Powder Structure Analysis of Vapochromic Quinolone Antibacterial

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Powder Structure Analysis of Vapochromic Quinolone Antibacterial Agent Crystals Aya Sakon, Akiko Sekine, and Hidehiro Uekusa Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.6b00719 • Publication Date (Web): 22 Jun 2016 Downloaded from http://pubs.acs.org on June 28, 2016

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Crystal Growth & Design

Powder Structure Analysis of Vapochromic Quinolone Antibacterial Agent Crystals Aya Sakon, Akiko Sekine, and Hidehiro Uekusa* Department of Chemistry and Materials Science, Tokyo Institute of Technology, Ookayama 2-12-1, Meguro-ku, Tokyo 152-8551, Japan

Pipemidic acid crystals were found to undergo a reversible color change upon exposure to acetonitrile vapor via dehydration/hydration transformations. The mechanistic aspects of these transformations and the crystalline color change were revealed using X-ray analysis and theoretical calculations.

Author for correspondence: Hidehiro Uekusa: E-mail: [email protected]; Phone & Fax: +81-3-5734-3529

ACS Paragon Plus Environment

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Powder Structure Analysis of Vapochromic Quinolone Antibacterial Agent Crystals Aya Sakon, Akiko Sekine, and Hidehiro Uekusa* Department of Chemistry and Materials Science, Tokyo Institute of Technology, Ookayama 212-1, Meguro-ku, Tokyo 152-8551, Japan

Author for correspondence: [email protected]


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ABSTRACT

Vapochromic materials, or those that show a reversible color change induced by vapor, are expected to serve as valuable sensors for volatile organic compounds (VOC) or humidity. Crystals of pipemidic acid (PPA), a quinolone antibacterial agent, were found to exhibit vapochromism, as they undergo a reversible color change in the presence of acetonitrile vapor. The colorless trihydrate phase transformed into a yellow anhydrous phase upon exposure to acetonitrile vapor, and returned to the trihydrate phase under high humidity. Ab initio structure determination from powder diffraction and solid state 13C-NMR measurements revealed that the molecule exists in its zwitterionic form in the colorless trihydrate phase, whereas it is nonzwitterionic in the anhydrous phase because of the rearrangement of hydrogen bonds, due to dehydration in the crystal state. Theoretical calculations revealed that the color change in PPA is due to the change in the molecular electronic state upon taking the non-zwitterionic form, which generates a new HOMO state, thus leading to a HOMO-LUMO transition with a lower energy.


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INTRODUCTION

Chromic materials, or those that exhibit a reversible color change upon exposure to external stimuli, are expected to serve as sensors for variations in light (photochromism),1,2 heat (thermochromism),3,4 solvent (solvatochromism),5,6 pressure (piezochromism),7,8 and vapor (vapochromism)9,10 among others. Elucidation of the mechanistic details behind the color change based on molecular and crystal structures is critical to the development of chromic materials. Among chromic materials, photochromic and thermochromic materials have been widely investigated due to their applications in commercial products such as optical information memory elements, sunglasses, and thermometers. Reports regarding vapochromism are less common; however, vapochromic materials should attract considerable attention because there are no other methods capable of detecting vapors by visible means. Most reported vapochromic materials are crystals of transition metal-containing complexes. The vapochromism mechanisms in metal complex crystals are classified into three types: vapochromism by desolvation-solvation,11 by solvent exchange,12 and by a change in the coordination environment owing to solvent molecule ligation (chemical reaction).13-15 In general, the color of metal complexes is sensitive to changes in the coordination environment, and can easily be altered due to variations in the d-d transition energy. Thus, small changes in the crystal environment upon exposure to vapor can lead to a vapochromic color change in metal complex crystals. On the other hand, only a few reports on vapochromic organic crystals are available. The reported mechanisms for the observed color changes include intermolecular interactions16,17 such as charge transfer and π···π interactions, and a change in the molecular structure, such as


