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Journal logoCRYSTALLOGRAPHIC
COMMUNICATIONS
ISSN: 2056-9890
Volume 81| Part 5| May 2025| Pages 433-437
https://doi.org/10.1107/S2056989025003226

Crystal structure and Hirshfeld surface analysis of ketorolac tromethamine

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Anna M. Shaposhnyk,a* Vitalii V. Rudiukb and Vyacheslav N. Baumera

aInstitute of Functional Materials Chemistry, SSI `Institute for Single Crystals' NAS of Ukraine, 60 Nauky Ave., Kharkiv 61001, Ukraine, and bFarmak JSC, 63 Kyrylivska str., Kyiv 04080, Ukraine
*Correspondence e-mail: [email protected]

Edited by J. Ellena, Universidade de Sâo Paulo, Brazil (Received 11 February 2025; accepted 9 April 2025; online 24 April 2025)

Ketorolac tromethamine or 1,3-dihy­droxy-2-(hy­droxy­meth­yl)propan-2-am­inium 5-benzoyl-2,3-di­hydro-1H-pyrrolizine-1-carboxyl­ate, C15H12NO3+·C4H12NO3−, was studied by single-crystal and powder X-ray diffraction methods. One cation and one anion are present in the asymmetric unit. In the crystal, N—H⋯O and O—H⋯O hy­dro­gen bonds link the cation and anion. All the hy­dro­gen-bond inter­actions result in the formation of a di-periodic layer in the (100) crystallographic plane.

CCDC reference: 2442550

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1. Chemical context

Ketorolac tromethamine is a non-steroidal anti-inflammatory drug (NSAID) that belongs to the class of heteroaryl acetic acid derivatives and the nonselective COX inhibitor group (Gilman, 2001[Gilman, G. (2001). The Pharmacological Basis of Therapeutics, 10th ed., p. 1825. New York: McGraw-Hill Professional.]).

[Scheme 1]

Ketorolac tromethamine produces analgesia and decreases inflammation by inhibiting the enzyme cyclo­oxygenase, resulting in a decrease in the formation of prostaglandins and sensitization to pain at sites of inflammation (Boyer et al., 2010[Boyer, K. C., McDonald, P. & Zoetis, T. (2010). Int. J. Toxicol. 29, 467-478.]). It has also been used effectively for analgesia in advanced cancer (Joishy & Walsh, 1998[Joishy, S. K. & Walsh, D. (1998). J. Pain Symptom Manage. 16, 334-339.]). It has a chiral centre and is com­posed of (+)R and (−)S enanti­omers in equal proportions. The pharmacological (analgesic and COX inhibitory) activity is retained almost exclusively in the S-enanti­omer (Mroszczak et al., 1990[Mroszczak, E. J., Jung, D., Yee, J., Bynum, L., Sevelius, H. & Massey, I. (1990). Pharmacotherapy, 10, 33S-39S.]). It is commercially available as a tromethamine salt, which augments its water solubility (Litvak et al., 1990[Litvak, K. M. & McEvoy, G. K. (1990). Clin. Pharm. 9, 921-935.]) and can be given via routes such as intra­venous, subcutaneous, oral and intra­muscular, and is the only NSAID currently available as a nasal spray (He & Hersh, 2012[He, A. & Hersh, E. V. (2012). Curr. Med. Res. Opin. 28, 1873-1880.]). The analgesic efficacy of ketorolac depends on the racemic mixture concentrations of S and R enanti­omers (Jamali et al., 1989[Jamali, F., Mehvar, R. & Pasutto, F. M. (1989). J. Pharm. Sci. 78, 695-715.]; Mroszczak et al., 1996[Mroszczak, E., Combs, D., Chaplin, M., Tsina, I., Tarnowski, T., Rocha, C., Tam, Y., Boyd, A., Young, J., Depass, L. & Clin, J. (1996). Pharmacology, 36, 521-539.]). In the present work, we have analyzed the mol­ecular and crystal structures of ketorolac tromethamine (denoted KT) or 1,3-dihy­droxy-2-(hy­droxy­meth­yl)pro­pan-2-aminium 5-benzoyl-2,3-di­hydro-1H-pyrrolizine-1-carbox­yl­ate.

