2′-Deoxy-2′,2′-di­fluoro­cytidine mono­hydro­chloride (Gemcitabine hydro­chloride)

Sivalakshmidevi, A.; Vyas, K.; Om Reddy, G.; Sivaram, S.D.V.N.; Swamy, P.V.; Puranik, R.; Sairam, P.

doi:10.1107/S1600536803018816

2′-Deoxy-2′,2′-difluorocytidine monohydrochloride (Gemcitabine hydrochloride)

A. Sivalakshmidevi, K. Vyas, G. Om Reddy, S. D. V. N. Sivaram, P. V. Swamy, R. Puranik and P. Sairam

Gemcitabine hydrochloride (2′-deoxy-2′,2′-difluorocytidine hydrochloride), C₉H₁₂N₃F₂O₄⁺·Cl⁻, is a β-nucleoside that is of pharmaceutical interest as an antitumor agent. The N atom of the cytidine ring is protonated due to salt formation. The sugar residue adopts a C3′-endo and C4′-exo conformation. In the asymmetric unit, gemcitabine cations and chloride ions are linked by N—H

Cl hydrogen bonds. In the crystal structure, screw-related gemcitabine cations are linked by O—H

O hydrogen bonds to form molecular columns along the c axis and adjacent columns are interlinked by N—H

Cl and O—H

Cl hydrogen bonds.

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Supporting information

	Crystallographic Information File (CIF) https://doi.org/10.1107/S1600536803018816/ci6255sup1.cif Contains datablocks global, I
	Structure factor file (CIF format) https://doi.org/10.1107/S1600536803018816/ci6255Isup2.hkl Contains datablock I

CCDC reference: 225693

checkCIF report

Key indicators

Single-crystal X-ray study
T = 298 K
Mean (C-C) = 0.005 Å
R factor = 0.060
wR factor = 0.060
Data-to-parameter ratio = 10.9

checkCIF/PLATON results

No syntax errors found



Alert level A
PLAT029_ALERT_3_A _diffrn_measured_fraction_theta_full Low .......       0.96
PLAT052_ALERT_1_A (Proper) Absorption Correction Method Missing ..          ?

Alert level C
PLAT057_ALERT_3_C Correction for Absorption Required   RT(exp)   =       1.11
PLAT340_ALERT_3_C Low Bond Precision on C-C bonds (x 1000) Ang ...          5
PLAT431_ALERT_2_C Short Inter HL..A Contact  F1     ..  O2       =       2.92 Ang.
PLAT790_ALERT_4_C Centre of Gravity not Within Unit Cell: Resd.  #          2
              Cl

Alert level G
REFLT03_ALERT_4_G Please check that the estimate of the number of Friedel pairs is
            correct. If it is not, please give the correct count in the
            _publ_section_exptl_refinement section of the submitted CIF.
           From the CIF: _diffrn_reflns_theta_max           67.86
           From the CIF: _reflns_number_total               2108
           Count of symmetry unique reflns         1283
           Completeness (_total/calc)            164.30%
           TEST3: Check Friedels for noncentro structure
           Estimate of Friedel pairs measured       825
           Fraction of Friedel pairs measured     0.643
           Are heavy atom types Z>Si present          yes

   2 ALERT level A = In general: serious problem
   0 ALERT level B = Potentially serious problem
   4 ALERT level C = Check and explain
   1 ALERT level G = General alerts; check

   1 ALERT type 1 CIF construction/syntax error, inconsistent or missing data
   1 ALERT type 2 Indicator that the structure model may be wrong or deficient
   3 ALERT type 3 Indicator that the structure quality may be low
   2 ALERT type 4 Improvement, methodology, query or suggestion

Computing details top

Data collection: MSC/AFC Diffractometer Control Software (Molecular Structure Corporation, 1994); cell refinement: MSC/AFC Diffractometer Control Software; data reduction: TEXSAN (Molecular Structure Corporation, 1995); program(s) used to solve structure: SIR92 (Altomare et al., 1993); program(s) used to refine structure: CRYSTALS (Watkin et al., 1996); molecular graphics: CrystalStructure (Rigaku/MSC, 2003); software used to prepare material for publication: CrystalStructure.

