held together through hydrogen bonds from N atoms N7 and N16 to two different Cl anions (Table 1) forming one-dimensional infinite chains of molecules running perpendicular to the b axis along the base vector (101), in a head-to-tail fashion. The chains of molecules are held together by van der Waals interactions and weak hydrogen bonds of the type C—H···O (Steiner, 1997; Desiraju, 1996). The existence of this type of carbon-hydrogen bonds is facilitated by the presence of the adjacent activating groups NO2 and N+, and Cl ions. The chloride ion is coordinated by four hydrogen atoms (H7, H16, H6B and H8A) forming a tetrahedron with almost perfect geometry.

Experimental top

The crystals were obtained as colourless prisms by solvent evaporation from a methanol-ethyl acetate mixture.

Refinement top

Ranitidine HCl crystallized in the monoclinic system; space group P21/n from the systematic absences. Hydrogen atoms, except for H7 at N7 which was found from a difference map, were calculated geometrically. During the refinement H atoms were treated isotropically and were riding on parent atoms (at distances 0.93 to 0.98 Å) except for H7 which had its positional and isotropic temperature parameters refined independently.

Computing details top

Data collection: Nonius KappaCCD Server Software; cell refinement: DENZO-SMN (Otwinowski & Minor, 1997); data reduction: DENZO-SMN; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEP-3 for Windows (Farrugia, 1998); software used to prepare material for publication: SHELXL97.