2. Structural commentary

KT crystallizes in the monoclinic space group I2/a, with the asymmetric unit containing one anion and one cation (Fig. 1[link]). The positive charge of the cation is located at the protonated amino group of the tromethamine mol­ecule. A result of protonation of the amino group is a lengthening of the N1—C17 distance [1.489 (3) Å] in the cation com­pared to the average Csp3—N value of 1.467 Å (Orpen et al., 1994[Orpen, A. G., Brammer, L., Allen, F. H., Kennard, O., Watson, D. G. & Taylor, R. (1994). Structure Correlation, edited by H. Bürgi &J. Dunitz, pp. 752-858. Weinheim: VCH Publishers.]). The H atoms on atom N1 were determined from a difference Fourier map. A negative charge is located on the deprotonated carboxyl­ate group of ketorolac, as follows from the lengthening of the C4—C1 distance [1.530 (3) Å] com­pared to the average Csp3—Csp2(carb­oxy­lic acid) value of 1.502 Å (Orpen et al., 1994[Orpen, A. G., Brammer, L., Allen, F. H., Kennard, O., Watson, D. G. & Taylor, R. (1994). Structure Correlation, edited by H. Bürgi &J. Dunitz, pp. 752-858. Weinheim: VCH Publishers.]), and the C4—O1 [1.245 (3) Å] and C4—O2 [1.258 (3) Å] distances (C—O2− = 1.254 Å; Orpen et al., 1994[Orpen, A. G., Brammer, L., Allen, F. H., Kennard, O., Watson, D. G. & Taylor, R. (1994). Structure Correlation, edited by H. Bürgi &J. Dunitz, pp. 752-858. Weinheim: VCH Publishers.]). In the 2,3-di­hydro-1H-pyrrolizine fragment, the saturated ring adopts an envelope conformation, where the deviation of the C2 atom from the C1/C7A/N4/C3 plane is 0.116 Å. The arene group of the benzaldehyde fragment is located in a +synperiplanar (+sp) position with respect to the 2,3-di­hydro-1H-pyrrolizine bicycle [the C6—C5—C8—C9 torsion angle is 13.0 (4)°] and is turned with respect to the C8=O3 bond [the O3—C8—C9—C14 torsion angle is 39.5 (3)°]. The carboxyl­ate group is in an equatorial position with respect to the 2,3-di­hydro-1H-pyrrolizine fragment and is almost coplanar with the endocyclic C1—C2 bond [the C3—C2—C1—C4 and C2—C1—C4—O2 torsion angles are 127.8 (3) and −8.1 (3)°, respectively]. The cation and anion are connected by inter­molecular N1—H1A⋯O1 and O6—H6A⋯O2 hy­dro­gen bonds (Table 1[link]), which form a characteristic R22(9) graph-set motif (Etter et al., 1990[Etter, M. C., MacDonald, J. C. & Bernstein, J. (1990). Acta Cryst. B46, 256-262.]).

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A D—H H⋯A D⋯A D—H⋯A
O4—H4⋯O3i 0.82 1.92 2.731 (3) 172
O5—H5⋯O6ii 0.82 1.95 2.762 (3) 174
O6—H6A⋯O2 0.82 1.85 2.667 (2) 177
N1—H1A⋯O1 0.89 1.89 2.771 (2) 172
N1—H1B⋯O2iii 0.89 2.05 2.926 (3) 169
N1—H1C⋯O1iv 0.89 1.92 2.756 (3) 155
Symmetry codes: (i) Mathematical equation; (ii) Mathematical equation; (iii) Mathematical equation; (iv) Mathematical equation.
[Figure 1]
Figure 1
The mol­ecular structure of KT. Displacement ellipsoids are drawn at the 50% probability level. O—H⋯O and N—H⋯O hy­dro­gen bonds are indicated by dotted lines.

3. Supra­molecular features

The main packing fragment in KT is a mono-periodic layer in the (100) plane with a characteristic R44(18) graph-set motif (Etter et al., 1990[Etter, M. C., MacDonald, J. C. & Bernstein, J. (1990). Acta Cryst. B46, 256-262.]). In one layer, tromethamine cations form one-dimensional chains along [010], which are repeated over a/2 and c/2 via the O5—H5⋯O6ii hy­dro­gen bonds (Table 1[link]). One cation inter­acts with four ketorolac anions via a series of hy­dro­gen bonds (O4—H4⋯O3i, O6—H6A⋯O2, N1—H1A⋯O1, N1—H1B⋯O2 and N1—H1C⋯O1; Table 1[link]), forming a layer in the (100) plane. Van der Waals inter­actions are observed between neighbouring layers (Fig. 2[link]).