2'-deoxy-2',2'-difluorocytidine monohydrochloride top

Crystal data top

C₉H₁₂F₂N₃O₄⁺·Cl⁻	F(000) = 616.00
M_r = 299.66	D_x = 1.659 Mg m⁻³
Orthorhombic, P2₁2₁2₁	Cu Kα radiation, λ = 1.5418 Å
Hall symbol: P 2ac 2ab	Cell parameters from 25 reflections
a = 11.4680 (7) Å	θ = 22.6–24.8°
b = 15.5987 (9) Å	µ = 3.27 mm⁻¹
c = 6.706 (2) Å	T = 298 K
V = 1199.6 (4) Å³	Block, colourless
Z = 4	0.50 × 0.50 × 0.40 mm

Data collection top

Rigaku AFC-7S diffractometer	2032 reflections with F² > 2σ(F²)
Radiation source: X-ray tube	R_int = 0.028
Graphite monochromator	θ_max = 67.9°, θ_min = 2.8°
ω–2θ scans	h = −13→13
Absorption correction: ψ scan (North et al., 1968)	k = −18→18
T_min = 0.175, T_max = 0.271	l = −7→7
2540 measured reflections	3 standard reflections every 150 reflections
2083 independent reflections	intensity decay: 1.3%

Refinement top

Refinement on F	(Δ/σ)_max = 0.041
R[F² > 2σ(F²)] = 0.060	Δρ_max = 0.77 e Å⁻³
wR(F²) = 0.060	Δρ_min = −0.57 e Å⁻³
S = 1.13	Extinction correction: Larson (1970), eq. 22
2082 reflections	Extinction coefficient: 110 (9)
191 parameters	Absolute structure: Flack (1983), 828 Friedel pairs
H atoms treated by a mixture of independent and constrained refinement	Absolute structure parameter: 0.00 (3)
Chebychev polynomial with 3 parameters (Carruthers & Watkin, 1979): 2.0710, 1.3167 and 0.0135

Special details top

Experimental. The scan width was (0.94 + 0.14tanθ)° with an ω scan speed of 16° per minute (up to 5 scans to achieve I/σ(I) > 15). Stationary background counts were recorded at each end of the scan, and the scan time:background time ratio was 2:1.

Geometry. Bond distances, angles etc. have been calculated using the rounded fractional coordinates. All e.s.d.'s are estimated from the variances of the (full) variance-covariance matrix. The cell e.s.d.'s are taken into account in the estimation of distances, angles and torsion angles

Refinement. Refinement using all reflections. The weighted R-factor (wR), goodness of fit (S) and R-factor (gt) are based on F, with F set to zero for negative F. The threshold expression of F² > 2.0 σ(F²) is used only for calculating R-factor (gt).

