Structural considerations on acridine/acridinium derivatives: Synthesis, crystal structure, Hirshfeld surface analysis and computational studies

Accepted Manuscript

Structural considerations on acridine/acridinium derivatives: synthesis, crystal

structure, Hirshfeld surface analysis and computational studies

Michał Wera, Piotr Storoniak, Illia E. Serdiuk, Beata Zadykowicz

PII:

S0022-2860(15)30343-4

10.1016/j.molstruc.2015.10.041

MOLSTR 21886

DOI:

Reference:

To appear in: Journal of Molecular Structure

Received Date: 6 July 2015

Revised Date: 21 September 2015

Accepted Date: 19 October 2015

Please cite this article as: M. Wera, P. Storoniak, I.E. Serdiuk, B. Zadykowicz, Structural considerations

on acridine/acridinium derivatives: synthesis, crystal structure, Hirshfeld surface analysis and

computational studies, Journal of Molecular Structure (2015), doi: 10.1016/j.molstruc.2015.10.041.

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Graphical abstract

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Structural considerations on acridine/acridinium

derivatives: synthesis, crystal structure, Hirshfeld

surface analysis and computational studies

Michał Wera^*, Piotr Storoniak, Illia E. Serdiuk, Beata Zadykowicz^*

Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, Poland

^*Corresponding author. Tel.: +48 58 523 51 13; fax: +48 58 523 50 12 (M. Wera, B. Zadykowicz);

E-mail address: michal.wera@ug.edu.pl (M. Wera); beata.zadykowicz@ug.edu.pl (B. Zadykowicz).

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Abstract

This article describes a detailed study of the molecular packing and intermolecular interactions in crystals of four

derivatives of acridine, i.e. 9-methyl-, 9-ethyl, 9-bromomethyl- and 9-piperidineacridine (1, 2, 3 and 4, respectively)

and three 10-methylacridinium salts containing the trifluoromethanesulphonate anion and 9-vinyl-, 9-bromomethyl,

and 9-phenyl-10-methylacridinium cations (5, 6 and 7, respectively). The crystal structures of all of the compounds

are stabilized by long-range electrostatic interactions, as well as by a network of short-range C–H O (in hydrates

and salts 3 and 5−7, respectively), C–H π, π–π, C–F π and S–O π (in salts 5−7) interactions. Hirshfeld surface

analysis shows that various intermolecular contacts play an important role in the crystal packing, graphically

exhibiting the differences in spatial arrangements of the acridine/acridinium derivatives under scrutiny here.

Additionally, computational methods have been used to compare the intermolecular interactions in the crystal

structures of the investigated compounds. Computations have confirmed the great contribution of dispersive

interactions for crystal lattice stability in the case of 9-substituted acridine and electrostatic interactions for the

crystal lattice stability in the case of 9-substituted 10-methylacridinium trifluoromethanesulphonates. The value of

crystal lattice energy and the electrostatic contribution in the crystal lattice energy of monohydrated acridine

derivatives have confirmed that these compounds have behave as acridinium derivatives.

Keywords Acridine and 10-methylacridinium derivatives · Crystal structure · Intra- and intermolecular interactions ·

Hirshfeld surface analysis

Introduction

Natural and synthetic acridine derivatives are among the oldest classes of bioactive agents. These

compounds exhibit fungicidal, antimicrobial, anti-parasitic, anti-inflammatory, anticancer and antiviral activities [1–

4]. Their anti-proliferative properties have been reported as well. Some acridine derivatives can bind DNA through

intercalation [1], which leads to cell apoptosis. In addition, acridine-based derivatives have been studied as

anticancer agents, which are believed to express their activity through the binding of DNA [2,5]. Similarly, 10-

substituted acridinium derivatives, with a rigid aromatic tricyclic ring system, have been shown to possess potent

chemo-sensitization pharmacophores [6].

On the other hand, an interesting group of acridine derivatives are those capable of chemiluminescence.

This property is displayed by acridinium cations alkyl-substituted at the endocyclic nitrogen atom and containing

electron-attracting substituents at C9. This latter atom is thus susceptible to the attack of anionic oxidants, e.g.

hydrogen peroxide and persulphates [7−13]. Oxidation gives rise to electronically excited N-alkyl-9-acridinones;

their relaxation is accompanied by the emission of light, i.e. chemiluminescence [7,8,10,11]. The efficiency of

chemiluminescence, no greater than a few per cent [7,11], can be affected by the presence of various substances in

the medium, including nucleophilic species, competing with oxidants for substitution at C9 [7,8,14]. This effect is

utilized in the assay of oxidants, nucleophiles or other entities, and in such cases acridinium cations serve as

chemiluminogenic indicators [7,9,14]. Acridinium chemiluminogens can also be linked by a spacer (e.g. an alkyl

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chain) to an active group capable of reacting with appropriate fragments of macromolecules. Such chemiluminescent

labels are widely used in chemical, medical, biological and environmental analyses [7–9,12].

We investigated the crystal structure as well as the intra- and intermolecular interactions of 10-methyl-9-

phenoxycarbonylacridinium derivatives [14−19] and 10-methyl-9-cyanoacridinium cations [20]. A disadvantage of

these acridinium derivatives is the relatively inefficiency of their chemiluminescence. This encouraged us to search

for new acridinium-based derivatives capable of reacting more efficiently with oxidizing agents to produce light. 9-

Alkylacridine is the precursor of the 10-methyl-9-alkylacridinium cation, which displays a promising

chemiluminogenic ability [21,22].

