Anion-controlled networks of intermolecular interactions in the crystal structure of 9-aminoacridinium salts

Article abstract of DOI:10.1016/j.tet.2010.12.027

A series of salts, with the 9-aminoacridinium cation (9-AA) and aromatic carboxylic acid: benzoate (1), ortho-phthalate (2), and salicylate (3) anions have been synthesized and characterized using X-ray diffraction. In the crystal packing, the ions are li

Full text of DOI:10.1016/j.tet.2010.12.027

Tetrahedron 67 (2011) 1479e1484
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Anion-controlled networks of intermolecular interactions in the crystal structure
of 9-aminoacridinium salts
*
ꢀ
Artur Sikorski , Damian Trzybinski
ꢀ
ꢀ
Faculty of Chemistry, University of Gdansk, J. Sobieskiego 18, 80-952 Gdansk, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 August 2010
Received in revised form 6 November 2010
Accepted 9 December 2010
Available online 16 December 2010
A series of salts, with the 9-aminoacridinium cation (9-AA) and aromatic carboxylic acid: benzoate (1),
ortho-phthalate (2), and salicylate (3) anions have been synthesized and characterized using X-ray dif-
fraction. In the crystal packing, the ions are linked via NeH/O, OeH/O, and CeH/O hydrogen bonds.
Analysis of the hydrogen bonds in the crystal lattices of the title compounds shows that the cations and
anions form tetramers. The ions in these tetramers are linked via N(amino)eH/O(carboxy) hydrogen
bonds forming R22(8) (1 and 3) or R42(15) (2) hydrogen bond ring motifs. The cations interact through
pep
This paper is dedicated to Professor Jerzy
_
B1azejowski on his 65th birthday
interactions in the ABBA (1), AB (2) or ABA (3) arrangement to form columns (1 and 2) or chains (3).
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Crystal structure
9-Aminoacridine
Hydrogen bonds
pep Stacking
Crystal engineering
1. Introduction
9-Aminoacridine (9-AA) and its derivatives present a very in-
teresting object of research. This group of compounds exhibits
a wide spectrum of biological activities: antiamoebic, antibacterial,
antiprion, antitumor, antiinflammatory, antiimplantation, hyper-
tensive, and mutagenic.1 The potency of acridines as agents is due
to their ability to bind DNA through intercalation.2 9-AA is also used
as a D
pH-probe in a variety of biological systems.3
X-ray crystallographic investigations have been carried out on
the salts of 9-aminoacridine derivatives with different kind of acids
in attempts to understand their specific properties.4
Scheme 1. Donoreacceptor system in the 9-aminoacridiniumearomatic carboxylic
acid anion salts, where X¼eH (1), eCOOH (2), and eOH (3).
In this communication we report the synthesis and X-ray char-
acterization of a series of salts with the 9-aminoacridine cation and
the anions of aromatic carboxylic acidsebenzoic (1), ortho-phthalic
(2), and salicylic (3).
9-AA is one of the simplest representatives of the group of or-
ganic bases able to interact with biomolecules. The 9-AA cation
With such a structure, this cation can interact with different
kinds of anions via strong NeH/X or weak CeH/X, NeH/
p,
CeH/ hydrogen bonds, and estacking interactions. On the
p
p
other hand, aromatic carboxylic acid anions have two O atoms that
are strong hydrogen bonding acceptors and an aromatic ring,
which may interact through a CeH/X hydrogen bond or play
consists of three conjugated aromatic rings with an extended
p
system and contains two basic sites situated in the heterocyclic (in
the acridine skeleton) and exocyclic (in the amino-group) N atoms
(Scheme 1).
a
peelectron donor/acceptor role. In this context, an un-
derstanding of how these ions aggregate in crystal structures may
provide some interesting insight into the influences of different
kind anions on the geometry and packing of the 9-AA cation in the
crystal lattice.
* Corresponding author. Tel.: þ48 58 523 5425; fax: þ48 58 523 54 72; e-mail
address: art@chem.univ.gda.pl (A. Sikorski).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.12.027