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conformational change18 or intramolecular H+ transfer (Fig. S1).19 However, there are no general guidelines regarding how to achieve vapochromic organic materials, because the number of reported examples is so few, and because known vapochromic molecules have no structural or chemical similarities. In this study, we employed a strategy to obtain vapochromic organic materials based on an intramolecular H+ transfer, which was previously reported for 5-aminoisophthalic acid.19 The H+ transfer has a relatively small energy barrier, so even small environmental changes around a molecule such as a crystalline phase transition can induce it. Notably, exposure to vapor induced a dehydration/hydration in the crystal phase, which was accompanied by a color change (vapochromism) in 5-aminoisophthalic acid crystals. The mechanism involved an intramolecular H+ transfer between the carboxylic and amino group, which was induced by a change in the crystal structure. Following this strategy, many compounds with carboxylic and amino groups were explored in an effort to identify novel vapochromic materials. In this study, a quinolone antibacterial agent with carboxylic and amino groups, namely pipemidic acid (PPA; Fig. 1 left), was found to exhibit vapochromism upon dehydration. Interestingly although the chemical structure is rather similar, enoxacin (ENX; Fig. 1 right), which is analogous compound of PPA, did not show color change upon dehydration. In general, single crystal structure analysis, a standard technique used to elucidate the mechanistic aspects of the dynamic behavior of crystalline phases, should be used to shed light on the differences of crystal structures by dehydration and vapochromism. However, single crystals of the starting forms disintegrate into powdery crystals during dehydration upon exposure to vapor or heating; thus this technique is not applicable. In such case, ab initio powder X-ray diffraction analysis (or SDPD; structure determination from powder X-ray diffraction data) is a powerful technique for the analysis of the


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three dimensional crystal structures from XRD when single crystals are not obtained because of grinding,20,21 solid state reactions,22,23 desolvation,24,25 or polymorphic transformations.26,27 As such, the aim of this study is the mechanistic elucidation of the phase transformations and vapochromism in PPA, and ENX for comparison mainly based on the crystal structures revealed by ab initio powder structure analysis. Additionally, PPA and ENX are active pharmaceutical ingredients (API), and crystal phase transformations of APIs are important in the pharmaceutical field because certain physicochemical properties can be altered by changes in the crystal structure.28-31 In fact, other quinolone antibacterial agents showing dehydration/hydration or polymorphism were reported.3235

Notably, color changes in APIs due to dehydration/hydration could potentially be used as a

quality control method.

Figure 1. Molecular structures of PPA and ENX.


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EXPERIMENTAL SECTION

Preparation. PPA and ENX were purchased from Tokyo Chemical Industry Co. Ltd. and were confirmed as the pure PPA trihydrate phase and ENX sesquihydrate phase by PXRD (powder Xray diffraction data). Powdery crystals of the PPA anhydrous A and B phases were prepared from the trihydrate by heating to 90 °C and 200 °C, respectively (pure PPA anhydrous A phase was not obtained and 3% of anhydrous B phase was present, as revealed by Rietveld analysis).36 The ENX trihydrate phase was obtained by recrystallizing the purchased sesquihydrate phase from methanol, and the ENX anhydrous phase was obtained from the trihydrate by heating at 100 °C. The samples were subjected to TGA/DTA (thermogravimetric analysis/differential thermal analysis), PXRD, UV/Vis (ultraviolet/visible) spectroscopy, solid state

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C CP/MAS

NMR (cross polarization/magic angle spinning nuclear magnetic resonance), and FT-IR (Fourier-transform infrared spectroscopy) measurements.

Phase Transformations upon Exposure to Solvent Vapors. The apparatus used to expose the crystalline materials to various solvent vapors is shown in Fig. 2. The solvent vapors used in this experiment were water, methanol, ethanol, 2-propanol, acetone, 1,4-dioxane, THF (tetrahydrofuran), methyl acetate, chloroform, dichloromethane, hexane, diethyl ether, and DMSO (dimethylsulfoxide). Powdery crystals of each phase were placed in a petri dish on a beaker to expose the sample to solvent vapors. All experiments were performed at ambient temperature. After three days, PXRD data were recorded on a Rigaku SmartLab diffractometer (described in detail subsequently).


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Figure 2. Illustration of experimental setup for vapor exposure.

UV/Vis Spectra Measurements. The UV/Vis spectra of each phase were measured at 25 °C with a JASCO V-560 spectrometer equipped with the option (ISV-469) for diffuse reflectance spectroscopy. Analytical samples were prepared by mixing the powdery crystals of each phase (7 mg) with BaSO4 powder (350 mg). Thermal Analysis. TGA and DTA were simultaneously measured on a Rigaku Thermo Plus EVO II TG8120 instrument. The PPA trihydrate phase (28.479 mg) and ENX trihydrate phase (22.063 mg) were heated from 30 to 300 °C at a rate of 3 °C/min under a dry nitrogen atmosphere (100 mL/min flow rate). Powder X-ray Diffraction Measurements. PXRD data were recorded at 20 °C on a Rigaku SmartLab diffractometer with CuKα radiation and a D/teX Ultra detector covering 5~40 ° (2θ). Synchrotron PXRD data of PPA anhydrous A and B phases and the ENX anhydrous phase were recorded at 27 °C on beamline 4B2 (Multiple Detector System; parallel beam with analyzer monochromators) at Photon Factory in KEK with wavelength 1.1964821(3) Å for ab initio structure determination from PXRD data. The sample was placed in a 2.0 mm diameter borosilicate glass capillary under low humidity (RH = 3%) in the presence of CsF (cesium fluoride) saturated aqueous solution. The data collection times were about 5 h each.