Figures top
[Figure 1] Fig. 1. ORTEP-3 (Farrugia, 1997) view of the molecule showing 50% probability displacement elipsoids. H atoms are drawn as small circles of arbitrary radius.
[Figure 2] Fig. 2. Superposition of the ranitidine hydrochloride (small circles) and the Z isomer in the disordered structure of ranitidine hydrochloride (large circles) after 114° rotation of the present structure about the C12—C13 bond.
N-(2-{[5-(Dimethylaminomethyl)-2-furanyl]methylthio}ethyl)-N' -methyl-2-nitro-1,1-ethanediamine hydrochloride top
Crystal data top
C13H23N4O3S+·ClF(000) = 744
Mr = 350.86Dx = 1.331 Mg m3
Monoclinic, P21/nMo Kα radiation, λ = 0.71073 Å
a = 12.1918 (6) ÅCell parameters from all reflections reflections
b = 6.5318 (3) ŵ = 0.35 mm1
c = 22.0382 (8) ÅT = 100 K
β = 93.985 (3)°Prism, colourless
V = 1750.76 (13) Å30.45 × 0.25 × 0.23 mm
Z = 4
Data collection top
Nonius Kappa CCD
diffractometer
2680 reflections with I > 2σ(I)
Radiation source: rotating-anodeRint = 0.000
Graphite monochromatorθmax = 27.5°, θmin = 3.1°
ω rotation scansh = 015
3994 measured reflectionsk = 08
3994 independent reflectionsl = 2828
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)] = 0.042Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.130H atoms treated by a mixture of independent and constrained refinement
S = 0.80 w = 1/[σ2(Fo2) + (0.0488P)2]
where P = (Fo2 + 2Fc2)/3
3994 reflections(Δ/σ)max < 0.001
210 parametersΔρmax = 0.29 e Å3
0 restraintsΔρmin = 0.27 e Å3
Crystal data top
C13H23N4O3S+·ClV = 1750.76 (13) Å3
Mr = 350.86Z = 4
Monoclinic, P21/nMo Kα radiation
a = 12.1918 (6) ŵ = 0.35 mm1
b = 6.5318 (3) ÅT = 100 K
c = 22.0382 (8) Å0.45 × 0.25 × 0.23 mm
β = 93.985 (3)°
Data collection top
Nonius Kappa CCD
diffractometer
2680 reflections with I > 2σ(I)
3994 measured reflectionsRint = 0.000
3994 independent reflections
Refinement top
R[F2 > 2σ(F2)] = 0.0420 restraints
wR(F2) = 0.130H atoms treated by a mixture of independent and constrained refinement
S = 0.80Δρmax = 0.29 e Å3
3994 reflectionsΔρmin = 0.27 e Å3
210 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
Cl10.40889 (4)0.24606 (8)0.03956 (2)0.02621 (16)
O10.49639 (13)0.0598 (2)0.20041 (6)0.0242 (3)
C20.48856 (19)0.0926 (3)0.26160 (9)0.0248 (5)
C30.3902 (2)0.0294 (4)0.27828 (11)0.0324 (6)
H30.36510.03480.31720.0330 (15)*
C40.3312 (2)0.0481 (4)0.22433 (11)0.0316 (5)
H40.26030.10150.22150.0330 (15)*
C50.39872 (19)0.0284 (3)0.17855 (10)0.0248 (5)
C60.38943 (18)0.0802 (3)0.11325 (10)0.0253 (5)
H6A0.31220.08670.09940.0330 (15)*
H6B0.42300.02800.09080.0330 (15)*
N70.44348 (15)0.2813 (3)0.09936 (9)0.0249 (4)
H70.438 (3)0.281 (5)0.0564 (15)0.062 (10)*
C80.56184 (19)0.2861 (4)0.12042 (11)0.0311 (5)
H8A0.5960 (6)0.409 (2)0.1044 (6)0.0330 (15)*
H8B0.5983 (6)0.164 (2)0.1058 (6)0.0330 (15)*
H8C0.5692 (2)0.289 (2)0.1650 (6)0.0330 (15)*
C90.3838 (2)0.4605 (4)0.12235 (11)0.0310 (5)
H9A0.3851 (10)0.4542 (12)0.1660 (7)0.0330 (15)*
H9B0.3089 (12)0.4586 (13)0.1055 (6)0.0330 (15)*
H9C0.4188 (9)0.5846 (19)0.1104 (6)0.0330 (15)*
C100.58691 (19)0.1792 (4)0.29512 (10)0.0277 (5)
H10A0.60650.30580.27550.0330 (15)*
H10B0.56860.21270.33610.0330 (15)*
S110.70691 (5)0.00941 (9)0.29966 (3)0.02977 (17)
C120.6502 (2)0.2250 (3)0.32782 (10)0.0261 (5)
H12A0.70460.33270.32610.0330 (15)*
H12B0.58690.26390.30120.0330 (15)*
C130.61514 (19)0.2095 (3)0.39289 (9)0.0255 (5)
H13A0.56700.09240.39620.0330 (15)*
H13B0.67950.18880.42060.0330 (15)*
N140.55837 (15)0.3938 (3)0.40989 (8)0.0238 (4)
H140.48990.40210.39780.0330 (15)*
C150.60016 (18)0.5520 (3)0.44215 (9)0.0218 (5)
N160.70553 (15)0.5547 (3)0.46272 (8)0.0245 (4)
H160.74610.45220.45430.0330 (15)*
C170.75598 (19)0.7213 (3)0.49855 (10)0.0265 (5)
H17A0.7435 (10)0.8480 (19)0.4773 (4)0.0330 (15)*
H17B0.8334 (11)0.6976 (12)0.5049 (6)0.0330 (15)*
H17C0.7242 (10)0.7281 (14)0.5370 (6)0.0330 (15)*
C180.53295 (17)0.7231 (3)0.45492 (9)0.0219 (5)
H180.56370.82590.47990.0330 (15)*
N190.42754 (16)0.7450 (3)0.43301 (8)0.0245 (4)
O200.37837 (13)0.6112 (3)0.39817 (7)0.0304 (4)
O210.37558 (14)0.9062 (3)0.44580 (8)0.0344 (4)
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
Cl10.0270 (3)0.0248 (3)0.0266 (3)0.0053 (2)0.0002 (2)0.0041 (2)
O10.0268 (9)0.0239 (8)0.0216 (7)0.0027 (6)0.0006 (6)0.0020 (6)
C20.0321 (13)0.0204 (11)0.0220 (11)0.0016 (10)0.0017 (9)0.0028 (9)