Intermolecular interactions, such as hydrogen bonds and π–π interactions, are of fundamental importance for

supramolecular assembly and consequently for the properties of organic and inorganic compounds [23–25]. Self-

assembly and molecular recognition processes of the compounds play a significant role in the context of their use as

technological materials, drugs, or biologically active molecules [26–29]. Strong (O–H···O and N–H···O) and weak

(C–H···O) hydrogen bonding [30–35] remains the most reliable and widely used means of enforcing molecular

recognition of crystalline materials. On the other hand, other weaker forces (π–π interactions) [29,32,36–39] have

also been successfully utilized for such purposes. The increased interest in the understanding of the geometry,

energies and nature of hydrogen bonding [30–35] and π–π interactions [29,32,36–39] in the past two decades,

expressed primarily by the increasing number of publications on this topic, is understandable, given the enormous

importance of these forces in building supramolecular self-assemblies.

In this paper, we report the results of the X-ray crystal structure determination of seven new 9-substituted

acridine derivatives and 9-substituted-10-methylacridinium trifluoromethanesulphonates (Scheme 1). A comparative

characterization of the title compounds is carried out, and details regarding the structural differences between them

are discussed in the context of the intermolecular interactions present in the crystal state. In addition, intermolecular

non-covalent interactions were studied using the Hirshfeld surface analysis [40−42]. In order to understand the

nature of intra- and intermolecular interactions, we applied computational methods (CRYSTAL09 program at the

DFT level of theory). The latter approach, the crystal lattice energies (E_L), together with the electrostatic (E_c) and

dispersive contribution (E(D*)) to the crystal lattice energy, and basis set superposition error energy correction

(E_BSSE) were calculated and interpreted.

Materials and methods

Synthesis

The chemicals were purchased from Sigma-Aldrich unless indicated otherwise. The purity of the

compounds was checked by HPLC (Waters 600 E Multisolvent Delivery System, Waters 2487 Dual λ Absorbance

Detector; mobile phase: acetonitrile/water = 70%/30% supplemented with 0.1% of TFA; stationary phase: C-8

column, 3×150mm, ‘Symmetry’) (the relative areas under the main signal were >99% in all cases) and their identity

confirmed by mass spectrometry. The compounds obtained were subjected to elemental analyses (EAGER 200,

1

Carlo Erba Instruments) and TLC tests in the above-mentioned system. H spectra were recorded at room

temperature on a Bruker AVANCE III 500 MHz.

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9-Methylacridine (1). A mixture of 10 g of diphenylamine (59.1 mmol), acetic acid (10.0 mL), and anhydrous zinc

chloride (40.0 g, 293.5 mmol) was heated at 220°C for 17 h. The reaction mixture was digested with hot 10%

aqueous sulphuric acid and then strongly alkalified with concentrated aqueous ammonia to dissolve the zinc chloride.

The insoluble residue was extracted with toluene. The organic phase was washed with water (100 mL) and dried over

sodium sulphate. After evaporation of the solvent, the crude product was purified by column chromatography (eluent

n-hexane/ethyl acetate = 5/1 v/v). Yield 81 %; m.p. = 391 K; the % of elements found/calculated, C 86.93/87.01, H

1

5.74/5.74, N 7.09/7.25; H NMR (CD₃CN), δ, ppm (J, Hz): 3.06 (3H, s); 7.52 (2H, t, J = 7.5); 7.71 (2H, t, J = 7.4);

8.04 (2H, d, J = 8.6); 8.28 (2H, d, J = 8.8).

9-Ethylacridine (2). A mixture of 0.17 g of diphenylamine (1 mmol), 1.1 ml propionic acid (15 mmol) and 0.46 g

zinc chloride (3 mmol) was stirred and microwave-irradiated at 110°C and 120 W for 2h. The mixture was diluted

with dichloromethane, washed with water, diluted with sodium hydroxide, washed again with water and dried over

magnesium sulphate. After evaporation of the solvent, the crude product was purified by column chromatography

(eluent 1−3% 2-propanol in chloroform). Yield 87 %; m.p. = 387 K; the % of elements found/calculated, C

86.69/86.92, H 6.34/6.32, N 6.71/6.76; ¹H NMR (CDCl₃), δ, ppm (J, Hz): 1.47 (3H, t, J = 7.7); 3.65 (2H, q, J = 7.7);

7.56 (2H, t, J = 7.7); 7.77 (2H, t, J = 8.0); 8.26 (4H, d, J = 8.8).

9-Bromomethylacridine (3) was synthesized according to the procedure described in [43]. Yield 77 %; m.p. = 443 K;

the % of elements found/calculated, C 61.26/61.79, H 3.64/3.70, N 5.03/5.15; ¹H NMR (CDCl₃), δ, ppm (J, Hz): 5.38

(2H, s); 7.62 (2H, t, J = 7.7); 7.78 (2H, t, J = 7.7); 8.31 (4H, d, J = 8.8).

