Solvent and Isotopic Effects on Acridine and ... - ACS Publications

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Solvent and Isotopic Effects on Acridine and Deuterated Acridine Polymorphism Published as part of the Crystal Growth & Design virtual special issue In Honor of Prof. G. R. Desiraju A. Kupka,† V. Vasylyeva,† D. W. M. Hofmann,*,‡ Kirill V. Yusenko,□ and K. Merz*,† †

Inorganic Chemistry 1, Ruhr-University Bochum, Universitätstrasse 150, 44801 Bochum, Germany CRS4, Piscina Manna 1, 09010 Pula, Italy □ Solid-Chem GmbH, Universitätsstr. 136, D-44799 Bochum, Germany ‡

S Supporting Information *

ABSTRACT: The influence of pure solvents (p.a.) and impure solvents (techn. quality) on the crystallization of polymorphic forms of non-, partial-, and per-deuterated acridine from solution was investigated. Remarkably different crystallization behavior of acridine and deuterated acridine related to the used solvents was observed, especially shown in the case of acetone.

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INTRODUCTION The smallest possible change in the molecular structure is the substitution of hydrogen by deuterium. This change in mass affects obviously all physical properties that depend directly on the proton or deuterium.1 Surprisingly, isotopic substitution also could influence the formation of crystalline polymorphs. Remarkable aggregation behavior, based on weak intermolecular interactions, has been observed in a few deuterated small organic compounds. In the case of pyridine, the existence of an additional lowtemperature crystallographic phase for d5-pyridine was discovered, in contrast to nondeuterated pyridine.2 Phase transition induced by H/D substitution is not restricted to pyridine. Recent investigations have shown that deuterated alloxane transforms to a new orthorhombic isotopomorphic phase with Z′ > 1.3 Comparable phenomena could be observed for pyridine derivatives. Our own investigations of pyridine-Noxide have shown that the aggregation of molecules in the solid state is very sensitive to small changes of the substitution pattern of the molecules, using partially deuterated pyridine-Noxides as examples. By careful controlling the thermal behavior, it is possible to obtain a low-temperature phase for per- and partially deuterated pyridine-N-oxides reproducibly. This phase does not exist for nondeuterated pyridine-N-oxide.4 Furthermore, recent interesting findings have shown that even the substitution of the reaction medium by its deuterated counterpart, e.g., heavy water for water, controls the formation of polymorphic modifications of simple amino acid glycine.5 Considering these examples of isotopic polymorphism under various conditions, we interested ourselves in investigating the © 2012 American Chemical Society

influence of pure solvents (p.a.) and impure solvents (techn. quality) on the crystallization process of deuterated and nondeuterated polymorphic acridine forms. Acridines are well used for different applications such as syntheses of antimalarials binding to protoporphyrin6 and anticancer DNA intercalating drugs.7 Crystallization from solution is a standard purification process for a wide range of industrial products and has an important role in the controlled isolation of polymorphs. Controlled crystallization of desired polymorphic acridine forms could have a crucial importance for the development of acridine based compounds.

In this work we focus on the crystallization of acridine, partially deuterated and per-deuterated acridine from ethanol and acetone. These solvents were chosen based on the investigations of McCabe into the self-association processes of acridine in solution.8 The authors postulated that different Received: July 11, 2012 Revised: October 27, 2012 Published: November 1, 2012 5966