C30.0306 (14)0.0376 (14)0.0301 (12)0.0005 (11)0.0088 (10)0.0073 (10)
C40.0214 (12)0.0365 (14)0.0369 (13)0.0018 (10)0.0031 (10)0.0073 (11)
C50.0218 (12)0.0219 (11)0.0302 (11)0.0012 (9)0.0015 (9)0.0045 (9)
C60.0225 (12)0.0244 (11)0.0285 (11)0.0038 (9)0.0018 (9)0.0028 (9)
N70.0224 (10)0.0273 (10)0.0247 (10)0.0026 (8)0.0004 (7)0.0046 (8)
C80.0224 (12)0.0379 (14)0.0324 (12)0.0065 (10)0.0020 (9)0.0111 (10)
C90.0311 (14)0.0274 (12)0.0346 (12)0.0006 (10)0.0038 (10)0.0058 (10)
C100.0352 (14)0.0231 (11)0.0248 (11)0.0052 (10)0.0014 (9)0.0030 (9)
S110.0258 (3)0.0331 (3)0.0304 (3)0.0063 (2)0.0020 (2)0.0058 (2)
C120.0281 (12)0.0245 (12)0.0261 (11)0.0020 (9)0.0043 (9)0.0007 (9)
C130.0318 (13)0.0205 (11)0.0242 (11)0.0019 (9)0.0020 (9)0.0023 (9)
N140.0221 (10)0.0223 (9)0.0271 (9)0.0001 (8)0.0023 (7)0.0014 (7)
C150.0257 (12)0.0224 (11)0.0177 (10)0.0002 (9)0.0046 (8)0.0043 (8)
N160.0247 (10)0.0208 (9)0.0279 (9)0.0051 (8)0.0010 (8)0.0020 (7)
C170.0209 (12)0.0263 (12)0.0315 (12)0.0032 (9)0.0027 (9)0.0040 (9)
C180.0230 (12)0.0227 (11)0.0201 (10)0.0012 (9)0.0017 (8)0.0017 (8)
N190.0236 (10)0.0256 (10)0.0246 (9)0.0027 (8)0.0032 (7)0.0005 (8)
O200.0250 (9)0.0331 (9)0.0326 (9)0.0011 (7)0.0009 (7)0.0056 (7)
O210.0284 (9)0.0310 (9)0.0437 (10)0.0111 (8)0.0007 (7)0.0067 (8)
Geometric parameters (Å, º) top
O1—C21.375 (2)C10—H10A0.9700
O1—C51.379 (3)C10—H10B0.9700
C2—C31.344 (3)S11—C121.807 (2)
C2—C101.477 (3)C12—C131.528 (3)
C3—C41.438 (3)C12—H12A0.9700
C3—H30.9300C12—H12B0.9700
C4—C51.352 (3)C13—N141.451 (3)
C4—H40.9300C13—H13A0.9700
C5—C61.475 (3)C13—H13B0.9700
C6—N71.511 (3)N14—C151.335 (3)
C6—H6A0.9700N14—H140.8600
C6—H6B0.9700C15—N161.332 (3)
N7—C91.485 (3)C15—C181.425 (3)
N7—C81.485 (3)N16—C171.456 (3)
N7—H70.95 (3)N16—H160.8600
C8—H8A0.9797C17—H17A0.9574
C8—H8B0.9797C17—H17B0.9574
C8—H8C0.9797C17—H17C0.9574
C9—H9A0.9614C18—N191.349 (3)
C9—H9B0.9614C18—H180.9300
C9—H9C0.9614N19—O211.270 (2)
C10—S111.833 (2)N19—O201.284 (2)
C2—O1—C5106.88 (16)S11—C10—H10A108.7
C3—C2—O1110.16 (19)C2—C10—H10B108.7
C3—C2—C10133.6 (2)S11—C10—H10B108.7
O1—C2—C10116.16 (19)H10A—C10—H10B107.6
C2—C3—C4106.6 (2)C12—S11—C10102.03 (11)
C2—C3—H3126.7C13—C12—S11113.89 (15)
C4—C3—H3126.7C13—C12—H12A108.8
C5—C4—C3106.7 (2)S11—C12—H12A108.8
C5—C4—H4126.6C13—C12—H12B108.8
C3—C4—H4126.6S11—C12—H12B108.8
C4—C5—O1109.57 (19)H12A—C12—H12B107.7
C4—C5—C6134.2 (2)N14—C13—C12110.92 (17)
O1—C5—C6116.26 (19)N14—C13—H13A109.5
C5—C6—N7113.09 (18)C12—C13—H13A109.5
C5—C6—H6A109.0N14—C13—H13B109.5
N7—C6—H6A109.0C12—C13—H13B109.5
C5—C6—H6B109.0H13A—C13—H13B108.0
N7—C6—H6B109.0C15—N14—C13127.48 (19)
H6A—C6—H6B107.8C15—N14—H14116.3
C9—N7—C8111.42 (19)C13—N14—H14116.3
C9—N7—C6112.65 (17)N16—C15—N14121.0 (2)
C8—N7—C6112.52 (18)N16—C15—C18118.4 (2)
C9—N7—H7110 (2)N14—C15—C18120.6 (2)
C8—N7—H7108 (2)C15—N16—C17123.76 (19)
C6—N7—H7101.5 (19)C15—N16—H16118.1
N7—C8—H8A109.5C17—N16—H16118.1
N7—C8—H8B109.5N16—C17—H17A109.5
H8A—C8—H8B109.5N16—C17—H17B109.5
N7—C8—H8C109.5H17A—C17—H17B109.5
H8A—C8—H8C109.5N16—C17—H17C109.5
H8B—C8—H8C109.5H17A—C17—H17C109.5
N7—C9—H9A109.5H17B—C17—H17C109.5
N7—C9—H9B109.5N19—C18—C15124.0 (2)
H9A—C9—H9B109.5N19—C18—H18118.0
N7—C9—H9C109.5C15—C18—H18118.0
H9A—C9—H9C109.5O21—N19—O20118.51 (18)
H9B—C9—H9C109.5O21—N19—C18119.08 (19)
C2—C10—S11114.36 (16)O20—N19—C18122.38 (18)
C2—C10—H10A108.7
C5—O1—C2—C30.3 (2)O1—C2—C10—S1166.0 (2)
C5—O1—C2—C10177.59 (18)C2—C10—S11—C1251.41 (18)
O1—C2—C3—C40.2 (3)C10—S11—C12—C1367.15 (18)
C10—C2—C3—C4177.6 (2)S11—C12—C13—N14173.02 (15)
C2—C3—C4—C50.6 (3)C12—C13—N14—C1598.5 (2)
C3—C4—C5—O10.8 (3)C13—N14—C15—N160.4 (3)
C3—C4—C5—C6179.0 (2)C13—N14—C15—C18179.86 (19)
C2—O1—C5—C40.7 (2)N14—C15—N16—C17179.44 (19)
C2—O1—C5—C6179.14 (18)C18—C15—N16—C171.1 (3)
C4—C5—C6—N798.0 (3)N16—C15—C18—N19175.1 (2)
O1—C5—C6—N781.8 (2)N14—C15—C18—N194.4 (3)
C5—C6—N7—C969.5 (2)C15—C18—N19—O21178.11 (18)
C5—C6—N7—C857.4 (3)C15—C18—N19—O200.1 (3)
C3—C2—C10—S11111.2 (3)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N7—H7···Cl10.94 (3)2.13 (3)3.070 (2)172 (3)
N14—H14···O200.861.932.612 (3)135
N16—H16···Cl1i0.862.373.166 (2)155
C6—H6A···O20ii0.972.333.263 (3)160
C6—H6B···Cl1iii0.972.803.712 (2)158
C8—H8A···Cl1iv0.982.663.568 (3)153
C9—H9B···O21ii0.962.473.424 (3)171
C18—H18···O21v0.932.473.399 (3)173
Symmetry codes: (i) x+1/2, y+1/2, z+1/2; (ii) x+1/2, y1/2, z+1/2; (iii) x+1, y, z; (iv) x+1, y+1, z; (v) x+1, y+2, z+1.