9-Piperidylacridine (4). 0.213 g (1.0 mmol) of 9-chloroacridine hydrochloride was dissolved in 2 ml piperidine and

heated to 90°C with constant stirring for 6 h. The solvent was evaporated under vacuum at 50°C. The residue was

washed with aqueous methanol and dried in a vacuum. Yield 91 %; m.p. = 383 K; the % of elements

1

found/calculated, C 81.96/82.41, H 7.01/6.92, N 10.93/10.68; H NMR (CDCl₃), δ, ppm (J, Hz): 1.80 (2H, m); 1.84

(4H, m); 3.59 (4H, m); 7.38 (2H, t, J = 7.6); 7.64 (2H, t, J = 7.6); 8.15 (2H, d, J = 8.6); 8.28 (2H, d, J = 8.9).

General procedure for the synthesis of 10-methylacridinium trifluoromethanesulphonate derivatives To a solution of

1 mmol of an acridine derivative in 10 ml dry dichloromethane were added 4 mmol 2,6-ditert-butylpyridine and 5

mmol methyl trifluoromethanesulphonate. The solution was stirred at room temperature for 3 h. The precipitate was

filtered off and washed with dichloromethane. The filtrate was evaporated under vacuum at room temperature to 5

ml and diluted with diethyl ether. The precipitate was filtered and vacuum-dried.

10-Methyl-9-vinyl-acridinium trifluoromethanesulphonate (5). First, we synthesized the precursor of 10-methyl-9-

vinylacridinium trifluoromethanesulphonate − 9-vinylacridine – following the procedure described below. To a

suspension of 0.535 g (1.5 mmol) triphenylmethylphosphonium bromide in 10 ml dry diethylether was added 0.168

g (1.5 mmol) of potassium tert-butylate and stirred for 30 min. Then 0.207 g (1.0 mmol) acridine-9-carboxaldehyde

was added and the mixture stirred at ambient temperature overnight. After dilution with 50 ml dichloromethane, the

solution was washed with water three times, after which the organic layer was separated, dried over magnesium

sulphate and evaporated to dryness. The target compound was purified by column chromatography (eluent 1% 2-

propanol in chloroform). Yield 73 %; m.p. = 350 K; the % of elements found/calculated, C 87.27/87.77, H 5.66/5.40,

N 6.48/6.82; ¹H NMR (CDCl₃), δ, ppm (J, Hz): 5.60 (1H, d, J = 11.8); 5.98 (1H, d, J = 11.8); 7.32 (1H, dd, J = 11.8);

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7.39 (2H, t, J = 7.5); 7.65 (2H, t, J = 7.5); 8.13 (4H, d, J = 8.9). Pure 9-vinylacridine was converted to 10-

methylacridinium derivatives according to the general procedure for synthesizing 10-methylacridinium

1

trifluoromethanesulphonate derivatives described above. Yield 83 %; m.p. = 442 K; H NMR (CD₃CN), δ, ppm (J,

Hz): 4.78 (3H, s); 5.94 (1H, d, 17.5); 6.46 (1H, d, 11.8); 7.80 (1H, m); 7.97 (2H, m); 8.42 (2H, m); 8.58 (2H, d, J =

8.4); 8.74 (2H, d, J = 7.7).

9-Bromomethyl-10-methylacridinium trifluoromethanesulphonate (6). Yield 87 %; m.p. = 487 K; ¹H NMR (CD₃CN),

δ, ppm (J, Hz): 4.79 (3H, s); 5.73 (2H, s); 8.10 (2H, t, J = 7.3); 8.43 (2H, t, J = 7.3); 8.63 (2H, d, J = 9.2); 8.81 (2H, d,

J = 8.7).

10-Methyl-9-phenyl-acridinium trifluoromethanesulphonate (7). Yield 79 %; ¹H NMR (CD₃CN), δ, ppm (J, Hz): 4.87

(3H, s); 7.62 (1H, d, 8.8); 7.78 (2H, m); 7.89 (4H, m); 8.07 (2H, d, 8.8); 8.40 (2H, t, 7.6); 8.65 (2H, d, J = 8.8).

Crystals suitable for X-ray investigations were grown by slow evaporation of dichloromethane in the

case of 1, 3, 4, 5, 6 and 7 and dichloromethane:acetonitrile (1:1 v/v) solution in the case of 2.

Single crystal X-ray diffraction analysis

Crystallographic data were collected on an Oxford Diffraction Gemini R Ultra Ruby CCD diffractometer

with graphite-monochromatic Cu-K_αradiation (λ = 1.54184 Å) at 295 K. Data sets were collected using the ω scan

technique. The CrysAlis CCD [44] and CrysAlis RED [45] programs were used for data collection, cell refinement

and data reduction, and a multi-scan absorption correction was applied. Crystal data and details concerning the

structural refinement are given in Table 1.

Structures were solved by direct methods using SHELXS-97 [46]. The initial model was refined by the full-

matrix least squares method on F²with SHELXL2013 [47], adopting anisotropic thermal parameters for non-

hydrogen atoms. The H-atoms of the water molecules were located on a Fourier-difference map, restrained by DFIX

command 0.85 for O–H distances and by DFIX 1.39 for H···H distance and refined as riding with U_iso(H) =

1.5U_eq(O). All other hydrogen atoms were positioned stereochemically and refined with fixed individual isotropic

2

3

displacement parameters [U_iso(H)=1.2Ueq (C_sp) or 1.5Ueq(C_sp)] using a riding model with C–H bond lengths of

2

3

either 0.93 Å(C_sp) or 0.96 Å(methyl C_sp) and 0.97 Å(non-methyl C_sp).