[Figure 2]
Figure 2
The crystal packing of KT, viewed along [010]. Hydrogen bonds are shown as dashed lines.

4. Database survey

A search of the Cambridge Structural Database (CSD, Version 5.44, last update June 2024; Groom et al., 2016[Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171-179.]) for the 5-benzoyl-2,3-di­hydro-1H-pyrrolizine-1-carboxyl­ate unit resulted in one hit (CSD refcode HOJSAB; Jasinski et al., 2008[Jasinski, J., Butcher, R., Narayana, B., Swamy, M. & Yathirajan, H. (2008). Anal. Sci. X, 24, X205-X206.]). In this structure, 5-benzoyl-2,3-di­hydro-1H-pyrrolizine-1-carboxyl­ate exists as a neutral mol­ecule. A search for the 1,3-dihy­droxy-2-(hy­droxy­meth­yl)propan-2-aminium unit or tromethamine as a cation resulted in 88 hits. 40 of these hits contain the com­pound as an anion with the carb­oxy­lic acid group deprotonated, for example, CIKQIY (Zhang et al., 2013[Zhang, Ch.-G., Li, Yu., Luo, Ya.-H. & Sun, B.-W. (2013). J. Chem. Crystallogr. 43, 576-584.]), COZBAX (Rossi et al., 2020[Rossi, P., Paoli, P., Chelazzi, L., Milazzo, S., Biagi, D., Valleri, M., Ienco, A., Valtancoli, B. & Conti, L. (2020). Cryst. Growth Des. 20, 226-236.]) and EDALEC (Bhattacharya et al., 2012[Bhattacharya, A., Chattopadhyay, B., Chakraborty, S., Roy, B. N., Singh, G. P., Godbole, H. M., Rananaware, U. B. & Mukherjee, A. K. (2012). J. Pharm. Biomed. Anal. 70, 280-287.]).

5. Synthesis and crystallization

Crystals of the title com­pound suitable for X-ray diffraction analysis were grown by recrystallization of the API ketorolac tromethamine from a water solution by the diffusion method with isopropyl alcohol at room tem­per­a­ture over a period of one week.

6. Hirshfeld surface analysis

Inter­molecular inter­actions can be analyzed using Hirshfeld surface analysis and 2D fingerprint plots (Turner et al., 2017[Turner, M. J., McKinnon, J. J., Wolff, S. K., Grimwood, D. J., Spackman, P. R., Jayatilaka, D. & Spackman, M. A. (2017). CrystalExplorer17. University of Western Australia. https://crystalexplorer.net/.]). Analysis and calculation of the Hirshfeld surface were carried out with CrystalExplorer17.5 (Spackman et al., 2021[Spackman, P. R., Turner, M. J., McKinnon, J. J., Wolff, S. K., Grimwood, D. J., Jayatilaka, D. & Spackman, M. A. (2021). J. Appl. Cryst. 54, 1006-1011.]).

The Hirshfeld surfaces were calculated for the structure under study using a standard high surface resolution, mapped over dnorm [Figs. 3[link](a) and 3(b)]. The red spots, corresponding to contacts that are shorter than the van der Waals radii sum of the closest atoms, are observed at the carboxyl­ate and carbonyl groups. To com­pare inter­molecular inter­actions of different types in a more qu­anti­tative way, their contributions to the total Hirshfeld surfaces were analysed and the main contributions are presented in Figs. 3[link](c) and 3(d). The main contribution for the cation and anion is provided by H⋯H short contacts. Stronger contributions of N—H⋯O and O—H⋯O hy­dro­gen bonds are observed in the structure. The contribution of C⋯H/H⋯C short contacts is significant for the anion [Fig. 3[link](c)].

[Figure 3]
Figure 3
Hirshfeld surfaces mapped over dnorm for (a) the anion and (b) the cation of KT. Contributions of inter­actions of different types to the total Hirshfeld surface of (c) the anion and (d) the cation of KT.

