Synthesis and structural characterization of a cocrystal salt containing acriflavine and 3,5-dinitrobenzoic acid Artur Sikorski ⇑ , Damian Trzybin ´ ski Faculty of Chemistry, University of Gdan ´sk, W. Stwosza 63, 80-308 Gdan ´sk, Poland article info Article history: Received 8 January 2014 Revised 30 January 2014 Accepted 20 February 2014 Available online 28 February 2014 Keywords: Acriflavine 3,5-Dinitrobenzoic acid Cocrystal Porous organic framework Crystal engineering abstract An acriflavine cocrystal salt with 3,5-dinitrobenzoic acid (stoichiometry 1:3) was synthesized and struc- turally characterized. This is the first crystal structure containing the acriflavine moiety to be docu- mented and also the first in which a trimer of an aromatic monocarboxylic acid has been identified. In the crystal packing the trimers of 3,5-dinitrobenzoic acid form a porous organic framework, in the voids of which are located p-stacked columns of acriflavine cations. Ó 2014 Elsevier Ltd. All rights reserved. In view of their numerous medicinal and therapeutic properties, which include antibacterial, 1 anticancer, 2 antiprion 3 and antiviral 4 activities, aminoacridines occupy a special place amongst heterocy- clic compounds. Researchers have long striven to determine their crystal structures. This is understandable, because accurate knowl- edge of the spatial arrangement of a molecule can provide valuable information for the better understanding of its specific biological properties. The upshot of years of studies is that we are now familiar with the crystal structures of a great number of aminoacridinium salts, for example, those containing 9-aminoacridine, 5 proflavine 6 and acridine orange 7 cations. To date, however, there have been no reports on the crystal structure of acriflavine, an important com- pound exhibiting antitumour 8 and antimicrobial 9 activities. The rea- son for this lack of knowledge is probably due to the difficulties in obtaining single crystals of appropriate quality for diffraction exper- iments. Crystal engineering may offer an indirect solution to this problem. 10 This discipline has been developed rapidly since the sec- ond half of the 20th century, particularly following the implementa- tion of modern crystallographic techniques in contemporary solid state chemistry. 11 A major topic of this branch is the synthesis of multicomponent crystalline systems (co-crystals, salts or sol- vates), 12 including those compounds that are hard to crystallize sep- arately. Our previous experience regarding the synthesis of crystalline solids containing 9-aminoacridine 13 suggested that in the case of acriflavine, an aromatic carboxylic acid substituted with nitro groups might be a good substrate for the preparation of a mul- ticomponent crystal. These groups are capable of participating in a large variety of intermolecular interactions which, besides the hydrogen bonds existing between the amino and carboxylic groups, could be used as a driving force to obtain complex and stable struc- tural networks in crystals. 14 Fortunately, our predictions proved to be correct and we were able to obtain good-quality single crystal specimens of an acriflavine cocrystal salt with 3,5-dinitrobenzoic acid (stoichiometry 1:3) (Scheme 1), the structure of which we present in this Letter. http://dx.doi.org/10.1016/j.tetlet.2014.02.074 0040-4039/Ó 2014 Elsevier Ltd. All rights reserved. ⇑ Corresponding author. Tel.: +48 58 523 5112; fax: +48 58 523 5012. E-mail address: [email protected](A. Sikorski). Scheme 1. Synthesis of the title compound. Tetrahedron Letters 55 (2014) 2253–2255 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Transcript
Tetrahedron Letters 55 (2014) 2253–2255
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier .com/ locate/ tet le t
Synthesis and structural characterization of a cocrystalsalt containing acriflavine and 3,5-dinitrobenzoic acid
http://dx.doi.org/10.1016/j.tetlet.2014.02.0740040-4039/� 2014 Elsevier Ltd. All rights reserved.
⇑ Corresponding author. Tel.: +48 58 523 5112; fax: +48 58 523 5012.E-mail address: [email protected] (A. Sikorski). Scheme 1. Synthesis of the title compound.
Artur Sikorski ⇑, Damian TrzybinskiFaculty of Chemistry, University of Gdansk, W. Stwosza 63, 80-308 Gdansk, Poland
a r t i c l e i n f o
Article history:Received 8 January 2014Revised 30 January 2014Accepted 20 February 2014Available online 28 February 2014
An acriflavine cocrystal salt with 3,5-dinitrobenzoic acid (stoichiometry 1:3) was synthesized and struc-turally characterized. This is the first crystal structure containing the acriflavine moiety to be docu-mented and also the first in which a trimer of an aromatic monocarboxylic acid has been identified. Inthe crystal packing the trimers of 3,5-dinitrobenzoic acid form a porous organic framework, in the voidsof which are located p-stacked columns of acriflavine cations.