ORTEP-3 [48] software was used to prepare the molecular graphics and the PLATON [49] and

CrystalExplorer 3.1 [50] programs to reveal and analyse the molecular interactions.

Computational details

Calculations were carried out using the periodic ab initio CRYSTAL09 program [51] at the density

functional theory (DFT) level [52], using the B3LYP functional [53–55] and 6-31G** basis sets [56,57]. For a given

experimental crystal structure, single point calculations of periodic wave function and energy were performed. Using

calculated total energies, being the sum of electronic and nuclear repulsion energy, the cohesive energy of the crystal

can be obtained according to the following formula [58]:

E_bulk

E_c=

− E_mol

Z

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where E_bulkis the total energy of the unit cell, Z is the number of molecules in the unit cell, and E_molis the total

energy of the molecule extracted from the bulk. The ab initio DFT total energy values obtained, were subsequently

corrected to take into account dispersive interactions. Here, we employed empirically modified Grimme dispersion

correction proposed by Civalleri et al. for molecular crystals (model in the original work referred to as B3LYP-D*)

[58].

In order to avoid overestimation of the strength of interactions within crystals, cohesive energies E_cwere additionally

corrected for basis set superposition error by the counterpoise method [59] implemented in the CRYSTAL09 code.

Final theoretical lattice energy, E_L, from CRYSTAL09 calculation comprises of three terms:

E_L= E_c+ E(D*) + E_BSSE

Theoretical cohesive energies E_Lmay be compared with lattice energies obtained from experimental sublimation

enthalpies.

Calculations of the atomic point charges on nitrogen (N10) atom, necessary for prediction of the

electrostatic energy interactions were carried out at the DFT level [52] by reproducing the electrostatic

potential around molecules (ESP fit charges) [60]. In these calculations the M06-2X [31,61] functional was

employed together with the 6-31++G** basis set [62]. Calculations were carried out using the Gaussian 09

program [63].

Results and discussion

Molecular and crystal structure

In the target compound molecules, the bond lengths and angles characterizing the geometry of the acridine

rings (1–4) and the acridinium moieties (5–7) (Table 1, Scheme 1) are typical of unmethylated [19,64] and

methylated [65–67] acridine-based derivatives.

The asymmetric unit in acridines consists of one (1 and 4) or two (2 and 3) crystallographically independent

acridine molecules (A and B) (Figs 1 a–d). The asymmetric unit of 3 also contains two water molecules. In the

acridinium salts the asymmetric unit consists of one (5 and 7) or two (6) crystallographically independent ion pairs

(Figs 1 e–g).

In acridines unmethylated at the N10 position (1–4) the rings 1, 2 and 3 are all planar with a small dihedral

angle between rings 3 and 2 (Scheme 2, Table 1S in Supplementary material), creating a planar acridine core except

for compound 4, whose dihedral angle is significantly larger at 4.1 (2)°. In the methylated acridines (5–7) the RMS

deviations from planarity for ring 1 are slightly higher and the dihedral angle between rings 3 and 2 varies from 3.4

(1) to 9.3 (2)°, causing the acridinium core to be distorted.

In compound 4 (Fig. 1d) atoms C16 and C19 of the piperidine fragment occupy two positions in the

crystalline solid phase, with occupancy factors of 0.828(4) and 0.172(4) for C16/C19 and C16X/C19X, respectively.

The piperidine ring 4 (N15/C16–C20) is not planar, having a total puckering amplitude, Q_T, of 0.545(2) Å and a

conformation resembling a chair [φ = 64(3)° and θ = 3(1)°]; the disordered ring 4 (N15/C16X/C17–C18/C19X/C20)

is not planar either, with a total puckering amplitude, Q_T, of 0.270(8) Å [φ = 7(1)° and θ = 131(11)°] [68]. The

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following discussion and interaction calculations take only the major disordered part into account. The piperidine

ring 4 is twisted at an angle of 60.0 (1)° relative to the acridine skeleton.

Ring 4 in 10-methyl-9-phenylacridinium trifluoromethanesulphonate (7) is planar and twisted relative to the

acridine skeleton at an angle of 68.1 (1)°.

The structural analysis carried out with aid of PLATON revealed various types of intra- and intermolecular

interactions in the crystal lattices of the target compounds. These are listed in Tables 2−4 and illustrated in Figs 1 and

2. The molecules in all the crystal structures of these compounds are involved in π–π contacts (Table 3) [36]. Strong

hydrogen bonds of types O–H···O and O–H···N (Table 2, Figs 1 and 2) [30] occur only in the crystal structure of 3,

owing to the presence of water molecules. Weak hydrogen bonds like C–H···O [31,69] (2, 3, 5, 6 and 7) and C–

H···π [70] (4) occur as well (Table 2, Fig. 2). Furthermore, other interactions like S–O···π (5, 6 and 7) [32] and C–

F···π [32] (5 and 6) are present in the crystal structure of acridinium salts (Table 4, Figs 1 and 2).