ꢀ
A. Sikorski, D. Trzybinski / Tetrahedron 67 (2011) 1479e1484
1480
2. Results and discussion
2.1. 9-Aminoacridiniun benzoate (1)
Single-crystal X-ray diffraction measurements show that com-
pound 1 crystallizes in the triclinic Pꢀ1 space group with two 9-AA
cations, benzoic acid anions, and water molecules in the asym-
metric unit (Fig. S1, Table S1, Supplementary data).
In the packing of the molecules in 1, the crystal structure is sta-
bilized by NeH/O, OeH/O, and CeH/O hydrogen bonds (Table
S2, Supplementary data) and
pep interactions (Table S3,
Supplementary data). Analysis of the hydrogen bonds in the struc-
tureof 1 has shown that the ions form tetramers in the crystal lattice.
In these tetramers the ions are inverted via crystallographic in-
version center, and both cations A and B and the anions from the
asymmetric unit are involved in the formation of the R22(8) hydrogen
bond ring motif (Fig.1). In this motif, amino groups from the cations
and one O-atom of the carboxy-group from the anions participate in
the hydrogen bonds. Additionally, the O(carboxy)-atoms engaged in
the formation of this motif also take part in weak C(acridine)eH/O
(carboxy) hydrogen bonds. The water molecules in the crystal lattice
of 1 act as linkers between the tetramers. The tetramers in 1 are
connected by N(acridine)eH/O(water) hydrogen bonds, where the
O-atoms from the water molecules are acceptors for H-atoms
bonded to endocyclic N-atoms from the acridine skeleton. The tet-
ramers of 1 are additionally linked via an O(water)eH/O(carboxy)
hydrogen bond, where the O-atoms from the carboxy-groups do not
participate in tetramer formation. The water molecules also interact
Fig. 1. Network the hydrogen bonds in the structure of 1 (R22(8) hydrogen bond ring
motif is highlighted in yellow).
adjacent ‘head to tail’ oriented acridine skeletons are linked via
p
-stacking interactions in the ABBA arrangement to form columns
(Fig. 2). All the aromatic rings from the acridine skeletons participate
in interactions and form a zigzag motif with centroid/centroid
ꢁ
with each other via OeH/O hydrogen bonds (O/O¼2.804 A)
pep
(Fig. 1a). Analysis of the
pep interactions in 1 shows that the
Fig. 2.
pep interactions in 1 (the column of acridine skeletons has shown as shadowed rectangle).

ꢀ
A. Sikorski, D. Trzybinski / Tetrahedron 67 (2011) 1479e1484
1481
ꢁ
distances from 3.583 to 3.810 A and distance between mean planes
ꢁ
of the neighboring acridine skeleton 3.488 A. In this arrangement,
the overlapping mode of neighboring cations shows that they are
alternately shifted along the longer axis of the acridine skeleton by
ꢁ
a distance of ca. 2.4 A. The neighboring ABBA arrangements are
ꢁ
shifted toward each other along the longer axis (by ca. 3.6 A) and the
ꢁ
shorter axis of the acridine skeleton (about ca. 2.1 A) and linked
through two, parallel
pep interactions between the A cations
ꢁ
(centroid/centroid¼3.828 A). Analysis of
pep interactions be-
tween the aromatic rings in the acid anions in 1 indicates that the
ꢁ
shortest centroid/centroid distance is equal 4.521 A. This shows
that the pestacking interactions are absent. In the supramolecular
architecture of 1, there are columns forming separated layers in
a stair-case motif (Fig. S2, Supplementary data).
2.2. 9-Aminoacridiniun ortho-phthalate (2)
Compound 2 form the orthorhombic crystals (Pbcaspace group)
with 9-AA cation, ortho-phtalate acid anion and water molecule in
the asymmetric unit (Fig. S3, Table S1, Supplementary data). The
crystal structure of 2 is stabilized by NeH/O, OeH/O, and
CeH/O hydrogen bonds (Table S4, Supplementary data) and pep
interactions (Table S5, Supplementary data).
Analysis of the hydrogen bonds in the structure of 2 has shown
that the ions, which form tetramers are linked via N(amino)eH/O
(carboxy) hydrogen bonds in the crystal lattice, as well as in 1.
However, in the tetramers of 2, the ions are inverted via the crys-
tallographic glide plane and forming the R42(15) hydrogen bond ring
motif (Fig. 3). The increase in the number of atoms forming the
hydrogen bond ring motif from eight in 1 to fifteen in 2 is a con-
sequence of the structure of the ortho-phthalic acid anion when
Fig. 3. Network the hydrogen bonds in the structure of 2 (R42(15) hydrogen bond ring
motif is highlighted in yellow).
Fig. 4.
pep interactions in 2.