� 2014 Elsevier Ltd. All rights reserved.
In view of their numerous medicinal and therapeutic properties, ticomponent crystal. These groups are capable of participating in a
which include antibacterial,1 anticancer,2 antiprion3 and antiviral4
activities, aminoacridines occupy a special place amongst heterocy-clic compounds. Researchers have long striven to determine theircrystal structures. This is understandable, because accurate knowl-edge of the spatial arrangement of a molecule can provide valuableinformation for the better understanding of its specific biologicalproperties. The upshot of years of studies is that we are now familiarwith the crystal structures of a great number of aminoacridiniumsalts, for example, those containing 9-aminoacridine,5 proflavine6
and acridine orange7 cations. To date, however, there have been noreports on the crystal structure of acriflavine, an important com-pound exhibiting antitumour8 and antimicrobial9 activities. The rea-son for this lack of knowledge is probably due to the difficulties inobtaining single crystals of appropriate quality for diffraction exper-iments. Crystal engineering may offer an indirect solution to thisproblem.10 This discipline has been developed rapidly since the sec-ond half of the 20th century, particularly following the implementa-tion of modern crystallographic techniques in contemporary solidstate chemistry.11 A major topic of this branch is the synthesis ofmulticomponent crystalline systems (co-crystals, salts or sol-vates),12 including those compounds that are hard to crystallize sep-arately. Our previous experience regarding the synthesis ofcrystalline solids containing 9-aminoacridine13 suggested that inthe case of acriflavine, an aromatic carboxylic acid substituted withnitro groups might be a good substrate for the preparation of a mul-
large variety of intermolecular interactions which, besides thehydrogen bonds existing between the amino and carboxylic groups,could be used as a driving force to obtain complex and stable struc-tural networks in crystals.14 Fortunately, our predictions proved tobe correct and we were able to obtain good-quality single crystalspecimens of an acriflavine cocrystal salt with 3,5-dinitrobenzoicacid (stoichiometry 1:3) (Scheme 1), the structure of which wepresent in this Letter.
2254 A. Sikorski, D. Trzybinski / Tetrahedron Letters 55 (2014) 2253–2255
The title compound, 3,6-diamino-10-methylacridin-10-ium3,5-dinitrobenzoate�3,5-dinitrobenzoic acid�3,5-dinitrobenzoicacid, was characterized by single crystal X-ray diffraction, NMRand FTIR spectroscopy and DSC analysis.15 To the best of ourknowledge, this is the first crystal structure containing the acrifla-vine moiety to be documented in the Cambridge Structural Data-base.16 Moreover, the structure of the title compound might beinteresting not only to crystallographers, but also to a broad groupof researchers interested in supramolecular chemistry. This is be-cause the structure presented here is the first in which a trimerof an aromatic monocarboxylic acid (containing three crystallo-graphically independent moieties of the acid) has been structurallyidentified. Surprisingly, this type of molecular arrangement has notbeen observed before, even in the case of structures where three17
or more18 carboxylic acid moieties are present in the asymmetricpart of the crystal unit cell.
Single-crystal X-ray diffraction revealed that the title compoundforms triclinic crystals with one cation of acriflavine and the trimerof 3,5-dinitrobenzoic acid in the asymmetric unit (Fig. 1).19 Thegeometrical parameters characterizing the acriflavine cation aresimilar to those observed in proflavine,6 and the acridine skeletonis nearly planar with an average deviation from planarity of0.012(2) Å (the right-hand half of the acridine skeleton makes anangle of 0.5(1)� with the left-hand half) (Fig. 1). The trimer of 3,5-dinitrobenzoic acid consists of one 3,5-dinitrobenzoate anion andtwo neutral molecules, which are linked via OAH� � �O hydrogenbonds (Fig. 1). The H� � �O and O� � �O distances in these interactionsare very similar [d(H� � �O) = 1.49(3)–1.53(3) Å, d(O� � �O) = 2.469(3)–2.516(3) Å], as is the CAO bond length, which is responsible forthe involvement of the O–atoms in the OAH� � �O hydrogen bonds[d(CAO) = 1.292(3)–1.299(3) Å and d(CAO) = 1.243(4)–1.256(4) Å,for the neutral and anionic forms, respectively]. The above indicatesthat proton transfer has not occurred.20 There are some differencesin the geometries of the neutral and anionic forms of 3,5-dinitroben-zoic acid. In the first neutral form (denoted A), the planar phenyl ringforms dihedral angles of 8.2(3)�, 13.9(3)� and 1.2(3)� with therespective planes delineated by the atoms of the carboxy and both
Figure 1. ORTEP showing the molecular structure of the title compound in the crystalwith the atom labelling scheme and 25% probability displacement ellipsoids (H atomsare spheres of arbitrary size). Hydrogen bonds are represented by dashed lines andNAO� � �p interactions by dotted lines. Selected bond lengths [Å] and angles [�]:C3AN15 1.367(4), C6AN17 1.345(4), N10AC16 1.515(5), C24AAO25A 1.292(3),C24AAO26A 1.206(3), C24BAO25B 1.243(4), C24BAO26B 1.256(4), C24CAO25C1.299(3), C24CAO26C 1.223(3), C12AN10AC14 124.2(3), O26AAC24AAO25A123.9(3), O26BAC24BAO25B 127.2(3), O26CAC24CAO25C 126.9(3),C1AC2AC3AN15 �179.2(3), N17AC6AC7AC8 �179.9(3), C9AC11AC12AN10 �0.9(4),C9AC13AC14AN10 0.5(4), C16 N10AC12AC4 2.3(4), C19AAC18A AC24AAO25A�7.2(4), C19BAC18BAC24BAO25B 1.7(4), C19CAC18CAC24CAO25C �0.3(4).