Compounds 1 and 3 crystallize in the orthorhombic crystal system and in the P2₁2₁2₁space group. In the

crystal structure of 1 aromatic rings 2 and 3 are involved in π−π contacts (Table 3) [36] between two parallely

oriented molecules, creating columns along the a axis (Fig. 3). Molecules in adjacent columns are inclined at angles

of 51.4(1), 62.4(1) and 85.0(1)°. In the asymmetric unit of 3 molecules A and B of the title compound are inclined at

an angle of 77.3(2)°. In the crystal structure molecules A and B of 3 are linked via a hydrogen bonding bridge (of

types O–H···O and O–H···N) [30] via two water molecules forming chains along the a axis, and stabilized through

multidirectional π–π contacts (Table 3, Fig. 2) [36] in columns of homonymous molecules. Moreover, a weak C—

H···O (Table 2, Fig. 2) [31,69] hydrogen bond links adjacent chains along the b axis. Homonymous molecules in the

columns are parallel. Molecules A and A in adjacent columns are inclined at an angle of 31.7(2)°, molecules B and B

at 38.5(2)° and molecules A and B at 87.8(2)°.

Compounds 2, 5 and 7 crystallize in the monoclinic crystal system. For 2 the space group is P2₁/c. In the

asymmetric unit, molecules A and B of 2 are inclined at an angle of 73.4(2)°. Two A molecules in the crystal

structure are connected by π–π (Table 3, Fig. 2) [36] contacts forming dimers, and two B molecules also form dimers

via π–π (Table 3, Fig. 2) [36] contacts. Additionally, B molecules from adjacent dimers are connected by a weak C–

H···O type hydrogen bond (Table 2, Fig. 2) [31,69]. Homonymous molecules assemble into layers parallel to the

(100) plane. Molecules A in dimers are parallel and inclined in adjacent dimers at an angle of 89.8 (2)°. Molecules B

in dimers are parallel and inclined in adjacent dimers at an angle of 88.6 (2)°. In adjacent dimers molecules A and B

are inclined at an angle of 73.4 (2) or 45.4 (3)°. Molecules A and B produce two independent herringbone patterns,

rotated by 73.4(2)°, in the crystal structure of 2 (Fig. 3). A herringbone pattern also occurs in the crystal lattice of 5

and 7, where the mean planes of the adjacent acridinium moieties are parallel or inclined at angles of 18.2 (1)° in 5

and 65.8 (1)° in 7 (Fig. 3). In the crystal structure of 5 two cations are linked by π–π (Table 3, Fig. 2) [36] contacts

forming dimers connected to anions via C–H···O (Table 2, Fig. 2) [31,69], S–O···π (Table 4, Fig. 2) [32] and C–

F···π (Table 4, Fig. 2) [30] interactions. In the crystal structure of 7 ion pairs are linked by weak C–H···O type

hydrogen bonds (Table 2, Fig. 2) [31,69]. The adjacent cations are linked by π–π (Table 3, Fig. 2) [36] contacts

forming layers (parallel to (20-2) and the neighbouring cations and anions via C–H···O (Table 2, Fig. 2) [31,69] and

S–O···π (Table 4, Fig. 2) [32] interactions.

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Compounds 4 and 6 crystallize in the triclinic crystal system and in the P–1 space group. The molecules in

the crystal structure of both 4 and 6 are parallel and involved in π–π contacts. In 4 these contacts between aromatic

rings 1, 2 and 3 of two inversely oriented molecules form dimers linked via a weak C—H···π (Table 2, Fig. 2) [70]

hydrogen bond, in turn forming columns along the b axis (Fig. 3). The ion pairs in the crystal structure of 6 are

linked by S–O···π (Table 4, Fig. 2) [32] and C–F···π (Table 4, Fig. 2) [30] interactions, and cations A and B are

linked by π–π (Table 3, Fig. 2) [36] contacts, thereby forming dimers connected to anions from adjacent dimers via

C–H···O (Table 2, Fig. 2) [31,69] interactions.

The crystal structure of acridinium salts (5–7) is stabilized by a network of the above-mentioned specific

short-range interactions and by long-range electrostatic interactions between ions. Analysis of the packing of

acridinium salts reveals the formation of layers of cations and anions (Fig. 4).

Hirshfeld analysis

In order to profoundly examine the strength and role of the above listed hydrogen bonds and other

intermolecular contacts, and to estimate their importance for the crystal lattice stability, Hirshfeld surface analysis

and computational study have been conducted. Comprehensive analysis of Hirshfeld surfaces (Figs 5 and 1S in

Supplementary material), the associated fingerprint plots [71,72] (Figs 6 and 2S in Supplementary material) and the

percentage contributions of various close intermolecular contacts to the Hirshfeld surface area (Fig. 7) generated

with the CrystalExplorer 3.1 program [50], carried out in accordance with the rules outlined in the literature and the

examples described [40,41], confirms the occurrence of the interactions revealed by PLATON [49] and listed in

Tables 2–4.