dx.doi.org/10.1021/cg300959w | Cryst. Growth Des. 2012, 12, 5966−5971

Crystal Growth & Design

Article

Table 1. Crystallographic Data of the Polymorphic Forms of Acridine polymorph

form II

form III

form IV

form V

form VI

form VII

space group a [Å] b [Å] c [Å] β V [Å3] R1 (I > 2σ(I)) wR2 (all data) literature

P21/n 11.253 5.951 13.602 99.53 898.3 0.0381 0.1155 12

P21/c 6.069 18.818 16.283 95.16 1852.2 0.0472 0.0950 13

P212121 6.179 15.719 29.312 90 2846.8 0.0524 0.0815 13

Aa 20.04 5.95 16.37 110.63 1826.8

Cc 6.174 23.498 12.868 96.48 1854.8 0.043 0.0808 12

P21/n 6.057 22.813 13.204 95.94 1814.6 0.0573 0.1517 12

polarities of the organic solvents influence the H-bond donor/ acceptor properties in such a way that it might be possible to nucleate the assembly of different polymorphic forms in solution. Acridine is known to crystallize in six different polymorphs. Different polymorphic forms were first described in the 1950s and 60s,9−11 with very little structural information. However, in recent years the crystal structures of most of the polymorphic forms were studied in detail by Wolf12 and Braga13 (Table 1). The crystal structures of all polymorphic forms do not exhibit strong intermolecular interactions. Depending on the polymorphic form, the molecules are arranged by weak C···H, N···H, and/or π···π intermolecular interactions.

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Table 2. Polymorphic Forms Obtained from Saturated Solutions of Acridine, d4-Acridine and d9-Acridinea acridine d4-acridine d9-acridine a

ethanol p.a.

ethanol tech.

acetone p.a.

aceton tech.

II/III

II/II,IV

III/IV

II/IV

II III III

II/II,III III/II III

Two forms appearing concomitantly are separated by a comma.

crystallization of d9-acridine from ethanol p.a. Furthermore, different crystallization behavior is observed when using ethanol tech. Concomitant polymorphic forms are only obtained in the case of nondeuterated acridine. The lower purity of the solvent ethanol inhibits the crystallization of the polymorphic form III. The nondeuterated and per-deuterated acridines crystallize in the thermodynamically favored form II.15 Additionally, in the case of perdeuterated acridine the formation of the polymorphic form IV was observed. The different crystallization behavior of acridine and perdeuterated acridine related to the used solvents is significant in the case of acetone. In all experiments, nondeuterated acridine crystallizes from acetone (p.a.) in form II. In contrast, using acetone (p.a.) partially deuterated and per-deuterated acridine crystallize in form III. Comparable to the crystallization behavior from ethanol (technical quality), the crystallization from acetone (technical quality) shows that impurities may affect the crystallization process. In contrast to per-deuterated acridine, nondeuterated and partially deuterated acridine crystallized both in form III and form II. The comparison of crystallization screening of nondeuterated and deuterated acridine shows clearly the influence of the solvent on the crystallization process. The formation of different polymorphic forms can be recognized as a function of the polarity of the used solvents. As described, the preformation of different acridine aggregates in solution related to the solvents was observed by McCabe.8 By evaporative crystallization under inert gas conditions, using a Radleys Greenhouse Blowdown, McCabe’s group was able to obtain form III of acridine from acetone. On the basis of the polarity of the solvent, hydrogen bonds play an important role in molecular recognition processes and could be responsible for the formation of the different polymorphic forms.8 However, it is evident that not only the solvent is responsible for the crystallization process; additionally, the isotopic substitution influences the formation of different polymorphic modifications. It is known that the insertion of one nitrogen atom in the aromatic backbone leads to a significant change in crystal packing. Maly16 investigated