nitro groups (Fig. 1). In the second neutral molecule (denoted C),the analogous angles are 3.9(3)�, 9.0(3)� and 2.3(3)�, respectively.In the anionic form (denoted B), the corresponding values are3.5(3)�, 25.2(3)� and 2.4(3)�. In the crystal packing there are differenttypes of interactions involving the nitro groups of both neutral andanionic forms of 3,5-dinitrobenzoic acid (Fig. 2). The structure ofthe trimer is stabilized by NAO� � �p interactions occurring betweenboth neutral forms of 3,5-dinitrobenzoic acid (A and C). Moreover,the neighbouring trimers are further linked via NAO� � �p andNAO� � �N interactions between both neutral forms (A and C).
Additionally, adjacent trimers are linked by the CAH� � �O(nitro)
hydrogen bonds occurring between the neutral (C) and anionic (B)forms, as well as by p–p interactions between the aromatic phenylrings of the inversely oriented neutral forms (C). This arrangementof moieties of 3,5-dinitrobenzoic acid gives rise to a porous organicframework. The ability of nitro-substituted aromatic systems toform such arrangements has been described previously in theliterature.21 The voids of this anionic framework contain p-stackedcolumns of acriflavine cations aligned with the crystallographica-axis. These columns are linked to the porous organic frameworkof 3,5-dinitrobenzoic acid by NAH� � �O hydrogen bonds (Fig. 2).Interestingly, only one amino group of the acriflavine cation
Figure 2. The hydrogen bonding network in the crystal packing of the titlecompound, viewed along the crystallographic a-axis. Hydrogen bonds and NAO� � �Ninteractions are represented by dashed lines,A NAO� � �p and p–p interactions bydotted lines.
A. Sikorski, D. Trzybinski / Tetrahedron Letters 55 (2014) 2253–2255 2255
interacts with the carboxylic groups of the monoanionic trimer viaan NAH� � �O hydrogen bond [d(N� � �O) = 3.065(3)–3.079(4) Å,<(NAH� � �O) = 155(3)–168(3)�], producing a centrosymmetricsupramolecular synthon R8
6 (28).22 The second amino group inter-acts via an NAH� � �O hydrogen bond with nitro groups of the neutral(A) and anionic (B) moieties of 3,5-dinitrobenzoic acid[d(N� � �O) = 2.997(4)–3.007(4) Å, <(NAH� � �O) = 128(3)–170(3)�].
In summary, this communication presents the first structurallycharacterized salt containing an acriflavine cation and the trimer of3,5-dinitrobenzoic acid. Ideas drawn from crystal engineeringenabled us to obtain crystals of the title compound. Examinationof the crystal structure and analysis of the intermolecular interac-tions occurring between the ions in the crystal of the titlecompound extend knowledge of acriflavine and may lead to a bet-ter understanding of the complex systems formed by aromatic car-boxylic acid moieties. Significantly, the knowledge that porousorganic frameworks can be formed by 3,5-dinitrobenzoic acidcould have great cognitive importance for supramolecular chemis-try and could be implemented in the future by crystal engineers inthe formation of stable, multicomponent crystalline systems, espe-cially those containing other aromatic nitrogenous bases.
Acknowledgments
This study was financed from the State Funds for Scientific Re-search through the National Science Center (NCN) in Poland, GrantNo. 2011/01/D/ST4/04943 (contract No. UMO-2011/01/D/ST4/04943). The authors would like to thank Dr. E. Sikorska for her helpwith the interpretation of the NMR spectra.