ꢀ
A. Sikorski, D. Trzybinski / Tetrahedron 67 (2011) 1479e1484
1482
there is one protonated and one deprotonated carboxy group. This
means that each deprotonated O-atom from the anion takes part in
the formation of this motif. ortho-Phthalic acid anions form dimers
via OeH/O hydrogen bond between the protonated and depro-
tonated groups of anions. This hydrogen bond stabilizes the tetra-
mers as well as the C(acridine)eH/O(carboxy) hydrogen bonds.
The tetramers in 2 are linked through N(acridine)eH/O(water)
and O(water)eH/O(carboxy) hydrogen bond, as in 1, but there is
no OeH/O hydrogen bond between the water molecules (Fig. 4).
Analysis of the
oriented neighboring acridine skeletons in 2 interact through
stacking interactions in an AB arrangement forming columns. In
this arrangement, the interactions with centroid/centroid
pep interactions in 2 shows that the ‘head to tail’
p-
pep
distances from 3.607 to 3.974 E and distance between mean planes
of the neighboring acridine skeleton 3.395 E form a zigzag motif, as
in 1. In the overlapping mode of the neighboring acridine skeletons,
adjacent cations are alternately shifted along the shortest axis of
ꢁ
the acridine skeletons for a distance of ca. 1.4 A. Analysis of
pep
interactions between the aromatic rings in the acid anions in 2
ꢁ
show that the shortest centroid/centroid distance is 4.034 A. This
indicates that the
Fig. 5. Network the hydrogen bonds in the structure of 3 (R22(8) hydrogen bond ring
motif is highlighted in yellow).
pestacking interactions between benzene rings
from the acid anions are very weak. In the supramolecular archi-
tecture of 2, there are columns that form separate monolayers in
a zigzag motif (Fig. S4, Supplementary data).
Supplementary data) and
data).
pep interactions (Table S7, Supplementary
Analysis of the hydrogen bonds in 3 shows that the ions form
tetramers in the crystal lattices and in these tetramers the neigh-
boring cations and anions are linked via N(amino)eH/O(carboxy)
hydrogen bonds, as well as in 1 and 2. In the structure of 3, the ions
in the tetramers, inverted around a center of symmetry, form the
R22(8) hydrogen bond ring motif, as in 1 (Fig. 5). However, in contrast
to 1, there are two kinds of tetramers forming this motif. The first
tetramer is formed only when A cations and anions from the
2.3. 9-Aminoacridiniun salicylate (3)
Compound 3 crystallizes in the triclinic Pꢀ1 space group. The
asymmetric unit of 3 consists of two 9-AA cations and two salicylic acid
anions the water molecules are unobserved (Fig. S5, Table S1,
Supplementary data). The crystal structure of 3 is stabilized by
NeH/O, OeH/O, and CeH/O hydrogen bonds (Table S6,
Fig. 6.
pep interactions in 3.