Experimental details

Crystal data
Chemical formulaC13H23N4O3S+·Cl
Mr350.86
Crystal system, space groupMonoclinic, P21/n
Temperature (K)100
a, b, c (Å)12.1918 (6), 6.5318 (3), 22.0382 (8)
β (°) 93.985 (3)
V3)1750.76 (13)
Z4
Radiation typeMo Kα
µ (mm1)0.35
Crystal size (mm)0.45 × 0.25 × 0.23
Data collection
DiffractometerNonius Kappa CCD
diffractometer
Absorption correction
No. of measured, independent and
observed [I > 2σ(I)] reflections
3994, 3994, 2680
Rint0.000
(sin θ/λ)max1)0.649
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.042, 0.130, 0.80
No. of reflections3994
No. of parameters210
H-atom treatmentH atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å3)0.29, 0.27

Computer programs: Nonius KappaCCD Server Software, DENZO-SMN (Otwinowski & Minor, 1997), DENZO-SMN, SHELXS97 (Sheldrick, 1997), SHELXL97 (Sheldrick, 1997), ORTEP-3 for Windows (Farrugia, 1998), SHELXL97.

Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N7—H7···Cl10.94 (3)2.13 (3)3.070 (2)172 (3)
N14—H14···O200.861.932.612 (3)135
N16—H16···Cl1i0.862.373.166 (2)155
C6—H6A···O20ii0.972.333.263 (3)160
C6—H6B···Cl1iii0.972.803.712 (2)158
C8—H8A···Cl1iv0.982.663.568 (3)153
C9—H9B···O21ii0.962.473.424 (3)171
C18—H18···O21v0.932.473.399 (3)173
Symmetry codes: (i) x+1/2, y+1/2, z+1/2; (ii) x+1/2, y1/2, z+1/2; (iii) x+1, y, z; (iv) x+1, y+1, z; (v) x+1, y+2, z+1.
 

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