Supplementary data
Supplementary data (CIF file, geometry of intermolecular inter-actions, NMR, FTIR and DSC data) associated with this article can befound, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.02.074.
References and notes
1. (a) Patel, M. M.; Mali, M. D.; Patel, S. K. Bioorg. Med. Chem. Lett. 2010, 20, 6324;(b) Ciric, L.; Mullany, P.; Roberts, A. P. J. Antimicrob. Chemother. 2011, 66, 2235;(c) Vehar, B.; Hrast, M.; Kovac, A.; Konc, J.; Mariner, K.; Chopra, I.; O’Neill, A.;Janezic, D.; Gobec, S. Bioorg. Med. Chem. 2011, 19, 5137.
2. (a) Guo, C.; Gasparian, A. V.; Zhuang, Z.; Bosykh, D. A.; Komar, A. A.; Gudkov, A.V.; Gurova, K. V. Oncogene 2009, 28, 1151; (b) Neidle, S. FEBS J. 2010, 277, 1118;(c) Bilsland, A. E.; Cairney, C. J.; Nicol Keith, W. J. Cell. Mol. Med. 2011, 15, 179.
5. (a) Talacki, R.; Carrell, H. L.; Glusker, J. P. Acta Crystallogr. 1974, B30, 1044; (b)Seeman, N. C.; Day, R. O.; Rich, A. Nature 1975, 253, 324; (c) Ghose, S.;Chakrabarti, C.; Dattagupta, J. K.; Le Page, Y.; Trotter, J. Acta Crystallogr. 1988,C44, 1810.
6. (a) Obendorf, S. K.; Carrell, H. L.; Glusker, J. P. Acta Crystallogr. 1974, B30, 1408;(b) Reddy, B. S.; Seshadri, T. P.; Sakore, T. D.; Sobell, H. M. J. Mol. Biol. 1979, 135,
787; (c) Aggarwal, A.; Islam, S. A.; Kuroda, R.; Neidle, S. Biopolymers 1984, 23,1025.
7. (a) Wang, A. H.-J.; Quigley, G. J.; Rich, A. Nucleic Acids Res. 1979, 6, 3879; (b)Mattia, C. A.; Mazzarella, L.; Vitagliano, V.; Puliti, R. J. Crystallogr. Spectrosc. Res.1984, 14, 71; (c) Kuban, R.-J.; Kulpe, S.; Schulz, B. Cryst. Res. Technol. 1985, 20,1073.
8. (a) Song, S.; Kwon, O. S.; Chung, Y. B. Xenobiotica 2005, 35, 755; (b) Lee, K.;Zhang, H.; Qian, D. Z.; Rey, S.; Liu, J. O.; Semenza, G. L. PNAS 2009, 106, 17910;(c) Hassan, S.; Laryea, D.; Mahteme, H.; Felth, J.; Fryknäs, M.; Fayad, W.; Linder,S.; Rickardson, L.; Gullbo, J.; Graf, W.; Påhlman, L.; Glimelius, B.; Larsson, R.;Nygren, P. Cancer Sci. 2011, 102, 2206.
9. (a) Gavini, E.; Sanna, V.; Juliano, C.; Bonferoni, M. C.; Giunchedi, P. AAPSPharmSciTech 2002, 3, 7; (b) Kawai, M.; Yamagishi, J.-I. Microbiol. Immunol.2009, 53, 481; (c) Polat, Z. A.; Karakus, G. Parasitol. Res. 2013, 112, 529.
10. Desiraju, G. R.; Vittal, J. J.; Ramanan, A. Crystal Engineering—A Textbook; WorldScientific: Singapore, 2011.
11. Glusker, J. P.; Trueblood, K. N. Crystal Structure Analysis: A Primer, 3rd ed.;Oxford University Press: New York, 2010.
12. (a)Organic Crystal Engineering—Frontiers in Crystal Engineering; Tiekink, E. R. T.,Vittal, J., Zaworotko, M., Eds.; John Wiley and Sons: New York, 2010; (b) Bhatt,P. M.; Desiraju, G. R. CrystEngComm 2008, 10, 1747; (c) Braga, D.; Grepioni, F.;Maini, L.; Polito, M. Struct. Bond. 2009, 132, 25; (d) Aakeröy, C. B.; Champness,N. R.; Janiak, C. CrystEngComm 2010, 12, 22.
13. (a) Sikorski, A.; Trzybinski, D. Tetrahedron Lett. 2013, 54, 1463; (b) Trzybinski,D.; Sikorski, A. CrystEngComm 2013, 15, 6808; (c) Sikorski, A.; Trzybinski, D. J.Mol. Struct. 2013, 1049, 90.