EXPERIMENTAL SECTION

Synthesis of d4-Acridine. Partially deuterated acridine was prepared by a Pt/Pd catalyzed reaction. A solution of 1 g (5.57 mmol) of acridine (ABCR, 98%), 0.017g of NaBD4, 0.05 g of Pt/C (10% loading) and 0.05g of Pd/C (10% loading) in 7 mL of D2O, was stirred for 1 h in an open vessel and then heated for 21 h at 155 °C in a closed vessel. The reaction mixture was taken up in CH2Cl2, filtered and washed several times with CH2Cl2. The organic phase was separated from the aqueous phase and evaporated. The product was obtained as a yellow crystalline solid. Yield: 0.74 g (3.99 mmol, 71.7%), 1H NMR [200 MHz, CD2Cl2]: δ (ppm) = 8.80, 8.19, 8.03, 7.78, 7.57, 13C NMR [50 MHz, CD2Cl2]: δ (ppm) = 150.0, 136.4, 130.6, 130.0, 128.7, 127.1, 126.2, 2H NMR [400 MHz, CH2Cl2]: δ (ppm) = 8.86, 8.25, 8.09, 7.84, 7.61, IR (ν [cm−1]): 3047, 2262, 1606, 1544, 1500, 1397, 1150, 1054, 961, 923, 820. Crystallization Screening. Ten milligrams of acridine (form II, ABCR, 98%), partially deuterated acridine and per-deuterated acridine (form II, Cambridge Isotopic Laboratories, Inc., 98%) were recrystallized respectively in 2 mL of the solvents acetone, technical acetone, ethanol, and technical ethanol at room temperature. The slow evaporation procedure was carried out at room temperature (∼21 °C) over 3−4 days in a glass vessel with a pierced lid. To reproduce the results of the crystallization investigations, the experiments were carried out three times on consecutive days. After removal of the solvents, the obtained crystalline materials were characterized by powder X-ray diffraction (PXRD), measured on a Bruker AXS Advance diffractometer in flat mode and Bragg−Brentano geometry using filtered CuKα radiation. Additionally the crystal structures of the polymorphic d9- and d4-acridine form III were determined by single crystal X-ray investigations.14 Depending on the degree of H/D exchange, a slight change in unit cell constants and cell volumes of d9and d4-acridine is observed. The results of the different crystallization behavior of non-, partially, and per-deuterated acridine are summarized in Table 2.

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RESULTS AND DISCUSSION Acridine crystallizes from ethanol p.a. in the polymorphic forms III and II (Table 2 and Supporting Information). In contrast, the polymorphic forms III and IV were obtained by 5967



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Figure 1. PXRD of (a) nondeuterated acridine from acetone p.a. adopting form II in four crystallization experiments, (b) nondeuterated acridine from acetone techn. adopting twice form II and once form II and III concomitantly, (c) per-deuterated acridine from acetone p.a. gives only form III in four crystallization experiments, (d) per-deuterated acridine from acetone techn. gives each time form III in three crystallization experiments.

Figure 2. (a) Intermolecular C−H···C interaction in the form II, (b) intermolecular C−H···N interaction in the form III, and (c) intermolecular C− H···N interaction in form IV.

the crystal structures of anthracene, acridine, phenazine, finding that while the hydrocarbons form on the basis of C−H···π interactions herringbone-like aggregation motifs, Hirshfeld surface analyses show that C−H···π interactions do not dominate the crystal structures of N-heterocyclic analogues. However, C−H···N interactions have a significant importance in the aggregation phenomena of N-heterocyclic analogues. The comparable importance of the C−H···N interactions could be responsible for the different crystallization behavior of nondeuterated and deuterated acridine from acetone (Figure 2). Clarke has shown15 that form III at slightly

elevated temperature rearranges into the thermodynamically more stable form II. On the basis of H/D-substitution, form III could be stabilized by forming C−D···N contacts and thus not easily rearranged to form II. To analyze the effect of the substitution of hydrogen by deuterium on a broader base, a comparison of all known aromatic deuterium compounds with their nondeuterated analogues was done. The analysis was performed by data mining. We used this method to derive separately for the deuterated and for the nondeuterated compounds effective pair 5968



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interactions gij(r) depend on the atom type and the distance. Four types of atoms have been defined: C, N, D, and H.