The two-dimensional (d_e/d_i) fingerprint plots exhibit significant differences resulting from the interactions

occurring in the crystal lattice of the target compounds (Figs 6 and 7 and 2S in Supplementary material). A quite

high contribution of H···H contacts to the total Hirshfeld surface of all acridine and acridinium moieties is common

in organic molecular crystals. All acridine and acridinium moieties are involved in π–π contacts, which is confirmed

by the presence of light-green areas of the C C contributions to the Hirshfeld surface. An intermolecular C–H π

interaction (Table 2) is involved in molecule 2B: surprisingly, however, the presence of such an interaction is not

evident and the contributions of H C and C H contacts of both crystallographically independent molecules are

similar. This is not the case for compound 4, in which the H C and C H fingerprint plot exhibits the presence of

wings associated with weak C–H π interactions. For 3 the conspicuous presence of strong O–H N hydrogen bonds

in both crystallographically independent molecules is marked by the occurrence of long spikes with the contribution

of H N and N H contacts to the total Hirshfeld surface of 4.0% and 3.7% for molecules A and B, respectively.

Since the weak C–H O hydrogen bond involves only the 3B molecule its existence is indicated by a small spike

with a contribution of H O and O H contacts of 4.2%. Such distinctive spikes associated with weak intermolecular

C–H O hydrogen bonds are also present in the fingerprint plots of 5, 6A, 6B and 7, with respective contributions of

17.8%, 16.4%, 16.2% and 15.4%. The contribution of C O and O C contacts to the total Hirshfeld surface,

ascribed to S–O···π contacts, is relatively small (3.6%, 2.9%, 3.9% and 1.4% for 5, 6A, 6B and 7, respectively) for

interactions between oppositely charged ions. The F C and C F contacts denote the existence of C–F π

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interactions involving molecules 5 and 6 with contribution of 4.5% and 2.5%, respectively. Due to the high

proportion of hydrogen atoms in relation to the non-hydrogen atoms in a molecule and their presence in the most

outer fragments of the molecule, it is understandable that their contribution to the Hirshfeld surfaces is significant.

Crystal lattice energies

The crystal lattice energies (E_L), which are important thermodynamic characteristics of crystalline substances,

calculated for all compounds, together with the electrostatic contribution calculated from the difference in electronic

and nuclear repulsion energy of bulk crystal and molecules in the bulk (E_c), and dispersive contribution derived from

modified Grimme model (E(D*)) to the crystal lattice energy, are shown in Table 5. The crystal lattice energy values

are corrected for the value of basis set superposition error energy correction (E_BSSE), which are less than 4.0 kJ mol^–1

in the case of 9-substituted acridine (1,2,4) and between 94.8 and 98.1 kJ mol^–1in the case of 9-substituted 10-

methylacridinium trifluoromethanesulphonates (5–7). Basis set superposition error energy correction values (E_BSSE

)

for 9-bromomethylacridine monohydrate (3) are higher than in the other investigated 9-substituted acridine (1,2,4)

(62.9 kJ mol^–1). The crystal lattice energies and their electrostatic and dispersive contributions of 9-substituted

acridine and their 9-substituted 10-methylacridinium trifluoromethanesulphonates (Table 5) are typical of acridine

derivatives and their salts containing complex monovalent ions [73,74]. Only in the case of 9-bromomethylacridine

monohydrate (3), the crystal lattice energy and the electrostatic contribution in the crystal lattice energy are

significantly higher than in the other investigated 9-substituted acridine (1, 2, 4). Following these results, we

investigated ESP fitted atomic partial charges on N10 atom of the acridine/acridinium derivatives using two

methods: first, where atomic partial charges were calculated for all atoms of the electroneutral asymmetric unit, and

second, where atomic partial charges were calculated separately for molecules in the unit cell (assuming charge +1

for acridinium molecule and –1 for trifluoromethanesulphonate counterpart). The value of atomic partial charges on

N10 atom is ca. 5 times lower in the case of 9-substituted acridines than in the case of 10-methylacridinium

trifluoromethanesulphonates (Table 5). The value of the atomic partial charges on N10 atom of 9-

bromomethylacridine monohydrate is ca. 3 times higher than in the case of others investigated 9-substituted acridines

(–0.25 and –0.74, respectively; the second value is average for 1, 2 and 4), where the atomic partial charges were

calculated for all atoms of the electroneutral asymmetric unit. When atomic partial charges were calculated

separately for molecules in the unit cell, the value of the atomic partial charges on N10 atom of 9-

bromomethylacridine monohydrate (3) was similar to the value of the atomic partial charges on N10 atom of others

investigated 9-substituted acridines (1, 2 and 4). Taking into account general chemical knowledge, as well as the

information mentioned above, we consider that monohydrated acridine derivatives behave as acridinium derivatives

or acid–base pair. Therefore, the crystal lattice energy, the electrostatic contribution in the crystal lattice energy and

the basis set superposition error energy correction of 9-bromomethylacridine monohydrate (3) are higher than in non-

monohydrated acridine derivatives (1, 2, 4).

Knowing the crystal lattice energy, the electrostatic and dispersive contributions to the values of this

quantity can be found. As the data in Table 5 demonstrates, the main contribution to the crystal lattice energy of 9-

substituted acridine is from dispersive interactions, and that of 9-substituted 10-methylacridinium

9

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trifluoromethanesulphonates from electrostatic interactions. Therefore, theoretical analysis shows that the cohesive

forces in acridine derivatives (1–4) and in 10-methylacridinium salts (5–7) are of different origin.