7. Powder diffraction characterization

An X-ray powder diffraction pattern of KT was recorded using a Siemens D500 powder diffractometer (Cu Kα radiation, Bragg–Brentano geometry, curved graphite monochromator on the counter arm, 4° < 2θ < 60°, 2θ = 0.02°). A Rietveld refinement (Fig. 4[link]) on the basis of the obtained pattern was carried out with the FullProf and WinPLOTR programs (Rodriguez-Carvajal & Roisnel, 1998[Rodriguez-Carvajal, J. & Roisnel, T. (1998). Int. Union Crystallogr. Newslett. 20, 35-36.]) using data of an external standard (NIST SRM1976) for the calculation of the instrumental profile function and the single-crystal data as the structure model for refinement. The main results of the Rietveld refinement are shown in Table 2[link]. On the basis of the Rietveld refinement, the experimental powder X-ray diffraction pattern coincides with the theoretical pattern calculated from the single-crystal X-ray study.

Table 2
Experimental data of the X-ray powder diffraction study performed at 293 K

Crystal system, space group Monoclinic, I2/a
a (Å) 20.3347 (15)
b (Å) 6.6301 (5)
c (Å) 27.981 (2)
β (°) 96.306 (4)
V (Å3) 3749.5 (5)
Dx (Mg m−3) 1.334
   
Refinement  
Rp 0.0720
Rwp 0.0915
Rexp  0.0178
RB 0.0580
RF 0.0727
[Figure 4]
Figure 4
Final Rietveld plots for KT. Observed data points are indicated by red circles, the best-fit profile (black upper trace) and the difference pattern (blue lower trace) are shown as solid lines. The vertical green bars correspond to the Bragg reflections.

8. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 3[link]. The H atoms were placed in calculated positions and treated as riding, with C—H = 0.96 Å, O—H = 0.82 Å and Uiso(H) = 1.5Ueq(C,O) for methyl and hydroxyl groups, and Car—H = 0.93 Å (ar is aromatic), Csp2—H = 0.97 Å, N—H = 0.89 Å and Uiso(H) = 1.2Ueq(C,N) for all other H atoms.

Table 3
Experimental details

Crystal data
Chemical formula C15H12NO3+·C4H12NO3−
Mr 376.40
Crystal system, space group Monoclinic, I2/a
Temperature (K) 293
a, b, c (Å) 20.3154 (13), 6.6466 (4), 28.0770 (15)
β (°) 96.389 (6)
V (Å3) 3767.6 (4)
Z 8
Radiation type Mo Kα
μ (mm−1) 0.10
Crystal size (mm) 0.56 × 0.22 × 0.07
 
Data collection
Diffractometer Rigaku Xcalibur Sapphire3
Absorption correction Multi-scan (CrysAlis PRO; Rigaku OD, 2018[Rigaku OD (2018). CrysAlis PRO. Rigaku Oxford Diffraction Ltd, Yarnton, Oxfordshire, England.])
Tmin, Tmax 0.584, 1.000
No. of measured, independent and observed [I > 2σ(I)] reflections 14262, 3734, 2314
Rint 0.085
(sin θ/λ)max (Å−1) 0.619
 
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.057, 0.179, 1.04
No. of reflections 3734
No. of parameters 249
H-atom treatment H atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å−3) 0.16, −0.19
Computer programs: CrysAlis PRO (Rigaku OD, 2018[Rigaku OD (2018). CrysAlis PRO. Rigaku Oxford Diffraction Ltd, Yarnton, Oxfordshire, England.]), SHELXS97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]), SHELXL2018 (Sheldrick, 2015[Sheldrick, G. M. (2015). Acta Cryst. C71, 3-8.]) and OLEX2 (Dolomanov et al., 2009[Dolomanov, O. V., Bourhis, L. J., Gildea, R. J., Howard, J. A. K. & Puschmann, H. (2009). J. Appl. Cryst. 42, 339-341.]).