potentials. The obtained potentials have been compared and general trends have been observed caused by the isotopic effect. Data mining is a well-known method in artificial intelligence. The method serves to optimize the parameters of an arbitrary model. In molecular modeling the model consists of the atom pair potentials and the parameters of the potentials. These parameters have been optimized separately for the deuterated and for the nondeuterated compounds. The application of data mining is especially advantageous for the understanding of the effects of hydrogen−deuterium substitution, since a force field parametrized by data mining calculates directly the free energy of a system. In particular, a data mining force field (DMFF) includes effects of temperature, pressure, and isotopic substitution, which is important in our case. An alternative would be the application of quantum chemistry. However, quantum chemistry gives as a primary result the enthalpy. Effects of temperature, pressure, and mass must be added here in subsequent and tedious calculations. Moreover, in a third step the results must be transformed to effective potentials, to allow a plausible interpretation of the result. Therefore, we preferred the direct way to obtain effective potentials by data mining. The basic idea of data mining on crystal structures is that a function exists, which assigns a global minimum to any experimental crystal structure, provided the crystal structure is stable and not metastable. In fact, thermodynamics states that for any chemical system in equilibrium such a function exists. This function is called Gibbs free energy, Gibbs energy, or Gibbs function, or free enthalpy. That any equilibrated chemical systems is a global minimum can be exploited to parametrize any model in chemistry by classification. For this purpose two sets of structures are necessary: The first set contains the experimental crystal structures, which exhibit a global minimum for the free energy. The second set contains contains virtual crystal structures, which are not at the global minimum. This set is generated “in silico”. With these two sets the computer is trained until it is able to divide experimental and virtual structures in two classes: is and is not a minimum of Gibbs function. The fact that this method produces as result the free energy rather than the enthalpy should be illustrated in a short example. The method is based to train the interaction potentials, till the energy function is assigned among all possible polymorphs, the lowest energy to the experimental structure. This means, for example, if a high pressure or temperature structure is used for training, afterward the energy function assigns to this polymorph the lowest energy. If a second polymorph is stable at low pressure/temperature the energy function assigns after training to this structure the lowest energy. Obviously this energy function is adequate to predict the relative stability of polymorphs and includes effects of temperature and pressure; this function corresponds to the Gibbs function G (p, T) rather than the enthalpy obtained by quantum chemical calculations. In this context it is important to keep in mind that the interaction potential by themselves are dependent on pressure and temperature, and we denote the atom pair potentials for this reason with gij rather than eij in common force fields. A general description about the method can be found in the recently published textbook Data mining in Crystallography.17 Subsequently the procedure for this specific case is described. The energy function G was assumed as a sum of atom pair interactions as it is the case in the most force fields in use for molecular mechanics and molecular dynamics. The atom pair

ai

g (r ) ∑ with i ∈ {1, 3, 6} r 2i

To determine the parameters ai of the atom pair potentials it is necessary to define a set of correct structures and a set of wrong structures. The correct structures of per-deuterated aromatic compounds, which contain only C, D, and N, were obtained from the CSD [Supporting Information]. Compounds with sp3 hybridized carbons and compounds with possible hydrogen bonds N−H···N were excluded. Additionally, structures of the analogous nondeuterated compounds were added. Since all of these compounds have manifold entrances in the database, 77 experimental crystal structures were obtained. The virtual crystal structures of the class “wrong” have been generated in two ways: One part was generated by minimization of the experimental crystal structures; the other part was generated by crystal structure prediction. The crystal structure prediction was performed with FlexCryst, and during the prediction the space groups from number 1 till number 20 were taken into account. After the prediction the list of the obtained crystal structures according to their free energy were sorted and the first and second ranks were retained for the further procedure. After the definition of these two classes the initial potential was refined by introducing an error function, which weights the separation of these two classes by the potential function. The refinement was done by an iterative minimization of error function error with the simplex method: 77

errortot =

∑ errori with error = r.e.1+r.e.2 +r.e.exp i=1

The relative error function r.e. for a given crystal structure x is hereby defined as relative error between the experimental structure and the structure x after minimization with the actual energy function. If the energy of the minimized structure is below the energy of the experimental structure and violates the principle that the experimental structure should be the global minimum, the relative error is added to the total error. If the minimized structure is above the energy of the experimental structure, the relative error function does not contribute to the total error. ⎫ ⎧ 0 if Gexp ≤ Gxmin ⎪ Gxmin −Gexp ⎪ min r.e.(x) = ⎨ if Gexp > Gx ⎬ 2 ⎪ Gxmin 2 + Gexp ⎪ ⎩ ⎭