Conclusion

Four derivatives of acridine, i.e. 9-methyl-, 9-ethyl, 9-bromomethyl- and 9-piperidineacridine and three 10-

methylacridinium salts containing the trifluoromethanesulphonate anion and 9-vinyl-, 9-bromomethyl, and 9-phenyl-

10-methylacridinium cations were obtained and structurally characterized.

The molecular arrangement in the crystals revealed that hydrogen bonds and van der Waals contacts play a

significant part in intermolecular interactions. The crystal structures of all of the target compounds are stabilized by

long-range electrostatic interactions, as well as by a network of short-range C–H O (in hydrates and salts, 3 and 5−7,

respectively), C–H π, π–π, and C–F π as well as S–O π (in salts 5−7) interactions. Hirshfeld surface analysis

shows that various intermolecular contacts play an important role in the crystal packing, revealing graphically the

differences in spatial arrangements of the investigated acridine/acridinium derivatives.

Computational methods have confirmed that crystal lattice energies and their electrostatic and dispersive

contributions of 9-substituted acridine and their 9-substituted 10-methylacridinium trifluoromethanesulphonates

(Table 5) are typical of acridine derivatives and their salts containing complex monovalent ions (ca. −140 and −530

kJ mol⁻¹, respectively). Computations have confirmed the great contribution of dispersive interactions for the crystal

lattice stability in the case of 9-substituted acridine and electrostative interactions for the crystal lattice stability in the

case of 9-substituted 10-methylacridinium trifluoromethanesulfonates. The value of crystal lattice energy, the

electrostatic contribution in the crystal lattice energy of monohydrated acridine derivatives have confirmed that these

compounds behave as acridinium derivatives.

An interesting aspect of the structural studies would be to correlate the structural parameters with the

physicochemical properties (obtained experimentally or computationally) of the target compounds. The correlations

would enable compounds with analytically interesting properties to be modelled. To shed more light on this issue,

however, it will be necessary to investigate the luminescent (fluorescent and/or chemiluminescent) properties of the

title compounds. This particular problem is one that we are currently investigating.

Supplementary data

Complete X-ray data have been deposited with the Cambridge Crystallographic Data Centre (CCDC) as

supplementary publications Nos. 1058681−1058687; copies of these data can be obtained, free of charge, on

application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44-(0)1223-336033 or e-mail:

deposit@ccdc.cam.ac.uk).

Acknowledgements This study was financed from the State Funds for Scientific Research through an NSC grant

2011/03/D/ST4/02419 (contract No. UMO-2011/03/D/ST4/02419). Calculations were carried out on the computers

of the Wroclaw Centre for Networking and Supercomputing (WCSS) (grants no. 196 and 215). This publication

10

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reflects the views only of the authors: the sponsor cannot be held responsible for any use which may be made of the

information contained herein.

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Table captions

Table 1 Crystal data and structural refinement

Table 2 Hydrogen bonds (Å, °)

Table 3 π–π contacts (Å, °)

Table 4 S–O∙∙∙π and C–F∙∙∙π interactions (Å, °)

Table 5 Theoretical lattice energies (E_L) calculated using CRYSTAL09 and contributions to the lattice energies: E_c

(cohesive energy calculated from the difference in electronic and nuclear repulsion energy of bulk crystal and

molecules in the bulk), E(D*) (dispersive contribution derived from modified Grimme model), E_BSSE(basis set

superposition error energy correction) and ESP fitted atomic partial charges on N10 atom of the

acridine/acridinium derivatives. All energies values in kJ mol^–1.

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Figure captions

Scheme 1 Canonical structures of the compounds investigated;

– 9-(bromomethyl)acridine monohydrate, – 9-piperidin-1-ylacridine,

trifluoromethanosulphonate, – 9-(bromomethyl)-10-methylacridinium trifluoromethanosulphonate,

1

– 9-methylacridine,

2 – 9-ethylacridine, 3

4

5

– 10-methyl-9-vinylacridinium

6

7 –

10-methyl-9-phenyl-acridinium trifluoromethanesulphonate

Scheme 2 Ring label and atom numbering scheme

Fig. 1 The molecular structure of compounds 1–7 (25% probability level ellipsoids represent non-H atoms;

small spheres of arbitrary radius represent H atoms) showing the labelling of atoms, the numbering of

aromatic ring centroids and O–H∙∙∙O, O–H∙∙∙N and C–H∙∙∙O (dashed lines) and S–O∙∙∙π and C–F∙∙∙π (dotted

lines) interactions

Fig. 2 The intermolecular in the crystal lattice of compounds investigated (see Tables 2–4 for details) (non-H atoms

are represented by 25% probability level ellipsoids; H atoms not involved in interactions have been omitted, those

involved in interactions are shown as small spheres of arbitrary radius). The O–H∙∙∙O, O–H∙∙∙N, C–H∙∙∙O and C–H∙∙∙π

interactions are represented by dashed lines; π∙∙∙π, S–O∙∙∙π and C–F∙∙∙π are represented by dotted lines

Fig. 3 The supramolecular arrangement of acridine (acridinium cation) moieties in the crystal structures

Fig. 4 Layers of cations and anions in the crystal structure of 5, 6 and 7

Fig. 5 The Hirshfeld surface (front (left) and reverse (right) views) of the acridine and acridinium cation moieties

reflecting the normalized contact distance (d_norm) with selected interactions listed in Tables 2–4