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
Cl1	0.28824 (8)	0.32194 (6)	−0.4814 (2)	0.0519 (3)
F1	0.2745 (2)	−0.0581 (2)	0.2133 (5)	0.0624 (8)
F2	0.3973 (3)	−0.0299 (2)	−0.0220 (4)	0.0642 (9)
O2	0.2558 (2)	0.1739 (2)	0.0510 (4)	0.0414 (9)
O1'	0.4719 (2)	0.0592 (2)	0.4248 (4)	0.0405 (8)
O3'	0.4475 (2)	−0.1666 (2)	0.3127 (5)	0.0449 (9)
O5'	0.6978 (2)	−0.0162 (2)	0.4448 (6)	0.0587 (13)
N1	0.4392 (2)	0.1239 (2)	0.1166 (5)	0.0357 (9)
N3	0.4038 (2)	0.2137 (2)	−0.1546 (5)	0.0361 (9)
N4	0.5456 (3)	0.2519 (2)	−0.3770 (6)	0.0473 (12)
C2	0.3600 (3)	0.1713 (2)	0.0061 (6)	0.0317 (8)
C4	0.5166 (3)	0.2106 (2)	−0.2169 (6)	0.0357 (10)
C5	0.5958 (3)	0.1621 (2)	−0.0999 (6)	0.0377 (12)
C6	0.5561 (3)	0.1200 (2)	0.0610 (6)	0.0360 (10)
C1'	0.3942 (3)	0.0638 (2)	0.2623 (6)	0.0370 (12)
C2'	0.3848 (3)	−0.0274 (2)	0.1796 (6)	0.0403 (12)
C3'	0.4747 (3)	−0.0792 (2)	0.2913 (6)	0.0363 (12)
C4'	0.4883 (3)	−0.0290 (2)	0.4822 (6)	0.0350 (12)
C5'	0.6065 (4)	−0.0360 (3)	0.5778 (7)	0.0483 (14)
H1	0.35140	0.24810	−0.22950	0.0434*
H2	0.67610	0.15960	−0.13460	0.0450*
H3	0.60870	0.08660	0.13820	0.0440*
H4	0.62410	0.25070	−0.42250	0.0570*
H5	0.48850	0.28320	−0.44910	0.0570*
H6	0.31990	0.08240	0.30750	0.0450*
H9	0.54610	−0.07540	0.21990	0.0430*
H10	0.42970	−0.04540	0.57460	0.0422*
H11	0.61680	−0.09300	0.62460	0.0580*
H12	0.60990	0.00260	0.68720	0.0580*
H13	0.384 (6)	−0.169 (4)	0.400 (3)	0.10 (2)*
H14	0.709 (5)	0.0425 (13)	0.460 (10)	0.10 (2)*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
Cl1	0.0417 (5)	0.0547 (6)	0.0594 (7)	0.0008 (4)	−0.0157 (5)	0.0127 (5)
F1	0.0353 (12)	0.0560 (10)	0.096 (2)	−0.0140 (10)	−0.0137 (13)	0.0210 (10)
F2	0.096 (2)	0.0560 (10)	0.0406 (13)	−0.0140 (10)	−0.0130 (10)	0.0013 (12)
O2	0.0243 (11)	0.0478 (13)	0.052 (2)	0.0051 (10)	−0.0004 (10)	0.0037 (12)
O1'	0.0440 (10)	0.0345 (12)	0.043 (2)	0.0044 (10)	−0.0051 (12)	0.0029 (10)
O3'	0.0438 (13)	0.0309 (11)	0.060 (2)	−0.0003 (10)	0.0000 (10)	−0.0007 (13)
O5'	0.0330 (13)	0.058 (2)	0.085 (3)	−0.0011 (12)	0.0030 (10)	−0.015 (2)
N1	0.0266 (13)	0.0324 (13)	0.048 (2)	0.0028 (11)	0.0010 (13)	0.0075 (13)
N3	0.0292 (13)	0.0312 (13)	0.048 (2)	0.0024 (11)	−0.0036 (13)	0.0063 (12)
N4	0.037 (2)	0.048 (2)	0.057 (2)	0.0000 (10)	0.005 (2)	0.014 (2)
C2	0.0290 (10)	0.0260 (10)	0.040 (2)	0.0015 (11)	−0.0010 (10)	0.001 (2)
C4	0.029 (2)	0.0290 (10)	0.049 (2)	−0.0026 (13)	0.002 (2)	0.0020 (10)
C5	0.026 (2)	0.037 (2)	0.050 (2)	0.0023 (13)	0.000 (2)	0.000 (2)
C6	0.0230 (10)	0.034 (2)	0.051 (2)	0.0041 (13)	−0.001 (2)	0.007 (2)
C1'	0.030 (2)	0.041 (2)	0.040 (2)	0.0020 (10)	0.002 (2)	0.008 (2)
C2'	0.037 (2)	0.047 (2)	0.037 (2)	−0.010 (2)	0.000 (2)	0.004 (2)
C3'	0.030 (2)	0.036 (2)	0.043 (2)	−0.0002 (13)	0.005 (2)	0.001 (2)
C4'	0.033 (2)	0.034 (2)	0.038 (2)	0.0018 (13)	0.004 (2)	0.006 (2)
C5'	0.048 (2)	0.045 (2)	0.052 (3)	0.006 (2)	−0.010 (2)	0.000 (2)

