Co-crystals and salts formed from 4-fluorobenzoic acid and heteroaromatic nitrogenous bases

Article abstract of DOI:10.1016/j.tetlet.2013.01.026

Acridine 4-fluorobenzoic acid (1) and 9-aminoacridinium 4-fluorobenzoate monohydrate (2) were synthesized and structurally characterized. The single-crystal structure was determined by X-ray diffraction. Analysis of the intermolecular interactions occurri

Full text of DOI:10.1016/j.tetlet.2013.01.026

Tetrahedron Letters 54 (2013) 1463–1466
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Co-crystals and salts formed from 4-fluorobenzoic acid and heteroaromatic
nitrogenous bases
⇑
´
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:
Acridine 4-fluorobenzoic acid (1) and 9-aminoacridinium 4-fluorobenzoate monohydrate (2) were
synthesized and structurally characterized. The single-crystal structure was determined by X-ray
diffraction. Analysis of the intermolecular interactions occurring in the crystal packing of both
compounds, especially those involving the fluorine atoms, was carried out. The formation of crystalline
salts or co-crystals from 4-fluorobenzoic acid was also examined.
Received 4 November 2012
Revised 16 December 2012
Accepted 8 January 2013
Available online 16 January 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Acridinium
4-Fluorobenzoic acid
X-ray crystal structure
Hydrogen bonding
Fluorine-involved interactions
The design and synthesis of multi-component crystalline sol-
ids—salts, co-crystals, and their solvates—occupy a special place
among the topics of modern crystal engineering.1–3 This important
field of solid state chemistry has developed rapidly since the 1960s,
particularly with the arrival of modern crystallographic tech-
niques.4 There is a strong preference for crystalline forms in the
context of medicinal applications, because they tend to be more
stable, reproducible, and amenable to purification than other types
of solids. Furthermore, such systems often exhibit widely different
physicochemical properties compared to their pure components. A
co-crystal differs from a crystalline salt in the following way: in a
salt, a proton is transferred from the acidic to the basic functional-
ity of the crystallization partner, whereas in a co-crystal no such
proton transfer takes place.5
Interesting research targets in this field are systems containing
the heteroaromatic nitrogenous bases acridine and 9-aminoacri-
dine. This is due to the well-known fact that acridine-based deriv-
atives exhibit biological activity, for example, antibacterial,6
antiviral,7 antiprion,8 antitumor,9 and antiprotozoal.10 This medic-
inal significance, in addition to their ability to react with suffi-
ciently strong carboxylic acids, makes them a natural target for
obtaining multi-component crystalline solids. Moreover, knowl-
edge of the nature (salt or co-crystal) of the crystalline products
arising from their reaction with acridine-based compounds is
important for a better understanding of molecular recognition
processes and may help in the preparation of pharmaceuticals. This
is particularly interesting in the case of organofluorine compounds,
which have applications in medicine11–13 and crystal engineering,
owing to their possible participation in C–HÁ Á ÁF, C–FÁ Á Á
p, and
FÁ Á ÁF intermolecular interactions.14–16
Here we present the crystal structure of two compounds ob-
tained in reactions of 4-fluorobenzoic acid with acridine (1) and
9-aminoacridine (2) (Scheme 1), and a detailed analysis of the
intermolecular interactions occurring in their crystal packing, with
particular emphasis on the interactions involving fluorine atoms.
To our knowledge, compound 2 is the first structurally character-
ized organic salt containing a 4-fluorobenzoate anion (excluding
metalloorganic compounds).
Single-crystal X-ray diffraction measurements show that com-
pound 1 crystallizes in the triclinic P-1 space group and forms
co-crystals with one acridine and one 4-fluorobenzoic acid mole-
cule in the asymmetric unit (Fig. S1a, Table S1).
The bond lengths and angles characterizing the geometry of the
acridine skeleton17 and 4-fluorobenzoic acid molecule18 are typical
of these groups of compounds.
Analysis of the hydrogen bonds in the structure of 1 shows that
the 4-fluorobenzoic acid and acridine molecules interact via strong
O
(carboxy)–HÁ Á ÁN(acridine) hydrogen bonds [d(O22Á Á ÁN10) = 2.673(3) Å
and \(O22–H22Á Á ÁN10) = 168(3)°] (Fig. S1a, Table S2). These pairs
of molecules are linked to the nearest pairs of molecules by
C
(acridine)–HÁ Á ÁO(carboxy) hydrogen bonds [d(C9Á Á ÁO23) = 3.265(3) Å
and \(C9–H9Á Á ÁO23) = 149°], inverted via the crystallographic
⇑
inversion center, to form tetramers generating an R44(18) hydrogen
Corresponding author. Tel.: +48 58 523 5425; fax: +48 58 523 54 72.
E-mail address: art@chem.univ.gda.pl (A. Sikorski).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.026