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Solid state 13C CP/MAS NMR Measurements. Solid state 13C CP/MAS NMR measurements were performed on a Bruker BioSpin Avance DSX-300 NMR spectrometer with a 4 mm MAS probehead at 27 °C. The observed frequency of 13C was 75.47 MHz. The sample rotor was spun at a rate of 10 kHz, and the contact time of the CP method was 1000 µs for 13C–1H. 13C chemical shifts were calibrated indirectly through an external adamantane low frequency signal (29.5 ppm) relative to tetramethylsilane (0 ppm). FT-IR Measurements. FT-IR spectra of each phase were measured at 20 °C with a JASCO FT / IR-4100 spectrometer via the potassium bromide disk method at 8 cm-1 resolution. Theoretical Calculations of UV/Vis Spectra. Theoretical calculations were carried out using Spartan’14.37 The molecular structures of the zwitterionic and non-zwitterionic forms of PPA were determined from the crystal structures of PPA trihydrate and PPA anhydrous A phase. As for the zwitterionic form, two NH4+ molecules were placed around the COO- instead of the hydrogen bonded NH2+ of PPA in the trihydrate crystal structure, with the purpose of the presentation of the crystal environment around one molecule. The hydrogen positions were optimized using MMFF molecular mechanics method.38 The molecular orbitals of the ground states were also calculated after the positions of the hydrogens were optimized using DFT (density functional theory) calculations (B3LYP, 6-311++G**).39,40 Electronic excitations were calculated using TD-DFT (time-dependent DFT; B3LYP, 6-311++G**) for UV/Vis spectra simulation.


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RESULTS AND DISCUSSION

Characterization of the Anhydrous Phase of PPA and ENX. TGA/DTA data obtained upon heating PPA trihydrate powdery crystals from 30 °C to 300 °C is shown in Fig. 3. The TGA curve shows a mass loss corresponding to dehydration at 108 °C with a 14.9% weight decrease (calculated mass decrease for three H2O molecule is 15.1%), and DTA revealed an endothermic transformation at this temperature. Upon further heating, the DTA data indicated that an exothermic transformation occurred at 180 °C with no weight decrease, which was determined to be a polymorphic phase transformation, followed by decomposition at 259 °C. The anhydrous phase prior to the exothermic transformation (ca. 108~180 °C) was named PPA anhydrous A phase and the anhydrous phase after the exothermic transformation (ca. 180~259 °C) was named PPA anhydrous B phase. These changes were also observed in the PXRD pattern (Fig. 4).

Figure 3. TGA/DTA plot of PPA trihydrate phase. The trihydrate phase dehydrates to anhydrous A phase at 108 °C with a weight loss of 14.9% (calculated value: 15.1%), and the anhydrous A phase transforms into the anhydrous B phase at 180 °C.


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Figure 4. PXRD patterns of (a) PPA trihydrate phase (intact), (b) PPA anhydrous A phase (trihydrate phase heated at 90 °C; the triangles indicate the peaks attributed to the anhydrous B phase), and (c) PPA anhydrous B phase (trihydrate phase heated at 200 °C). All of the PXRD patterns were measured at ambient temperature.

TGA/DTA data recorded upon heating a sample of ENX trihydrate powdery crystals from 30 °C is shown in Fig. 5. The TGA curve shows a mass loss corresponding to dehydration at 87 °C with a 14.4% weight decrease (calculated mass decrease for three H2O molecule is 14.4%), and DTA revealed an endothermic transformation at this temperature, followed by decomposition at 228 °C. These changes were also observed in the PXRD pattern (Fig. 6).


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Figure 5. TGA/DTA plot of the ENX trihydrate phase. The trihydrate phase dehydrates to the anhydrous phase at 87 °C with a weight loss of 14.4% (calculated value: 14.4%).