The obtained potentials are listed in Table 3. If the effective potentials are compared to van der Waals potentials in the literature, two particularities of effective potentials have to be considered. First, effective potentials are in native way dimensionless. The set of effective potentials is trained to assign to experimental structures a lower energy as to virtual structures. The multiplication of the energies with an arbitrary factor does not influence this property. The given potentials are scaled so that the carbon−carbon interaction at 3.8 Å has a value of 2.66. This coincides approximately to a calibration to kJ/mol. Second, the physical interpretation of van der Waals potentials does not necessarily hold. This concerns in particular 5969



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101.4 °C by substitution for deuterium. In addition, the potential is shifted to shorter distance. It is known that C−H bonds are slightly longer than C−D bonds and in consequence intermolecular distance slightly longer. However, this effect is very small (1.0145 times) and cannot explain the observed shift in our effective potential.18 The effect could be caused by the different techniques of the crystal structure determination. The deuterated compounds are very often determined with neutron scattering, but the nondeuterated are determined by X-ray scattering. Since X-ray scattering spots the position of the electrons, but neutron scattering the position of the nuclei, the X-ray scattering observe shorter distances for the intramolecular hydrogen bonds than the neutron scattering. As result, the effective potentials reflect that the electron cloud of hydrogen/ deuterium has a larger distance to neighboring atoms as the nucleus. Isotopic substitution can significantly modify thermodynamic properties. Such modification arises from the quantum mechanical nature of the motion of the nuclei, which leads to different vibrational energies and molar volumes. In the case of the molar volume isotope effect of hydrocarbons, the standard theory is that the volume differences arise from the C−H bond length being longer than the C−D bond length, because of the greater zero-point energy and vibrational amplitude of the C− H stretching vibration.19 In contrast Lacks20 has shown that the molar volume isotope effect of deuterated polyethylene is due to changes in the intermolecular distances rather than in the intramolecular distances. For the discussion of the different polymorphs, first the most stable polymorph of acridine and deutero-acridine have to be considered. For acridine it is known that the polymorph III can transform to polymorph II. Polymorphs III is built up by associated dimeric aggregates which interact by weak intermolecular C−H···N interactions. This indicates along with the former arguments that the dimer already might be a precursor in the solution, and, as a result, a metastable crystal is built up from these units rather than the thermodynamically stable crystal from the individual molecules. For deutero-acridine we observe the polymorphs II, III, and IV. The thermodynamically stable form might be II or IV. Comparing polymorph II and IV it can be found that polymorph II is built up of dimers, which interact by two C− H···π interactions. However, polymorph IV is built up from

Table 3. Parameter a1, a3, and a6 of the Intermolecular Interaction Potentials atom type 1

atom type 2

C C N H H H D D D

C N N H C N D C N

a1 0.540 −17.654 0.009 −3.519 −3.017 −5.608 −1.614 −4.189 −6.986

a3 −3 751 −629 −6 163 −7 96 −289 −2 114 −215

a6 [106] 11.259 2.312 14.653 0.114 0.004 0.492 0.072 0.005 0.188

the first term, the Coulomb term, which is interpreted as charge−charge interaction in van der Waals potentials. The parameter a1 can assume arbitrary values in effective potentials and does not have to coincide with a reasonable charge for a specific atom pair. The calculated effective intermolecular potentials are shown in Figure 3. Mainly the N···H potential is affected by the substitution by deuterium. The deuterium potential N···D is significantly lowered and shifted to a shorter distance in comparison to the hydrogen potential N···H. From the theoretical point of view, the first effect is expected. The second effect might be caused by an experimental bias for deuterium compounds. To understand the lowering of the C···H potential can be explained by a harmonic potential, where the zero-point vibration is given by

E=

h 4π

D μ

From this formula it follows that the interaction energy E increases with rising mass m. Since effective potentials include this isotopic effect, the minimum of the potential must go down. It is obvious that the effect becomes larger with a bigger force constant for D, and, as a consequence, the potential becomes narrower. This means that the substitution of hydrogen by deuterium mainly influences the narrow potentials and that it makes these interactions more likely and stronger for crystal structures and chemical systems of deuterated molecules; e.g., in heavy water the boiling point rises to