Supporting information

CCDC reference: 2442550

Crystal structure: contains datablock I. DOI: https://doi.org/10.1107/S2056989025003226/ex2090sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989025003226/ex2090Isup2.hkl

checkCIF report


Computing details top

1,3-Dihydroxy-2-(hydroxymethyl)propan-2-aminium 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate top
Crystal data top
C15H12NO3+·C4H12NO3−F(000) = 1600
Mr = 376.40Dx = 1.327 Mg m−3
Monoclinic, I2/aMo Kα radiation, λ = 0.71073 Å
a = 20.3154 (13) ÅCell parameters from 2134 reflections
b = 6.6466 (4) Åθ = 3.4–22.7°
c = 28.0770 (15) ŵ = 0.10 mm−1
β = 96.389 (6)°T = 293 K
V = 3767.6 (4) Å3Prism, colourless
Z = 80.56 × 0.22 × 0.07 mm
Data collection top
Rigaku Xcalibur Sapphire3
diffractometer		2314 reflections with I > 2σ(I)
Detector resolution: 16.1827 pixels mm-1Rint = 0.085
ω scansθmax = 26.1°, θmin = 3.2°
Absorption correction: multi-scan
(CrysAlis PRO; Rigaku OD, 2018)		h = −23→25
Tmin = 0.584, Tmax = 1.000k = −8→8
14262 measured reflectionsl = −34→33
3734 independent reflections
Refinement top
Refinement on F20 restraints
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.057H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.179 w = 1/[σ2(Fo2) + (0.0717P)2 + 0.7854P]
where P = (Fo2 + 2Fc2)/3
S = 1.04(Δ/σ)max < 0.001
3734 reflectionsΔρmax = 0.16 e Å−3
249 parametersΔρmin = −0.19 e Å−3
Special details top