Figure 6. PXRD patterns of (a) ENX trihydrate phase (recrystallized form methanol), and (b) ENX anhydrous phase (trihydrate phase heated at 120 °C). All of the PXRD patterns were measured at ambient temperature.

Dehydration/Hydration upon Exposure to Vapor and Color Change of PPA and ENX. Next, we investigated the phase transformations upon exposure to various solvent vapors by PXRD. Upon exposure to acetonitrile, the PPA trihydrate phase dehydrated into to anhydrous B phase via the anhydrous A phase, which is the same phase transformation that occurred upon heating. Dehydration upon exposure to acetonitrile vapor is not common, but a few examples are known;19,41,42 polar solvent vapors are known to be able to bring out water molecules from crystals. PPA trihydrate phase underwent dehydration only by acetonitrile vapor, not by other organic solvent vapors. PPA anhydrous A and B phases returned to the original trihydrate phase upon exposure to humidity. On the other hand, the ENX trihydrate phase did not undergo dehydration upon exposure to any solvent vapors. The original trihydrate phase could be


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obtained under humidity. The phase transformations upon exposure to solvent vapors are summarized in Table S1. The UV/Vis spectra and photos of each PPA phase (Fig. 7) revealed that the trihydrate phase was colorless, while the anhydrous A phase was pale yellow, and the anhydrous B phase was orange-yellow. The ENX trihydrate phase and ENX anhydrous phase were both colorless (Fig. 8). Therefore, PPA showed vapochromic behavior (reversible color change upon exposure to solvent vapor), while ENX did not.

Figure 7. UV/Vis spectra (left) and photos (right) of (a) PPA trihydrate phase (colorless), (b) PPA anhydrous A phase (pale-yellow), and (c) PPA anhydrous B phase (orange-yellow).

Figure 8. UV/Vis spectra (left) and photos (right) of (a) ENX trihydrate phase (colorless), and (b) ENX anhydrous phase (colorless).


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Structure Determination from ab initio Powder X-Ray Diffraction Data. Crystal structure determination of the PPA anhydrous A and B phases and ENX anhydrous phase was essential to clarify the dehydration/hydration processes, and to elucidate the mechanism behind the vapochromism. However, single crystals of PPA trihydrate and ENX trihydrate disintegrated into powdery crystals during dehydration upon exposure to vapor or heating. Therefore, the crystal structures were determined from high-resolution synchrotron PXRD data using ab initio powder X-ray diffraction analysis. The PXRD pattern of the ENX anhydrous phase was indexed using the program DICVOL04,43 giving the unit cell (M(20)44 = 30.2, F(20)45 = 92.8) of a = 7.94 Å, b = 8.67 Å, c = 10.23 Å, α = 91.6 °, β = 94.6 °, γ = 93.1 ° (reduced cell), and V = 700.1 Å3. Considering the volume of the unit cell and density, the number of molecules in the unit cell was estimated to be Z = 2 and P-1 was determined to be the space group. Profile fitting using the Pawley method46 in the program DASH47 gave Rwp = 10.70% and χ2 = 25.0 (calculated using the background subtracted intensity). The structure solution was obtained using the simulated annealing method in the program DASH. The model structural fragment was comprised of one ENX molecule, which has a total of 9 structural variables (3 translational variables, 3 orientational variables, and 3 torsional variables). Twenty runs with 107 simulated annealing moves per run were performed for the structure solution. The molecular model was taken from the crystal structure of the ENX trihydrate phase48 and the best solution had χ2 182.3 and intensity χ2 106.6. In the molecular structure of the best solution, the carboxylic or carboxylate moieties twist against the quinolone ring with a torsion angle of -22 °, which means the ENX anhydrous phase exists as the zwitterionic form with NH2+ and COO-. This was also confirmed by the solid state

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C-NMR

measurements (described subsequently).


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Rietveld refinement36 was carried out using the GSAS program.49 Standard restraints were applied to the bond lengths and angles, and restraints around the N18 atom (piperazine ring) were relatively loosened to determine the planarity around N, whose degree of freedom was not taken into account in the simulated annealing method in DASH. A global isotropic displacement parameter, Ueq, was used for non-H atoms, and constrained 1.2 Ueq was given to all hydrogen atoms. The final Rietveld refinement is summarized in Table S2 (crystallographic data) and Fig. 9 (Rietveld plot).