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A. Sikorski, D. Trzybinski / Tetrahedron Letters 54 (2013) 1463–1466
Scheme 1. Synthesis of complexes 1 and 2.
bond ring motif19,20 (Fig. S1b, Table S2). The tetramers are also sta-
bilized via interactions between parallel acridine moieties
skeleton and the aromatic ring of the 4-fluorobenzoic acid mole-
cule [d(H7Á Á ÁCg4) = 2.88 Å and \(C7–H7ÁÁÁCg4) = 150°] (Fig. 1,
Table S2). In the supramolecular architecture, the chains of rings
are arranged in layers along the crystallographic b-axis (Fig. S2).
Compound 2 forms triclinic crystals (P-1 space group) with two
9-aminoacridinium cations, two 4-fluorobenzoate anions and two
water molecules in the asymmetric unit, respectively, denoted A
and B (Fig. S3, Table S1). The geometric parameters (bond lengths
and angles) characterizing the 9-aminoacridinium21 and 4-fluor-
obenzoate22 moieties are typical for these units.
p–p
with centroidÁ Á Ácentroid distances (denoted by CgÁ Á ÁCg) from
3.660(1) to 3.790(1) Å, and with a separation between the mean
planes of the acridine skeleton of 3.470(1) Å (Fig. S2, Table S3).
The neighboring tetramers are linked via C(acridine)–HÁ Á ÁF hydrogen
bonds [d(C4Á Á ÁF24) = 3.225(3) Å and <(C4–H4Á Á ÁF24) = 122°] and
p–p interactions between the aromatic rings of the 4-fluorobenzo-
ic acid molecule [d(CgÁ Á ÁCg) = 3.914(1) Å] (the separation between
the mean planes of the aromatic rings is 3.494(1) Å) forming chains
of rings (Figs. 1 and S2, Tables S2 and S3). The neighboring chains
Analysis of the hydrogen bonds in the structure of 2 shows that
the ions are linked via N(amino)–HÁ Á ÁO(carboxy) hydrogen bonds
of rings exhibit C(acridine)–HÁ Á Á
p interactions between the acridine
Figure 1. Network of the intermolecular interactions in 1: O–HÁ Á ÁN, C–HÁ Á ÁO, C–HÁ Á ÁF, and C–HÁ Á Á
p hydrogen bonds are represented by dashed lines, and p–p interactions by
dotted lines. Symmetry codes: (i) Àx+1, Ày+2, Àz+1; (ii) Àx+1, Ày+1, Àz +1; (iii) Àx+2, Ày+1, Àz.