Figure 3. Calculated effective intermolecular potentials of D···C (light green), H···C (green), D···N (orange), H···N (red), D···D (light blue), and H···H (blue) interactions. 5970



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(3) Ibberson, R. M.; Marshall, W. G.; Budd, L. E.; Parsons, S.; Pulham, C. R.; Spanswick, C. K. CrystEngComm 2008, 10, 465. (4) Vasylyeva, V.; Kedziorski, T.; Metzler-Nolte, N.; Schauerte, C.; Merz, K. Cryst. Growth Des. 2010, 10, 4224. (5) Hughes, C. E.; Harris, K. D. M. New J. Chem. 2009, 33, 713. (6) (a) Peters, W.; Robinson, B. L. Ann. Trop. Med. Parasitol. 1992, 86, 455. (b) Dominguez, J. N. Curr. Top. Med. Chem. 2002, 2, 1173. (c) Ridley, R. G. Nature 2002, 415, 686. (d) Di Giorgio, C.; Delmas, F.; Filloux, N.; Robin, M.; Seferian, L.; Azas, N.; Gasquet, M.; Costa, M.; Timon-David, P.; Galy, J.-P. Antimicrob. Agents Chemother. 2003, 47, 174. (7) (a) Yang, X.; Robinson, H.; Gao, Y.-G.; Wang, A. H.-J. Biochemistry 2000, 39, 10950. (b) Baguley, B. C.; Wakelin, L. P. G.; Jacintho, J. D.; Kovacic, P. Curr. Med. Chem. 2003, 10, 2643. (c) Teulade-Fichou, M.-P.; Perrin, D.; Boutorine, A.; Polverari, D.; Vigneron, J.-P.; Lehn, J.-M.; Sun, J.-S.; Garestier, T.; Helene, C. J. Am. Chem. Soc. 2001, 123, 9283. (8) Musumeci, D.; Hunter, C. A.; McCabe, J. F. Cryst. Growth Des. 2010, 10, 1661. (9) Phillips, D. C. Acta Crystallogr. 1956, 9, 237. (10) Phillips, D. C.; Ahmed, F. R.; Barnes, W. H. Acta Crystallogr. 1960, 13, 365. (11) Herbstein, F. H.; Schmidt, G. M. J. Acta Crystallogr 1955, 8, 399. (12) Mei, X.; Wolf, C. Cryst. Growth Des. 2004, 4, 1099. (13) Rubini, K.; Mazzeo, P. P.; Maini, L.; Grepioni, F.; D.Braga, D. Thermochim. Acta 2010, 507, 1. (14) The crystal structure of polymorphic d9- and d4-acridine form III were also prepared by us using slow evaporation of acetone: Formula C13D9N; M = 188; crystal dimensions, 0.2 mm × 0.1 mm × 0.1 mm; monoclinic; space group, P21/c; a = 6.028(7) Å; b = 18.76(2) Å; c = 16.171(19) Å; β = 95.180(13)o, V = 1821(4) Å3; Z = 2, ρcalc = 1.373 g cm−3, 2θmax = 50°; T = 173 K, R1 (I > 2σ(I)) = 0.0709; wR2 (all data) = 0.1749; GOF = 1.077; Δρmax = 0.164 e Å3; Δρmin = −0,200 e Å3. Formula C13H3D4N; M = 183; crystal dimensions, 0.2 mm × 0.1 mm × 0.1 mm; monoclinic; space group, P21/c; a = 6.047(7) Å; b = 18.80(2) Å; c = 16.200(19) Å; β = 95.233(13)o, V = 1834(4) Å3; Z = 2, ρcalc = 1.342 g cm−3, 2θmax = 50°; T = 173 K, R1 (I > 2σ(I)) = 0.0364; wR2 (all data) = 0.0995; GOF = 1.030; Δρmax = 0.154 e Å3; Δρmin = −0.170 e Å3. Single-crystal X-ray diffraction measurements were carried out on a RigakuXtaLab Mini diffractometerusing graphitemonochromated Mo Kα radiation (λ = 0.71073). Structures were solved by the direct method, and all non-hydrogen atoms were refined anisotropically on F2 (program SHELXTL-97, G.M. Sheldrick, University of Göttingen, Göttingen, Germany). CIF-files giving Xray data with details of refinement procedures CCDC 891439 and 891440 are available free of charge via the Internet at http://pubs.acs. org. (15) Clarke, B. P.; Thomas, J. M.; Williams, J. O. Chem. Phys. Lett. 1975, 35, 251. (16) Maly, K. E. Cryst. Growth Des. 2011, 11, 5628. (17) Kuleshova, L. N.; Hofmann, D. W. M. Data Mining in Crystallography, Structure & Bonding; Springer Verlag: New York, 2010; Vol. 134. (18) Bates, F. S.; Wignall, G. D. Phys. Rev. Lett. 1986, 57, 1429. (19) Bartell, L. S.; Roskos, R. R. J. Chem. Phys. 1966, 44, 457. (20) Lacks, D. J. J. Chem. Phys. 1995, 103, 5085.