Figure 9. Final Rietveld refinement of the ENX anhydrous phase. The experimental PXRD pattern (red + marks), calculated PXRD pattern (green solid line), and difference profile (pink line) are shown. The black tick marks indicate the peak positions. The crystal structures of the PPA anhydrous A and B phases were determined in the same way as the ENX anhydrous phase. The unit cells from DICVOL04 were as follows: PPA anhydrous A phase: a = 7.90 Å, b = 8.09 Å, c = 11.94 Å, α = 94.1 °, β = 104.1 °, γ = 101.7 ° (reduced cell), and V = 718.3 Å3 (M(20) = 12.3, F(20) = 30.7); PPA anhydrous B phase: a = 4.58 Å, b = 10.69 Å, c = 15.47 Å, α = 72.6 °, β = 88.7 °, γ = 81.7 ° (reduced cell), and V = 714.8 Å3 (M(20) = 15.6, F(20) = 53.0). The number of molecules in the unit cell was estimated to be Z = 2 and the space group of both phases was determined to be P-1. Profile fitting using the Pawley method in the


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program DASH gave Rwp = 18.48% and χ2 = 95.1 for the PPA anhydrous A phase, and Rwp = 15.80% and χ2 = 95.9 for PPA anhydrous B phase. In the structure solution obtained using the simulated annealing method, the structural fragment was comprised of one PPA molecule (9 structural variables), and 20 runs with 107 simulated annealing moves per run were performed for each phase. The molecular model was taken from the crystal structure of the PPA trihydrate phase,50 and the best solution had profile χ2 686.5 and intensity χ2 52.4, and profile χ2 213.6 and intensity χ2 25.0, respectively. In the anhydrous A and B phases, the carboxylic or carboxylate moieties in the best solutions were coplanar to the quinolone ring with torsion angles of 6 ° and 1 °, respectively. This coplanar conformation strongly indicates that the carboxylic group forms intramolecular O-H···Ocarbonyl hydrogen bonds, and thus the molecules exist as the nonzwitterionic form with NH (terminal of piperazine ring) and COOH groups. The non-zwitterionic state was also confirmed by solid state 13C-NMR measurements (described subsequently). In the Rietveld refinement of the anhydrous A and B phases, the molecular model of the nonzwitterionic forms was used, and standard restraints were applied to the bond lengths and angles, and restrains around the N17 atom (piperazine ring) were relatively loosened to determine the planarity around N. A global isotropic displacement parameter, Ueq, was used for non-H atoms, and constrained 1.2 Ueq was given to all hydrogen atoms. For the PPA anhydrous A phase, the Rietveld refinement revealed that the proportion of the anhydrous A:anhydrous B was 97:3. The final Rietveld refinement is summarized in Tables S2 (crystallographic data) and Fig. 10 and Fig. 11, respectively.


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Figure 10. Final Rietveld refinement of PPA anhydrous A phase. The experimental PXRD pattern (red + marks), calculated PXRD pattern (green solid line), and difference profile (pink line) are shown. The black tick marks indicate the peak positions of the PPA anhydrous A phase and the red tick marks are those of PPA anhydrous B phase (3%).

Figure 11. Final Rietveld refinement of PPA anhydrous B phase. The experimental PXRD pattern (red + marks), calculated PXRD pattern (green solid line), and difference profile (pink line) are shown. The black tick marks indicate the peak positions.

Solid State

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C-NMR Measurements. Solid state

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C CP/MAS NMR measurements were

performed to confirm the positions of the protons (carboxylic acid or carboxylate forms) and elucidate the electronic state. The solid state 13C NMR spectra of PPA trihydrate and anhydrous


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A and B phases are shown in Fig. 12; those of ENX trihydrate and anhydrous phases are shown in Fig. 13. The peaks of C5 (carbon atom of carboxyl group) and C4 (carbon atom next to C5) of PPA anhydrous A and B phases shifted to a lower magnetic field than those of the PPA trihydrate phase, which means that PPA molecules of both anhydrous A and B phases were nonzwitterionic (COOH and amino NH; right molecule form of Fig. 12), while the PPA molecules of the trihydrate phase were in the zwitterionic form (COO- and amino NH2+; left molecule form of Fig. 12), as determined by single crystal structure analysis. On the other hand, the corresponding peaks of the ENX trihydrate phase and ENX anhydrous phase had similar chemical shifts (also close to the PPA trihydrate plot), which means the anhydrous phase of ENX exhibited the same zwitterionic phase as the ENX trihydrate phase. These assignments were also supported by FT-IR (Fig. S2 and S3).