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
O10.48593 (10)0.3303 (3)0.44078 (6)0.0655 (5)
O20.46522 (9)0.0085 (3)0.42405 (6)0.0637 (5)
O30.35641 (11)0.1436 (3)0.20682 (6)0.0760 (6)
O40.40104 (11)0.3531 (3)0.61861 (7)0.0787 (6)
H40.3844030.3475670.6438850.118*
O50.35501 (13)0.5730 (3)0.48159 (7)0.0869 (7)
H50.3649730.6924350.4839450.130*
O60.39150 (10)−0.0296 (3)0.49643 (7)0.0668 (5)
H6A0.415208−0.0198530.4747380.100*
N10.45003 (10)0.3145 (3)0.53307 (6)0.0518 (5)
H1A0.4578620.3258580.5026200.062*
H1B0.4708950.2065820.5460290.062*
H1C0.4646730.4238790.5491800.062*
N40.42765 (10)0.2619 (3)0.29261 (6)0.0528 (5)
C10.50058 (13)0.2230 (4)0.36263 (8)0.0555 (6)
H10.5429850.2945880.3647410.085 (3)*
C20.50442 (16)0.0358 (4)0.33042 (9)0.0688 (8)
H2A0.5498400.0126430.3242340.085 (3)*
H2B0.488949−0.0821410.3461880.085 (3)*
C30.46117 (17)0.0740 (4)0.28378 (10)0.0738 (8)
H3A0.4877340.0878910.2573190.085 (3)*
H3B0.429569−0.0342520.2767240.085 (3)*
C40.48286 (13)0.1827 (4)0.41333 (9)0.0535 (6)
C50.38028 (13)0.3803 (4)0.26721 (8)0.0523 (6)
C60.37220 (14)0.5445 (4)0.29638 (9)0.0602 (7)
H60.3430250.6506230.2889330.072*
C70.41437 (15)0.5256 (4)0.33830 (9)0.0639 (7)
H70.4186920.6150700.3639350.077*
C7A0.44886 (13)0.3480 (4)0.33472 (8)0.0533 (6)
C80.34637 (14)0.3153 (4)0.22233 (8)0.0562 (6)
C90.30014 (13)0.4507 (4)0.19276 (8)0.0545 (6)
C100.31445 (15)0.6490 (4)0.18368 (9)0.0645 (7)
H100.3513250.7095610.2003810.077*
C110.27477 (18)0.7578 (5)0.15022 (10)0.0821 (9)
H110.2858320.8898800.1435670.099*
C120.21897 (18)0.6728 (6)0.12661 (11)0.0872 (10)
H120.1924880.7465150.1037450.105*
C130.20222 (16)0.4788 (7)0.13672 (11)0.0866 (10)
H130.1632400.4231670.1218280.104*
C140.24326 (15)0.3657 (5)0.16906 (10)0.0714 (8)
H140.2327020.2324340.1749140.086*
C150.37749 (13)0.2929 (4)0.53536 (8)0.0551 (6)
C160.36743 (15)0.2196 (4)0.58508 (9)0.0663 (7)
H16A0.3205780.2170370.5889540.085 (3)*
H16B0.3849260.0845180.5899990.085 (3)*
C170.34462 (15)0.4973 (4)0.52700 (9)0.0673 (7)
H17A0.2974580.4849270.5291180.085 (3)*
H17B0.3627840.5904350.5516430.085 (3)*
C180.35096 (14)0.1436 (4)0.49694 (10)0.0646 (7)
H18A0.3065890.1031620.5025390.085 (3)*
H18B0.3481830.2085640.4658500.085 (3)*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
O10.0780 (14)0.0680 (12)0.0499 (10)−0.0143 (10)0.0042 (9)−0.0046 (9)
O20.0646 (13)0.0603 (11)0.0655 (11)−0.0026 (9)0.0045 (9)0.0066 (8)
O30.1105 (18)0.0615 (12)0.0521 (10)0.0029 (11)−0.0087 (10)−0.0072 (9)
O40.0914 (16)0.0912 (14)0.0542 (11)−0.0137 (12)0.0111 (11)−0.0006 (10)
O50.128 (2)0.0646 (12)0.0634 (12)0.0050 (13)−0.0105 (12)0.0097 (9)
O60.0719 (14)0.0568 (11)0.0715 (12)−0.0045 (9)0.0081 (10)−0.0008 (9)
N10.0542 (14)0.0564 (12)0.0435 (10)−0.0057 (9)−0.0004 (9)0.0008 (8)
N40.0605 (14)0.0546 (12)0.0425 (11)−0.0005 (10)0.0014 (9)−0.0023 (9)
C10.0518 (16)0.0641 (15)0.0495 (13)−0.0002 (12)0.0014 (11)0.0004 (11)
C20.077 (2)0.0726 (18)0.0556 (15)0.0166 (15)0.0014 (14)−0.0042 (13)