Geometric parameters (Å, º) top

F1—C2'	1.371 (4)	N4—H4	0.95
F2—C2'	1.360 (5)	N4—H5	0.95
O2—C2	1.233 (4)	C4—C5	1.419 (5)
O1'—C1'	1.409 (5)	C5—C6	1.343 (5)
O1'—C4'	1.441 (4)	C1'—C2'	1.531 (5)
O3'—C3'	1.406 (4)	C2'—C3'	1.509 (5)
O5'—C5'	1.410 (6)	C3'—C4'	1.509 (5)
O3'—H13	0.94 (5)	C4'—C5'	1.503 (6)
O5'—H14	0.93 (2)	C5—H2	0.95
N1—C6	1.393 (4)	C6—H3	0.95
N1—C2	1.386 (5)	C1'—H6	0.95
N1—C1'	1.449 (5)	C3'—H9	0.95
N3—C4	1.360 (4)	C4'—H10	0.95
N3—C2	1.361 (5)	C5'—H11	0.95
N4—C4	1.295 (5)	C5'—H12	0.95
N3—H1	0.95

Cl1···N3	3.068 (3)	N4···Cl1	3.224 (4)
Cl1···N4	3.224 (4)	N4···Cl1^xiv	3.158 (4)
Cl1···C4	3.608 (4)	N4···O3'ⁱⁱⁱ	3.187 (5)
Cl1···N4ⁱ	3.158 (4)	C2···F2	3.173 (5)
Cl1···C5ⁱ	3.580 (4)	C2···F1^vi	3.058 (5)
Cl1···O5'ⁱⁱ	3.212 (3)	C4···O3'^iv	3.345 (5)
Cl1···H1	2.1691	C4···Cl1	3.608 (4)
Cl1···H5	2.3846	C4···O1'^vii	3.408 (5)
Cl1···H2ⁱ	2.8927	C5···Cl1^xiv	3.580 (4)
Cl1···H4ⁱ	2.2896	C5···O2^xii	3.165 (4)
Cl1···H14ⁱⁱ	2.31 (3)	C5···O5'^xiii	3.297 (4)
Cl1···H9ⁱⁱⁱ	2.9549	C5···O3'^iv	3.331 (5)
Cl1···H11^iv	2.9447	C6···F2	3.016 (5)
F1···O3'	2.692 (4)	C6···O5'^xiii	3.346 (4)
F1···C2^v	3.058 (5)	C6···C3'	3.593 (5)
F1···F2^v	2.986 (4)	C3'···C6	3.593 (5)
F1···O2^v	2.918 (4)	C2···H13^vi	2.89 (7)
F2···C6	3.016 (5)	C4···H13^iv	3.06 (5)
F2···O3'	3.149 (4)	C5···H12^vii	2.8731
F2···N1	2.617 (4)	C5···H13^iv	2.97 (6)
F2···C2	3.173 (5)	H1···Cl1	2.1691
F2···F1^vi	2.986 (4)	H1···H5	2.2227
F1···H13	2.48 (6)	H2···H4	2.4703
F2···H10^vii	2.7413	H2···O5'^xiii	2.7163
F2···H6^vi	2.8605	H2···Cl1^xiv	2.8927
O2···F1^vi	2.918 (4)	H2···O2^xii	2.8098
O2···O3'^vi	2.829 (4)	H3···O1'	2.5175
O2···C5ⁱⁱ	3.165 (4)	H3···O5'	2.8005
O1'···C4^viii	3.408 (5)	H3···H14	2.5403
O1'···O5'	2.848 (4)	H3···O5'^xiii	2.7950
O3'···O2^v	2.829 (4)	H4···H2	2.4703
O3'···F1	2.692 (4)	H4···Cl1^xiv	2.2896
O3'···C5^ix	3.331 (5)	H5···Cl1	2.3846
O3'···F2	3.149 (4)	H5···H1	2.2227
O3'···N4^x	3.187 (5)	H5···O3'ⁱⁱⁱ	2.6641
O3'···C4^ix	3.345 (5)	H6···O2	2.3529
O5'···C5^xi	3.297 (4)	H6···F2^v	2.8605
O5'···Cl1^xii	3.212 (3)	H9···O5'	2.4807
O5'···O1'	2.848 (4)	H9···Cl1^x	2.9549
O5'···C6^xi	3.346 (4)	H10···F2^viii	2.7413
O2···H6	2.3529	H10···H13	2.3158
O2···H13^vi	1.90 (6)	H11···Cl1^ix	2.9447
O2···H2ⁱⁱ	2.8098	H12···C5^viii	2.8731
O1'···H14	2.74 (6)	H12···O5'^xi	2.8094
O1'···H3	2.5175	H13···F1	2.48 (6)
O3'···H5^x	2.6641	H13···H10	2.3158
O5'···H9	2.4807	H13···O2^v	1.90 (6)
O5'···H2^xi	2.7163	H13···C2^v	2.89 (7)
O5'···H3^xi	2.7950	H13···C4^ix	3.06 (5)
O5'···H12^xiii	2.8094	H13···C5^ix	2.97 (6)
O5'···H3	2.8005	H14···O1'	2.74 (6)
N1···F2	2.617 (4)	H14···H3	2.5403
N3···Cl1	3.068 (3)	H14···Cl1^xii	2.31 (3)