Figure 12. Solid state

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C-NMR spectra of (a) PPA trihydrate phase, (b) PPA anhydrous A

phase, and (c) PPA anhydrous B phase.


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Figure 13. Solid state

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C-NMR spectra of (a) ENX trihydrate phase and (b) ENX anhydrous

phase.

Crystal Structures and Transformation Mechanisms. Previously, the PPA trihydrate phase50 was reported to exist in the zwitterionic form (Fig. 14 (a)), as determined by single crystal structure analysis, and it was also confirmed by solid state

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C-NMR in this study (Fig.

12). The carboxylate moiety twists against the quinolone ring with a torsion angle of 19.8(4)° (O8-C6-C5-C9), and the sum of three bond angles around the N17 atom of the piperazine ring is 354.7° (C16-N17-C18, C16-N17-C22, and C18-N17-C22). The piperazine ring does not twist against the quinolone ring, as the torsion angle is 20.8(4)° (N13-C16-N17-C18). As shown in Fig. 14 (b), the molecules form a 1D chain structure via N+-H···O- charge assisted hydrogen bonds (2.735(4) Å) represented by green or blue arrows; the 1D chains lie in alternate directions (···green arrow···blue arrow···green arrow···) and form hydrogen bonds with water molecules, thus forming 2D sheet structures. The 2D sheets stack via hydrogen bonds with water molecules,


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as shown in Fig. 14 (c). In the PPA anhydrous A phase, the molecules exist as the nonzwitterionic form with an intramolecular O-H···O hydrogen bond between the carboxyl group and carbonyl O (Fig. 14 (d)). The conformation of the quinolone ring is similar to that of the trihydrate phase. The only difference is that the carboxylic acid lies coplanar to the quinolone ring with a torsion angle of -2.1(5)° by an intramolecular O-H···O hydrogen bond. The N17 atom of piperazine ring is planar as the sum of three bond angles around N17 is 358.5° and the piperazine ring does not twist against the quinolone ring with the torsion angle of -10.5(6)°. As shown in Fig. 14 (e), the molecules form a 1D chain structure via weak N-H···O hydrogen bonds (3.119(8) Å), which forms a 2D sheet structure similar to the trihydrate phase via weak intermolecular interactions (two C-H···N (3.227(6) Å) interactions and two C-H···O (3.244(6) Å)). The 2D sheets stack via π···π interactions (3.36 and 3.52 Å) as shown in Fig. 14 (f). In the PPA anhydrous B phase, the molecules are in the non-zwitterionic state, similar to the anhydrous A phase (Fig. 14 (g)). The conformation of the quinolone ring is almost the same as the anhydrous A phase. The carboxylic acid moiety is again coplanar to the quinolone ring with a torsion angle of 1.5(5)° owing to the intramolecular hydrogen bond, which is similar to the anhydrous A phase. The N17 atom of the piperazine ring takes a planar conformation as the sum of three bond angles around N17 is 359.3°; the piperazine ring does not twist against the quinolone ring with a torsion angle of 4.7(9)°. A molecular overlay showing the differences in the conformations of the piperazine rings in trihydrate and anhydrous A and B phases is shown in Fig. 14 (j). The 1D chain arrangements are similar to those in the anhydrous A phase, but the N-H···O hydrogen bond between molecules is not present because of the slight clockwise rotation of the molecules. Instead, molecules are connected by weak C-H···O (3.299(7) Å). Also, the 1D chain structures form 2D sheets via two C-H···N (3.400(6) Å) interactions and two C-


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H···O (3.165(4) Å) interactions (Fig. 14 (h)) like in the anhydrous A phase. The 2D sheets stack via π···π interactions (3.44 Å) as shown in Fig. 14 (i). Because all three phases have the very similar 2D sheet structures (Fig. 14 (b), (e), and (h)), both the dehydration of the PPA trihydrate phase and the polymorphic phase transformation from anhydrous A to B would maintain the 2D sheet structure. When the trihydrate phase is dehydrated and forms the anhydrate A phase, the water molecules are removed, and the PPA molecules move slightly to fill the voids, accompanied by a proton transfer to form a more stable intramolecular O-H···O hydrogen bond, taking the non-zwitterionic state. In this way, the dehydration process results in a small change in the molecular arrangement as shown in Fig. 14 (b) and (e). When the polymorphic phase transformation from PPA anhydrous A to B occurs, the 2D sheets are maintained, but they slide towards each other by one molecule length to become more stable as shown in Fig. 14 (f) and (i), and intra-layer weak N-H···O hydrogen bond (3.119(8) Å) of PPA anhydrous A phase slides over to inter-layer weak N-H···Ocarbonyl hydrogen bond (3.559(8) Å; increase in bond length) of PPA anhydrous B phase.