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A. Sikorski, D. Trzybinski / Tetrahedron Letters 54 (2013) 1463–1466
[d(NÁÁÁO) = 2.821(3)–3.132(3) Å and \(N–HÁ Á ÁO) = 158–162°] to
form tetramers (Fig. S3, Table S4). In these tetramers, the amino groups
of both 9-aminoacridinium cations and one of the O-atoms from the
carboxy groups of both 4-fluorobenzoate anions participate in the
hydrogen bonds, producing an R22(8) hydrogen bond ring motif.19,20
The O23A and O23B atoms from both carboxy groups involved in the
formation of the R22(8) hydrogen bond ring motif also take part in the
the layers are connected via C–FÁ Á Áp(4-fluorobenzoate) interactions
[d(F25AÁ Á ÁCg4B) = 3.583(3) Å and \(C19A–F25AÁ Á ÁCg4B) = 96.9(2)°]
between 4-fluorobenzoate anions, producing a three-dimensional
structure (Fig. S4, Table S6).
It is assumed that the formation of a crystalline salt or co-crys-
tal can be predicted from the pKa values of the components partic-
ipating in the formation of both forms.23,24 Generally, salt
formation requires a difference of about three pKa units between
C(acridine)–HÁÁÁO(carboxy) hydrogen bonds [d(CÁÁÁO) = 3.351(3)–3.370(3)
Å and \(C–HÁ ÁÁO) = 152–166°], which stabilizes these tetramers. In
addition, the N(amino)–HÁÁÁO(carboxy) hydrogen bond [d(N15BÁÁ ÁO24B) =
3.074(3) Å and \(N15B–H15CÁÁÁO24B) = 119°] is observed (Fig. S3,
Table S4). The neighboring tetramers interact directly via C(4-fluorobenzo-
the conjugate base and the conjugate acid [D
pKa >3].25,26 To ex-
plain why 4-fluorobenzoic acid (pKa = 4.14) forms a crystalline salt
or co-crystal, we evaluated the relationship between the formation
of these two forms and the
DpKa value for compounds 1 and 2, as
ate)–HÁÁÁO(carboxy) [d(C18AÁ ÁÁO23B) = 3.302(4)
Å
and \(C18A–
well as other known crystal structures containing heteroaromatic
nitrogenous bases and 4-fluorobenzoic acid (Table 1).27,28 Compar-
ison of the acidity of aromatic nitrogenous bases and 4-fluoroben-
H18AÁ Á ÁO23B) = 134°] hydrogen bonds and C(acridine)–HÁ Á Áp(4-fluor-
[d(H6AÁ Á ÁCg4B) = 2.96 Å and \(C6A–H6AÁ Á ÁCg4B) = 147°]
obenzoate)
interactions, or are linked indirectly through hydrogen bonds with
water molecules as donors/acceptors of H–atoms (Fig. 2, Table S4).
Thus, the tetramers inverted via the inversion center are linked by
zoic acid shows that co-crystals are formed when the
<1.56 (acridine, isonicotinamide), but that when pKa exceeds this
value, crystalline salts (9-aminoacridine) are formed. The pKa va-
DpKa value is
D
D
O
(water)–HÁ Á ÁO(carboxy) [d(OÁ Á ÁO) = 2.692(3)–2.764(3) Å and \(O–
lue is 1.56 for the compound containing lamotrigine and 4-fluoro-
benzoic acid, which crystallizes in two forms (neutral and ionic)
co-existing in the asymmetric part of the unit cell. This may sug-
gest that this compound exists in an intermediate state between
the formation of co-crystals and salts produced by 4-fluorobenzoic
acid.
HÁ Á ÁO) = 169(3)–177(3)°], O(water)–HÁ Á ÁO(water) [d(OÁ Á ÁO) = 2.830(3)
Å and \(O–HÁ Á ÁO) = 163(3)°] and N(acridine)–HÁ Á ÁO(water) [d(NÁÁÁO) =
2.731(3)–2.832(3) Å and \(N–HÁ Á ÁO) = 169–171°] hydrogen bonds,
forming layers along the crystallographic (101) plane (Fig. 2,
Table S4). In these layers, the acridinium skeletons interact via p–
p
interactions [d(CgÁ Á ÁCg) = 3.616(1)–3.830(1) Å with separations
To conclude, the products of reactions between acridine/9-ami-
noacridine and 4-fluorobenzoic acid are obtained in two crystalline
forms: a co-crystal [acridine and 4-fluorobenzoic acid adduct (1)]
from 3.355(1) to 3.495(1) Å], forming infinite
in the BAAB arrangement (Fig. 2, Table S5). In the crystal packing,
p–stacked columns
Figure 2. Network of intermolecular interactions in 2: N–HÁ Á ÁO, O–HÁ Á ÁO, and C–HÁ Á ÁO hydrogen bonds are represented by dashed lines, and C–HÁ Á Á
p and p–p interactions by
dotted lines (H atoms not involved in these interactions have been omitted). Symmetry codes: (i) Àx+2, Ày+1, Àz+1; (iii) Àx+2, Ày+1, Àz; (iv) Àx+1, Ày+1, Àz+1.

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A. Sikorski, D. Trzybinski / Tetrahedron Letters 54 (2013) 1463–1466
1466
Table 1
Supplementary data (experimental procedures, Figures and Ta-
bles) associated with this article can be found, in the online ver-
sion, at http://dx.doi.org/10.1016/j.tetlet.2013.01.026. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
Acidity of complexes of heteroaromatic nitrogenous bases and 4-fluorobenzoic acid
a
Compound
pKa
D
pKa
Crystalline form
References
Acridine
5.60
9.90
3.67
5.70
1.46
5.76
-0.47
1.56
Co-crystal
Salt
Co-crystal
Co-crystal and salt
This work
This work
27
9-Aminoacridine
Isonicotinamide
Lamotrigine
28
References and notes
a
The pKa value of 4-fluorobenzoic acid is 4.14.
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Crystallographic data for the structures reported in this Letter
have been deposited with the Cambridge Crystallographic Data
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