ꢀ
A. Sikorski, D. Trzybinski / Tetrahedron 67 (2011) 1479e1484
1483
asymmetric unit are present, and the second only when B ions
that form separate monolayers in
Supplementary data).
a
zigzag motif (Fig. S6,
aggregate in the tetramers. In both tetramers, only one O-atom
from the carboxy group is engaged in the hydrogen bond ring motif.
This atom is also involved in weak C(acridine)eH/O(carboxy)
hydrogen bonds, which stabilize the tetramers. The second O-atom
from the carboxy group is involved in an intramolecular OeH/O
hydrogen bond, where the hydroxyl groups are donors of H-atoms.
Despite the fact that there is no water molecule in the structure of
3, in contrast to the other compounds, this O-atom is involved in
the N(acridine)eH/O(carboxy) hydrogen bonds that link the tet-
ramers. In the crystal lattice of 3, the neighboring acridine skeletons
In comparison to the title compounds, in the crystal structure of
9-aminoacridine, which crystallizes as a hemihydrate,5 the mole-
cules are aggregated in tetramers via N(amino)eH/N(acridine)
hydrogen bond, forming the R22(8) hydrogen bond ring motif, as in 1
and 3 (Fig. 7a). The water molecule connects the tetramers to one
another by means of an O(water)eH/N(acridine) hydrogen bond.
It is interesting that there are no
pep interactions between the
acridine skeletons in the structure of the 9-aminoacridine mono-
hydrate. However, the acridine skeletons rotating around the center
are linked by
p
ep
interactions in the ABA arrangement forming
of symmetry interact through CeH/p interactions. In the crystal
chains (Fig. 6). This is caused by the fact that the adjacent acridine
skeletons are not shifted but rotated in-plane with respect to one
packing of the 9-aminoacridine monohydrate we can observe the
supramolecular helical tubes, which are not present in the lattices
of the title compounds (Fig. 7b).
another by approximately 130ꢁ. As a result of this rotation, the
pep
interactions between the acridine skeletons form a zigzag motif
ꢁ
with centroid/centroid distances in the 3.545e4.076 A range and
3. Conclusion
distance between mean planes of the neighboring acridine skeleton
ꢁ
3.405 A. In this arrangement, however, only two aromatic rings of
To conclude: we report on the structures of a series of 9-amino-
acridinium salts with aromatic carboxylic acids. Conformational
Analysis of the hydrogen bonds in the crystal lattices of the title
compounds shows that the cations and anions form tetramers and
that the building of anions influences the geometry of the hydrogen
bond ring motifs, which are observed in the crystal packing of all
compounds. The ions in these tetramers are linked via N(amino)e
H/O(carboxy) hydrogen bonds forming R22(8) (1 and 3) or R42(15) (2)
hydrogen bond ring motifs. We also observe that the presence of
different kinds of anion determines how acridine skeletons interact
between themselves in the crystal packing. The 9-AA cations interact
cation A are involved in the
neighboring B and A cations. Analysis of the centroid/centroid
distances in this sequence shows that the distance between one
pair of the lateral aromatic rings, equal to 4.325 A, is too long to be
classed as a pep interaction. Analysis of pep interactions between
the aromatic rings in the acid anions in 3 show that the shortest
centroid/centroid distances is 4.326 A. This indicates that the
-stacking interactions between benzene ring from the acid anions
p-stack interactions between the
ꢁ
ꢁ
p
are absent. In the supramolecular architecture of 2, there are chains
only through
rangementto formcolumns(1 and 2)orchains(3). Ontheotherhand,
analysis of interactions between the aromatic rings in the acid
pep interactions in the ABBA (1), AB (2) or ABA (3) ar-
pep
anions indicates that the shortest centroid/centroid distances are
ꢁ
4.521, 4.034, and 4.326 A in 1, 2, and 3, respectively. This shows that
the p-stacking interactions are either very weak (2) or absent alto-
gether (1 and 3).
4. Experimental
4.1. General
The synthesis of compounds 1, 2, and 3 is described in
Supplementary data. Single crystals of 1e3 were grown by slow
evaporation of an ethanol solution.
4.2. Crystal structure determination
Good-quality single-crystal specimens of 1, 2, and 3 were se-
lected for the X-ray diffraction experiments at T¼295(2) K. They
were mounted with epoxy glue at the tip of glass capillaries. Dif-
fraction data were collected on a Oxford Diffraction Gemini R ULTRA
ꢁ
Ruby CCD diffractometer with Mo K
a
radiation (
l
¼0.71073 A). In all
cases, lattice parameters were obtained by least-squares fit to the
optimized setting angles of the collected reflections by means of
CrysAlis CCD6 Datawere reduced by using CrysAlis RED software with
applying multi-scan absorption corrections (Empirical absorption
correction using spherical harmonics, implemented in SCALE3
ABSPACK scaling algorithm). The structural resolution procedure
was made using the SHELXS-97 package solving the structures by
direct methods and carrying out refinements by full-matrix least-
squares on F2 using SHELXL-97 program.7 All interactions demon-
strated were found by PLATON program.8
Crystallographic data for the structures reported in this paper
have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication no. CCDC-770732 (1), CCDC-
770733 (2), and CCDC-770734 (3). Copies of the data can be obtained
Fig. 7. Network of the intermolecular interactions in the crystal structure of 9-ami-
noacridine monohydrate: hydrogen bonds (a) and crystal packing (b).