Fig. 6 Comparison of full fingerprint plots of acridine and acridinium cation moieties of compounds investigated

Fig. 7 The percentage contributions of various close intermolecular contacts to the Hirshfeld surface area. Other

contacts constitute: (3A) C∙∙∙N, N∙∙∙C, C∙∙∙Br, Br∙∙∙Br, Br∙∙∙O; (3B) , C∙∙∙N, N∙∙∙C, C∙∙∙Br, Br∙∙∙C, Br∙∙∙Br, Br∙∙∙O; (4) C∙∙∙N,

N∙∙∙C; (5) N∙∙∙O, N∙∙∙F, N∙∙∙S, C∙∙∙S; (6A and 6B) Br∙∙∙F, Br∙∙∙Br, N∙∙∙O, C∙∙∙N, N∙∙∙C; (7) C∙∙∙N, N∙∙∙C, N∙∙∙O

15

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Table 1 Crystal data and structural refinement

Experimental details

1

2

3

4

5

6

7

Empirical formula

Formula weight

C₁₄H₁₁

N

C₁₅H₁₃

N

C₁₄H₁₀NBr∙H₂O

290.16

C₁₈H₁₈N₂

262.34

C₁₆H₁₄N∙CF₃SO₃

369.35

C₁₅H₁₃NBr∙CF₃SO₃

436.24

C₂₀H₁₆N∙CF₃SO₃

419.41

193.24

295(2)

207.26

295(2)

Temperature [K]

295(2)

Wavelength

1.54184

Crystal system, space group

Unit cell dimensions [Å,°]

Orthorhombic, P 2₁2₁2₁

Monoclinic, P 2₁/c

Orthorhombic, P 2₁2₁2₁

Triclinic, P-1

Monoclinic, P 2₁/n

a = 9.6193(3)

b = 13.0378(3) β = 101.766(3)

c = 13.2859(4)

Triclinic, P -1

Monoclinic, P 2₁/n

a = 6.8716(3)

b = 11.2769(5)

c = 13.1594(7)

a = 17.0354(3)

b = 9.45596(12) β = 115.476(2)

c = 15.6179(3)

a

= 4.76180(4)

a = 7.1506(3) α = 70.461(4)

b = 9.9307(4) β = 86.742(3)

c = 11.3298(4) γ = 69.887(4)

a = 11.4473(6) α = 101.023(4)

b = 11.7778(7) β = 93.300(4)

c = 13.6223(6) γ = 112.071(5)

a = 9.6457(2)

b = 12.5613(2) β = 105.642(2)

c = 16.1104(3)

b = 16.10280(12)

c = 31.7756(2)

Volume [A³]

1019.73(8)

4, 1.259

2271.20(8)

8, 1.212

2436.50(3)

8, 1.582

710.43(6)

2, 1.226

1631.23(8)

4, 1.504

1653.63(16)

4, 1.752

1879.69(6)

4, 1.482

Z, Calculated density [Mg/m³

]

Absorption coeff. μ [mm^–1

F(000)

]

0.564

0.539

4.447

0.556

2.228

5.030

2.010

408

880

1168

280

760

872

864

Crystal description, colour

Crystal size [mm]

Plate, white

Block, white

Plate, yellow

Prism, orange

Needle, yellow

Plate, yellow

0.83 x 0.46 x 0.14

5.17–67.24

0.73 x 0.68 x 0.57

5.49–67.32

0.63 x 0.23 x 0.15

3.91–67.53

0.73 x 0.53 x 0.34

6.79–67.43

0.52 x 0.17 x 0.15

4.80–67.55

0.25 x 0.22 x 0.085

3.34–67.48

0.55 x 0.20 x 0.10

4.53–67.31

Θ range for data collection [°]

Limiting indices

-8<=h<=5, -11<=k<=13, -14<=l<=15

2987 / 1611 [R_int= 2.26%]

98.4%

-20<=h<=20, -11<=k<=11, -18<=l<=16

39777 / 4069 [R_int= 2.91%]

99.0%

-5<=h<=5, -19<=k<=19, -38<=l<=38

56027 / 4393 [R_int= 4.13%]

99.5%

-8<=h<=8, -11<=k<=11, -13<=l<=13

13166 / 2523 [R_int= 7.91%]

98.2%

-11<=h<=11, -13<=k<=15, -15<=l<=15

18269 / 2942 [R_int= 3.53%]

99.5%

-13<=h<=12, -14<=k<=14, -16<=l<=15

19923 / 5903 [R_int= 4.85%]

98.6%

-11<=h<=11, -15<=k<=14, -19<=l<=19

11770 / 3358 [R_int= 2.78%]

98.8%

Reflections collected / unique

Completeness 2Θ = 67.684

Absorption correction

Tmin, Tmax

Semi-empirical from equivalents

0.953, 0.726

Semi-empirical from equivalents

0.978, 0.404

Semi-empirical from equivalents

0.987, 0.307

Semi-empirical from equivalents

0.853, 0.742

Semi-empirical from equivalents

0.983, 0.703

Semi-empirical from equivalents

0.983, 0.703

Semi-empirical from equivalents

0.823, 0.642

Refinement method