C1'—O1'—C4'	109.7 (3)	F2—C2'—C1'	112.3 (3)
C3'—O3'—H13	106 (4)	F2—C2'—C3'	114.0 (3)
C5'—O5'—H14	104 (4)	O3'—C3'—C2'	114.7 (3)
C2—N1—C1'	118.2 (3)	O3'—C3'—C4'	116.1 (3)
C6—N1—C1'	119.7 (3)	C2'—C3'—C4'	102.4 (3)
C2—N1—C6	120.7 (3)	O1'—C4'—C3'	104.8 (3)
C2—N3—C4	125.2 (3)	O1'—C4'—C5'	107.5 (3)
C2—N3—H1	117.40	C3'—C4'—C5'	114.7 (3)
C4—N3—H1	117.36	O5'—C5'—C4'	112.6 (4)
H4—N4—H5	119.99	C4—C5—H2	120.44
C4—N4—H5	120.06	C6—C5—H2	120.34
C4—N4—H4	119.95	N1—C6—H3	119.28
O2—C2—N3	122.4 (3)	C5—C6—H3	119.38
O2—C2—N1	121.5 (3)	O1'—C1'—H6	109.63
N1—C2—N3	116.2 (3)	N1—C1'—H6	109.70
N3—C4—N4	118.8 (3)	C2'—C1'—H6	109.65
N3—C4—C5	117.3 (3)	O3'—C3'—H9	107.64
N4—C4—C5	124.0 (3)	C2'—C3'—H9	107.77
C4—C5—C6	119.2 (3)	C4'—C3'—H9	107.82
N1—C6—C5	121.3 (3)	O1'—C4'—H10	109.83
O1'—C1'—N1	109.2 (3)	C3'—C4'—H10	109.93
O1'—C1'—C2'	106.1 (3)	C5'—C4'—H10	109.90
N1—C1'—C2'	112.5 (3)	O5'—C5'—H11	108.76
C1'—C2'—C3'	105.6 (3)	O5'—C5'—H12	108.62
F1—C2'—F2	104.5 (3)	C4'—C5'—H11	108.71
F1—C2'—C1'	109.3 (3)	C4'—C5'—H12	108.68
F1—C2'—C3'	111.2 (3)	H11—C5'—H12	109.45