C30.093 (2)0.0651 (17)0.0601 (16)0.0177 (16)−0.0038 (15)−0.0089 (13)
C40.0460 (15)0.0620 (16)0.0500 (13)0.0002 (11)−0.0059 (10)0.0021 (12)
C50.0540 (16)0.0590 (14)0.0425 (12)−0.0018 (12)−0.0003 (11)0.0009 (11)
C60.0700 (18)0.0572 (15)0.0514 (14)0.0053 (13)−0.0021 (12)−0.0032 (11)
C70.078 (2)0.0625 (16)0.0483 (13)0.0064 (14)−0.0069 (13)−0.0095 (12)
C7A0.0583 (16)0.0537 (14)0.0465 (13)−0.0026 (11)0.0002 (11)−0.0022 (10)
C80.0624 (17)0.0608 (15)0.0450 (13)−0.0079 (12)0.0043 (11)0.0004 (11)
C90.0526 (16)0.0680 (16)0.0421 (12)−0.0010 (12)0.0020 (11)−0.0045 (11)
C100.0650 (19)0.0667 (17)0.0588 (15)−0.0027 (13)−0.0068 (13)−0.0028 (12)
C110.096 (3)0.077 (2)0.0690 (18)0.0207 (18)−0.0128 (18)0.0017 (15)
C120.077 (2)0.116 (3)0.0642 (19)0.033 (2)−0.0136 (16)−0.0076 (18)
C130.0513 (19)0.139 (3)0.0670 (19)0.003 (2)−0.0064 (14)−0.022 (2)
C140.0592 (18)0.095 (2)0.0592 (16)−0.0165 (16)0.0048 (14)−0.0107 (14)
C150.0510 (16)0.0599 (15)0.0525 (14)−0.0032 (12)−0.0029 (11)0.0013 (11)
C160.0646 (19)0.0730 (18)0.0619 (16)−0.0060 (14)0.0102 (14)0.0032 (13)
C170.0662 (19)0.0673 (17)0.0658 (17)0.0085 (14)−0.0042 (14)0.0018 (13)
C180.0521 (17)0.0678 (17)0.0708 (17)−0.0031 (13)−0.0068 (13)−0.0043 (13)
Geometric parameters (Å, º) top
O1—C41.245 (3)C5—C81.434 (3)
O2—C41.258 (3)C6—H60.9300
O3—C81.247 (3)C6—C71.382 (4)
O4—H40.8200C7—H70.9300
O4—C161.413 (3)C7—C7A1.382 (4)
O5—H50.8200C8—C91.486 (4)
O5—C171.408 (3)C9—C101.379 (4)
O6—H6A0.8200C9—C141.388 (4)
O6—C181.416 (3)C10—H100.9300
N1—H1A0.8900C10—C111.374 (4)
N1—H1B0.8900C11—H110.9300
N1—H1C0.8900C11—C121.370 (5)
N1—C151.489 (3)C12—H120.9300
N4—C31.457 (3)C12—C131.371 (5)
N4—C51.379 (3)C13—H130.9300
N4—C7A1.341 (3)C13—C141.385 (4)
C1—H10.9800C14—H140.9300
C1—C21.545 (4)C15—C161.514 (3)
C1—C41.530 (3)C15—C171.521 (4)
C1—C7A1.491 (3)C15—C181.520 (3)
C2—H2A0.9700C16—H16A0.9700
C2—H2B0.9700C16—H16B0.9700
C2—C31.515 (4)C17—H17A0.9700
C3—H3A0.9700C17—H17B0.9700
C3—H3B0.9700C18—H18A0.9700
C5—C61.385 (3)C18—H18B0.9700
C16—O4—H4109.5O3—C8—C5120.1 (2)
C17—O5—H5109.5O3—C8—C9118.5 (2)
C18—O6—H6A109.5C5—C8—C9121.4 (2)
H1A—N1—H1B109.5C10—C9—C8123.3 (2)
H1A—N1—H1C109.5C10—C9—C14118.8 (3)
H1B—N1—H1C109.5C14—C9—C8117.5 (3)
C15—N1—H1A109.5C9—C10—H10119.7
C15—N1—H1B109.5C11—C10—C9120.6 (3)
C15—N1—H1C109.5C11—C10—H10119.7
C5—N4—C3135.6 (2)C10—C11—H11119.9
C7A—N4—C3113.9 (2)C12—C11—C10120.3 (3)
C7A—N4—C5110.5 (2)C12—C11—H11119.9
C2—C1—H1109.0C11—C12—H12120.0
C4—C1—H1109.0C11—C12—C13119.9 (3)
C4—C1—C2115.8 (2)C13—C12—H12120.0
C7A—C1—H1109.0C12—C13—H13120.0
C7A—C1—C2102.7 (2)C12—C13—C14120.1 (3)
C7A—C1—C4111.2 (2)C14—C13—H13120.0
C1—C2—H2A110.1C9—C14—H14119.9
C1—C2—H2B110.1C13—C14—C9120.1 (3)
H2A—C2—H2B108.4C13—C14—H14119.9
C3—C2—C1108.0 (2)N1—C15—C16107.9 (2)
C3—C2—H2A110.1N1—C15—C17109.1 (2)
C3—C2—H2B110.1N1—C15—C18107.9 (2)
N4—C3—C2103.5 (2)C16—C15—C17109.1 (2)
N4—C3—H3A111.1C16—C15—C18111.8 (2)
N4—C3—H3B111.1C18—C15—C17111.0 (2)
C2—C3—H3A111.1O4—C16—C15107.9 (2)