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Figure 14. Molecular and crystal structures of (a) ~ (c) PPA trihydrate phase, (d) ~ (f) anhydrous A phase, and (g) ~ (i) anhydrous B phase, and (j) molecular overlay of trihydrate, and anhydrous A and B phases. Hydrogen atoms are omitted for clarity in (b), (c), (e), (f), (h), and (i). The blue dashed lines indicate hydrogen bonds, the pink dashed lines indicate the weak interactions (C-


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H···N, C-H···O). (a) PPA molecules in the trihydrate phase are zwitterionic. The numbering of the atoms is different from the crystal structure previously reported.50 (d), (g) PPA molecules in anhydrous A and B phase are in the non-zwitterionic form. When the anhydrous A phase transforms into the anhydrous B phase, the shaded 2D sheet structures slide in the direction of the black arrow (i).

In the crystal structure of the ENX trihydrate phase,48 the ENX molecules exist in the zwitterionic form (Fig. 15 (a)). The carboxylate moiety is twisted against the quinolone ring with a torsion angle of -24.9(2)° (O8-C6-C5-C9), and the N18 atom of the piperazine ring takes a somewhat pyramidal conformation as the sum of three bond angles is 347.5° around N18 (C17N18-C19, C17-N18-C23, and C19-N18-C23), which is between the planar (360°) and pyramidal (329°) conformation. The piperazine ring is twisted slightly to the quinolone ring with a torsion angle of 41.9(2)° (C13-C17-N18-C19). Alternate 1D chain structures via N+-H···O charge assisted hydrogen bonds (2.676(1) Å) between ENX molecules are shown in Fig. 15 (b). The chains form 2D sheet structures via hydrogen bonds with water molecules (Fig. 15 (c)), which stack via hydrogen bonds with water molecules as shown in Fig. 15 (d). In the ENX anhydrous phase, the molecules take the zwitterionic form (Fig. 15 (e)), similar to the trihydrate. The carboxylate moiety has a torsion angle of -22.2(5)° to the quinolone ring, which is similar to the trihydrate phase. However, the N18 atom of the piperazine ring takes the planar conformation as the sum of three bond angles around N18 is 359.7°. Also, the piperazine ring has a smaller twist to the quinolone ring with a torsion angle of -15.3(6)°. The molecular overlay showing the difference in the conformations of the piperazine rings in the trihydrate and anhydrous phases is shown in Fig. 15 (i). In the anhydrous phase, a similar charge assisted hydrogen bonded 1D


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chain structure (2.386(7) Å) was observed, as shown in Fig. 15 (f). The 1D chain structures stack in the opposite direction to form a 2D sheet structure (Fig. 15 (g)) similar to the ENX trihydrate phase. Between the 1D chain structures, the NH2+ is weakly hydrogen bonded to the O- of adjacent 1D chains (3.069(7) and 4.036(8) Å) and π···π interactions are formed (3.48 and 3.46 Å). The 2D sheets are stacked with about a one-molecule offset (Fig. 15 (h)). When the water molecules are eliminated from the ENX trihydrate phase, the 2D sheet structures, which consist of 1D chains (Fig. 15 (c) and (g)), are maintained, but shift by one molecule because of the loss of water which connected the sheets (Fig. 15 (h)).

Figure 15. Molecular and crystal structures of (a) ~ (d) ENX trihydrate phase and (e) ~ (h) ENX anhydrous phase, and (i) molecular overlay of trihydrate and anhydrous phases. Hydrogen atoms are omitted for clarity in (b) ~ (d) and (f) ~ (h). The blue dashed lines in 1D chain and 2D sheet in (b), (c), (f), and (g) indicate the hydrogen bonds, and were omitted in the stacking (d). (a) The


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ENX molecules in the trihydrate phase are in the zwitterionic form. The numbering of the atoms is different from the crystal structure previously reported.48 (e) The ENX molecules in the anhydrous phase are in the zwitterionic form. When the trihydrate phase is dehydrated to form the anhydrous phase, the shaded 2D sheet structures slide in the direction of the black arrow (h).