14. (a) Jetti, R. K. R.; Thallapally, P. K.; Nangia, A.; Lam, C.-K.; Mak, T. C. W. Chem.Commun. 2002, 952; (b) Gagnon, E.; Maris, T.; Malyz, K. E.; Wuest, J. D.Tetrahedron 2007, 63, 6603; (c) Mossakowska, I.; Wójcik, G. M. J. Mol. Struct.2010, 967, 119.
15. Synthesis of the 3,6-diamino-10-methylacridin-10-ium 3,5-dinitrobenzoate�3,5-dinitrobenzoic acid�3,5-dinitrobenzoic acid : A mixture of commercially availableacriflavine hydrochloride (250 mg) and 3,5-dinitrobenzoic acid (613 mg) inabsolute EtOH (200 ml) was heated at reflux temperature for 15 min. Theresulting clear solution was allowed to evaporate for few days to give dark-orange single crystals of the title compound (mp = 159.6 �C); analysiscalculated/found for C35H25N9O18: C 48.9/48.8, H 2.9/2.9, N 14.6/14.6; 1HNMR: (500 MHz, DMSO-d6) d = 3.96 (s, 3H, CH3), 6.88 (d, 2H, J = 1.7 Hz, C4,5-H),7.00 (dd, 2H, J = 1.7 Hz, 8.9 Hz, C2,7-H), 7.85 (d, 2H, J = 8.9 Hz, C1,8-H), 8.74 (s,1H, C9-H), 8.91 (d, 6H, J = 2.2 Hz, C2,6-H DNBA), 8.95 (t, 3H, J = 2 Hz, C4-HDNBA); 13C NMR (125.7 MHz, DMSO-d6): d = 35.10, 93.85, 116.73, 133.56,142.87, 128.72, 120.97, 157.22 (C12,14), 143.62 (C3,6), 116.43 (C11,13), 137.29 (C1
Database (version 5.34, 2013).17. Smith, G.; Lynch, D. E.; Byriel, K. A.; Kennard, C. H. L. Aust. J. Chem. 1995, 48,
1133.18. Clegg, W.; Russo, L. Cryst. Growth Des. 2009, 9, 1158.19. Crystal structure analysis of the title compound: Single crystals were grown from
absolute ethanol. Diffraction data were collected at 100 K on an OxfordDiffraction Gemini R Ultra Ruby CCD diffractometer, employing a graphitemonochromated MoKa radiation source (k = 0.71073 Å). Crystal data for thetitle compound: C35H25N9O18, Mr = 859.64, triclinic, space group P-1,a = 7.3033(3) Å, b = 15.8416(6) Å, c = 17.3865(6) Å, a = 112.734(3)�,b = 95.075(3)�, c = 90.408(4)�, V = 1846.12(13) Å3, Z = 2, qcalcd = 1.546 g cm�3.The final R factor was 0.0611 (Rw = 0.1530) for 6478 reflections with I > 2r(I),GOF = 1.049. The lattice parameters were obtained by least-squares fit to theoptimized setting angles of the reflections by means of CrysAlis CCD. Thestructural resolution procedure was carried out with the SHELXS-97 package,solving the structure by direct methods and carrying out refinements by full-matrix least-squares on F2 using the SHELXL-97 program. CCDC 963583contains Supplementary crystallographic data for this Letter. These data can beobtained free of charge from the Cambridge Crystallographic Data Centre viawww.ccdc.cam.ac.uk/data_request/cif.
20. (a) Middlemiss, D. S.; Facchini, M.; Morrison, C. A.; Wilson, C. C. CrystEngComm2007, 9, 777; (b) Gavezzotti, A. Acta Crystallogr. 2008, B64, 401; (c) Ratajczak-Sitarz, M.; Katrusiak, A. J. Mol. Struct. 2011, 995, 29.
21. (a) Pedireddi, V. R.; Ranganathan, A.; Chatterjee, S. Tetrahedron Lett. 1998, 39,9831; (b) Arora, K. K.; Pedireddi, V. R. Tetrahedron 2004, 60, 919; (c) Arora, K.K.; Reddy, J. P.; Pedireddi, V. R. Tetrahedron 2005, 61, 10793.
22. (a) Etter, M. C. Acc. Chem. Res. 1990, 23, 120; (b) Etter, M. C.; MacDonald, J. C.;Bernstein, J. Acta Crystallogr. 1990, B46, 256; (c) Aakeröy, C. B. Acta Crystallogr.1997, B53, 569.