C2—C3—H3B111.1O4—C16—H16A110.1
H3A—C3—H3B109.0O4—C16—H16B110.1
O1—C4—O2125.0 (2)C15—C16—H16A110.1
O1—C4—C1115.9 (2)C15—C16—H16B110.1
O2—C4—C1119.1 (2)H16A—C16—H16B108.4
N4—C5—C6105.4 (2)O5—C17—C15110.6 (2)
N4—C5—C8121.5 (2)O5—C17—H17A109.5
C6—C5—C8132.8 (2)O5—C17—H17B109.5
C5—C6—H6125.4C15—C17—H17A109.5
C7—C6—C5109.2 (2)C15—C17—H17B109.5
C7—C6—H6125.4H17A—C17—H17B108.1
C6—C7—H7126.7O6—C18—C15112.2 (2)
C7A—C7—C6106.7 (2)O6—C18—H18A109.2
C7A—C7—H7126.7O6—C18—H18B109.2
N4—C7A—C1111.3 (2)C15—C18—H18A109.2
N4—C7A—C7108.2 (2)C15—C18—H18B109.2
C7—C7A—C1140.4 (2)H18A—C18—H18B107.9
O3—C8—C9—C10−133.1 (3)C6—C5—C8—O3−168.6 (3)
O3—C8—C9—C1439.5 (3)C6—C5—C8—C913.0 (4)
N1—C15—C16—O453.9 (3)C6—C7—C7A—N4−0.8 (3)
N1—C15—C17—O560.4 (3)C6—C7—C7A—C1−179.8 (3)
N1—C15—C18—O645.6 (3)C7A—N4—C3—C25.9 (3)
N4—C5—C6—C70.5 (3)C7A—N4—C5—C6−1.0 (3)
N4—C5—C8—O34.4 (4)C7A—N4—C5—C8−175.7 (2)
N4—C5—C8—C9−174.0 (2)C7A—C1—C2—C36.5 (3)
C1—C2—C3—N4−7.5 (3)C7A—C1—C4—O1−69.9 (3)
C2—C1—C4—O1173.4 (2)C7A—C1—C4—O2108.6 (3)
C2—C1—C4—O2−8.1 (3)C8—C5—C6—C7174.3 (3)
C2—C1—C7A—N4−3.0 (3)C8—C9—C10—C11169.7 (3)
C2—C1—C7A—C7176.0 (3)C8—C9—C14—C13−172.6 (2)
C3—N4—C5—C6−178.0 (3)C9—C10—C11—C122.4 (5)
C3—N4—C5—C87.4 (4)C10—C9—C14—C130.4 (4)
C3—N4—C7A—C1−1.9 (3)C10—C11—C12—C130.7 (5)
C3—N4—C7A—C7178.8 (2)C11—C12—C13—C14−3.1 (5)
C4—C1—C2—C3127.8 (3)C12—C13—C14—C92.5 (4)
C4—C1—C7A—N4−127.5 (2)C14—C9—C10—C11−2.9 (4)
C4—C1—C7A—C751.5 (4)C16—C15—C17—O5178.0 (2)
C5—N4—C3—C2−177.2 (3)C16—C15—C18—O6−72.9 (3)
C5—N4—C7A—C1−179.5 (2)C17—C15—C16—O4−64.5 (3)
C5—N4—C7A—C71.2 (3)C17—C15—C18—O6165.0 (2)
C5—C6—C7—C7A0.2 (3)C18—C15—C16—O4172.3 (2)
C5—C8—C9—C1045.3 (4)C18—C15—C17—O5−58.4 (3)
C5—C8—C9—C14−142.0 (2)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O4—H4···O3i0.821.922.731 (3)172
O5—H5···O6ii0.821.952.762 (3)174
O6—H6A···O20.821.852.667 (2)177
N1—H1A···O10.891.892.771 (2)172
N1—H1B···O2iii0.892.052.926 (3)169
N1—H1C···O1iv0.891.922.756 (3)155
Symmetry codes: (i) x, −y+1/2, z+1/2; (ii) x, y+1, z; (iii) −x+1, −y, −z+1; (iv) −x+1, −y+1, −z+1.
Experimental data of the X-ray powder diffraction study performed at 293 K top
Crystal system, space groupMonoclinic, I2/a
a (Å)20.3347 (15)
b (Å)6.6301 (5)
c (Å)27.981 (2)
β (°)96.306 (4)
V (Å3)3749.5 (5)
Dx (Mg m-3)1.334
Refinement
Rp0.0720
Rwp0.0915
Rexp0.0178
RB0.0580
RF0.0727
 

Acknowledgements

The authors are grateful to Farmak JSC for support and to the FAIRE programme provided by the Cambridge Crystallographic Data Centre (CCDC) for the opportunity to use the Cambridge Structural Database (CSD) and associated software.

Funding information

The following funding is acknowledged: National Academy of Sciences of Ukraine (grant No. 0123U103072).

References

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ISSN: 2056-9890
Volume 81| Part 5| May 2025| Pages 433-437
https://doi.org/10.1107/S2056989025003226
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