units of three molecules, which interact via two C−D···N interactions. This coincides very well with our considerations that the substitution of hydrogen by deuterium should favor the formation of additional C−D···N interactions. Another peculiarity, which was observed in the crystallization behavior of acridine, is the crystal structures obtained from acetone. The acridine itself forms the thermodynamically stable polymorph II, the deutero-acridine the metastable polymorph III. This requires that the deutero-acridine forms associated dimeric aggregates in solution. The associated dimeric aggregates of acridine are held together by two C−H/D···N interactions. Obviously the substitution of hydrogen by deuterium increases these interactions so strongly that for the deutero-acridine, the dimer is stable in acetone, while for acridine, this is not the case. This unit makes up part of the polymorph III. A comparable phenomenon is observed in pyridine and d5-pyridine. The stabilization of the C−H···N intermolecular interaction by H/D-substitution leads, in the case of d5-pyridine, to the polymorphic form II.2 In conclusion, crystallization experiments on acridine and deuterated acridine from solution revealed both the influence of the selected solvent, and the H/D substitution on the formation of different polymorphic forms. While acridine crystallized from acetone preferred to adopt the form II, similar crystallization experiments on per-deuterated acridine led exclusively to form III. The different crystallization behavior could be due to the different crystal packing in the forms II and III. H/D-substitution stabilizes C−H···N intermolecular interaction in form III and prevents the rearrangement into the more stable form II. The results of the investigations show that deuterium substitution as a weak directing substituent, may have quite an influence on the formation of polymorphic forms, taking into account the absence of strong specific intermolecular interactions in crystal structures such as acridine.

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ASSOCIATED CONTENT

S Supporting Information *

PXRD of the obtained crystalline materials: CSD query for deuterated compounds. Crystallization screening of acridine and per-deuterated acridine from ethanol (p.a. and techn.) and d4-acridine from acetone (p.a. and techn.). This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*(K.M.) Phone: + 49 234 24187. Fax: + 49 234 14378. E-mail: [email protected]. (D.W.H.) Phone: + 39 0709250369. Fax: 39 0709250216. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors gratefully acknowledge the Deutsche Forschungsgemeinschaft (FOR 618: “Molecular Aggregation” and Collaboration Germany-Italy: “ME 1869/3-1”) for financial support.

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REFERENCES

(1) Matsuo, T.; Inaba, A.; Yamamuro, O.; Onoda-Yamamuro, N. J. Phys.: Condens. Matter 2000, 12, 8595. (2) Crawford, S.; Kircher, M. T.; Bläser, D.; Boese, R.; David, W. I. F.; Dawson, A.; Gehrke, A.; Ibberson, R. M.; Marshall, W. G.; Parsons, S.; Yamamuro, O. Angew. Chem., Int. Ed. 2009, 48, 755. 5971


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