C4'—O1'—C1'—N1	−136.1 (3)	C4—C5—C6—N1	−0.8 (5)
C4'—O1'—C1'—C2'	−14.6 (4)	O1'—C1'—C2'—F1	112.5 (3)
C1'—O1'—C4'—C3'	30.9 (3)	O1'—C1'—C2'—F2	−132.0 (3)
C1'—O1'—C4'—C5'	153.3 (3)	N1—C1'—C2'—C3'	112.1 (3)
C6—N1—C2—O2	178.4 (3)	O1'—C1'—C2'—C3'	−7.2 (4)
C1'—N1—C2—O2	12.1 (5)	N1—C1'—C2'—F1	−128.2 (3)
C1'—N1—C2—N3	−167.3 (3)	N1—C1'—C2'—F2	−12.7 (4)
C6—N1—C2—N3	−0.9 (5)	F2—C2'—C3'—O3'	−85.0 (4)
C2—N1—C1'—O1'	−147.2 (3)	F2—C2'—C3'—C4'	148.4 (3)
C2—N1—C6—C5	0.3 (5)	C1'—C2'—C3'—O3'	151.3 (3)
C1'—N1—C6—C5	166.5 (3)	F1—C2'—C3'—C4'	−93.7 (3)
C6—N1—C1'—C2'	−71.2 (4)	F1—C2'—C3'—O3'	32.9 (5)
C2—N1—C1'—C2'	95.3 (4)	C1'—C2'—C3'—C4'	24.7 (4)
C6—N1—C1'—O1'	46.3 (4)	O3'—C3'—C4'—O1'	−159.2 (3)
C2—N3—C4—N4	177.6 (3)	O3'—C3'—C4'—C5'	83.1 (4)
C4—N3—C2—O2	−177.1 (3)	C2'—C3'—C4'—C5'	−151.1 (3)
C2—N3—C4—C5	−2.8 (5)	C2'—C3'—C4'—O1'	−33.5 (3)
C4—N3—C2—N1	2.3 (5)	C3'—C4'—C5'—O5'	52.9 (5)
N3—C4—C5—C6	1.9 (5)	O1'—C4'—C5'—O5'	−63.2 (4)
N4—C4—C5—C6	−178.4 (4)

Symmetry codes: (i) x−1/2, −y+1/2, −z−1; (ii) x−1/2, −y+1/2, −z; (iii) −x+1, y+1/2, −z−1/2; (iv) −x+1, y+1/2, −z+1/2; (v) −x+1/2, −y, z+1/2; (vi) −x+1/2, −y, z−1/2; (vii) x, y, z−1; (viii) x, y, z+1; (ix) −x+1, y−1/2, −z+1/2; (x) −x+1, y−1/2, −z−1/2; (xi) −x+3/2, −y, z+1/2; (xii) x+1/2, −y+1/2, −z; (xiii) −x+3/2, −y, z−1/2; (xiv) x+1/2, −y+1/2, −z−1.

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N3—H1···Cl1	0.95	2.17	3.068 (3)	157
N4—H4···Cl1^xiv	0.95	2.29	3.158 (4)	151
N4—H5···Cl1	0.95	2.38	3.224 (4)	147
O3′—H13···O2^v	0.94 (5)	1.90 (6)	2.829 (4)	173 (5)
O5′—H14···Cl1^xii	0.93 (2)	2.31 (3)	3.212 (3)	165 (5)
C1′—H6···O2	0.95	2.35	2.734 (5)	103
C3′—H9···O5′	0.95	2.48	2.928 (4)	109

Symmetry codes: (v) −x+1/2, −y, z+1/2; (xii) x+1/2, −y+1/2, −z; (xiv) x+1/2, −y+1/2, −z−1.

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2′-Deoxy-2′,2′-di­fluoro­cytidine mono­hydro­chloride (Gemcitabine hydro­chloride)

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2′-Deoxy-2′,2′-difluorocytidine monohydrochloride (Gemcitabine hydrochloride)