ꢀ
A. Sikorski, D. Trzybinski / Tetrahedron 67 (2011) 1479e1484
1484
free of charge on application to CCDC,12 Union Road, Cambridge CB2
References and notes
1EZ, UK (fax: þ44 1223 336 033; e-mail: deposit@ccdc.cam.ac.uk).
1. Shubber, E. K.; Jacobson-Kram, D.; Williams, J. R. Cell Biol. Toxicol. 1986, 3,
379e399; Stark, M. M.; Hall, N. C.; Nicholson, R. J.; Soelberg, K. Oral Surg., Oral
Med., Oral Pathol. 1968, 26, 560e562; Nguyen Thi, H. T.; Lee, C.-Y.; Teruya, K.; Ong,
W.-Y.; Doh-ura, K.; Go, M.-L. Bioorg. Med. Chem. 2008, 16, 6737e6746; Belmont,
P.; Bosson, J.; Godet, T.; Tiano, M. Anticancer Agents Med. Chem. 2007, 7, 139e169;
Sondhi, S. M.; Singh, N.; Kumar, A.; Lozach, O.; Meijer, L. Bioorg. Med. Chem. 2006,
14, 3758e3765; Asthana, P.; Rastogi, S.; Ghose, S.; Das, S. R. Indian J. Chem. 1991,
30B, 893e900; Salamanca, D. A.; Khalil, R. A. Biochem. Pharmacol. 2005, 70,
1537e1547; Sakore, T. D.; Jain, S. C.; Tsai, C.-C.; Sobell, H. M. Proc. Natl. Acad. Sci.
U.S.A. 1977, 74, 188e192.
Acknowledgements
This study was financed by the State Funds for Scientific Re-
search (DS/8220-4-0087-10 and BW 8220-5-0466-0). The authors
would like to thank J. Zawadzka, N. Targowska and W. Badzia˛g for
their help in the crystallization of title compounds.
ꢀ
2. Martínez, R.; Chacon-García, L. Curr. Med. Chem. 2005, 12, 127e151.
Supplementary data
3. Casadio, R.; Melandri, B. A. Arch. Biochem. Biophys. 1985, 238, 219e228.
4. Ghose, S.; Chakrabarti, C.; Dattagupta, J. K. J. Crystallogr. Spectrosc. Res. 1987, 17,
197e201; Ghose, S.; Chakrabarti, C.; Dattagupta, J. K.; Le Page, Y.; Trotter, J. Acta
Crystallogr. 1988, C44, 1810e1813; Smith, G.; Wermuth, U. D. Acta Crystallogr.
2008, C64, o428eo430; Smith, G.; Wermuth, U. D.; Sagatys, D. S. Acta Crystallogr.
2009, C65, o131eo133.
5. Chaudhuri, S. J. Chem. Soc., Chem. Commun. 1983, 1242e1243.
6. CrysAlis CCD and CrysAlis RED; Oxford Diffraction: Yarnton, England, 2008.
7. Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112e122.
Electronic supplementary data (ESI) available: experimental
details; crystal and structure refinement data for 1, 2, and 3; fig-
ures; hydrogen bonds; and pep interactions geometry. For ESI and
crystallographic data in CIF or other electronic format are available.
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.12.027.
8. Spek, A. L. Acta Crystallogr. 2009, D65, 148e155.