In PPA crystals, the dehydration transformation is associated with the intramolecular proton transfer from the zwitterionic to non-zwitterionic form; however, this does not occur in ENX crystals owing to the differences in hydrogen bonding in the molecular arrangements. In the ENX trihydrate phase, the NH2+ forms hydrogen bonds with the OCOO- atom in the same layer and Owater atom (Fig. 16 (a)); in the ENX anhydrous phase, one of the N-H forms a hydrogen bond with two OCOO- atoms (bifurcated) and the other forms a hydrogen bond with OCOO- atoms of the ENX molecule in an adjacent layer, forming (4) and (12) hydrogen bond motifs (Fig. 16 (b)). Therefore, the hydrogen bonding in the trihydrate and anhydrous phases of ENX are almost the same, and thus the molecules in both phases exist as the zwitterionic forms. In the PPA trihydrate phase, the NH2+ forms hydrogen bonds with OCOO- atoms in the same layer and the adjacent layer (Fig. 16 (c)). Interestingly, (12) hydrogen bond motif shown in ENX anhydrous phase also exists in PPA trihydrate, but not in ENX trihydrate phase. After the dehydration transformation, in the PPA anhydrous A and B phase, there are no hydrogen bond acceptors for the assumed NH2+ moiety (Fig. 16 (d) and (e). The pink circles indicate possible H+ positions as NH2+. Therefore, the H+ transfer occurs from NH2+ to COO- to become NH and COOH groups, and to form a more stable intramolecular O-H···O hydrogen bond in the PPA anhydrous A and B phases (Fig. 14 (d) and (g)) resulting in the non-zwitterionic state.


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Figure 16. Hydrogen bonding around terminal N (yellow circled) in ENX and PPA crystal structures: (a) ENX trihydrate phase (zwitterionic form), (b) ENX anhydrous phase (zwitterionic form), (c) PPA trihydrate phase (zwitterionic form), (d) PPA anhydrous A phase (nonzwitterionic form), and (e) PPA anhydrous B phase (non-zwitterionic form). The blue dotted lines indicate the hydrogen bonds and the pink circles in (d) and (e) indicate assumed H+ positions.

Theoretical Calculation for Color Change Mechanism. The crystal structure analyses of the hydrates and anhydrous phases of PPA and ENX clearly indicated that the molecules exist as the zwitterionic form (carboxyl H+ transfer to terminal amino N) in the colorless PPA trihydrate phase and are non-zwitterionic in the pale yellow PPA anhydrous A phase and orange-yellow anhydrous B phase.


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In order to reveal the mechanism of the color change based on the molecular electronic states, UV/Vis spectra of single molecules of PPA zwitterionic and non-zwitterionic forms in a vacuum were calculated using TD-DFT. The calculated UV/Vis spectra adequately reproduced the measured UV/Vis spectra shown in Fig. 17. Accordingly, the main cause of coloration is the non-zwitterionic form of the molecule, which changes the electronic state of the single molecule.

Figure 17. (a) Measured UV/Vis spectra of PPA trihydrate phase (green line) and anhydrous A phase (orange line). The triangles indicate the peak tops near the visible region. (b) Calculated UV/Vis spectra of zwitterionic PPA trihydrate (green line) and non-zwitterionic anhydrous A phase (orange line). The triangles ((i) ~ (iii) corresponding to Fig. 18) indicate the strong peak position of the transition energies near the visible region.

Comparing the two calculated spectra (Fig. 17 (b)), there are two similar molecular orbitals related to strong π-π* transitions at 322 nm (Fig. 17 (b, i) and Fig. 18 (i)) in the zwitterionic (HOMO (highest occupied molecular orbital)-1 to LUMO (lowest unoccupied molecular


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orbital)+1) form and at 304 nm (Fig. 17 (b, ii), and Fig. 18 (ii)) in the non-zwitterionic form (HOMO-1 to LUMO). Interestingly, in the non-zwitterionic form, there is a new HOMO state (Fig. 18 (iii)), which leads to a relatively strong intramolecular CT (π-π*) absorption band at 364 nm (Fig. 17 (b, iii)). Therefore, the color of the PPA anhydrous A phase is due to the change in the molecular electronic state to the non-zwitterionic form because of the proton transfer accompanied by the phase transformation and change in the crystalline environment, which generates a new HOMO state leading to a lower HOMO-LUMO transition. The same mechanism should be applicable to the PPA anhydrous B phase (non-zwitterionic form).

Figure 18. The calculated HOMO and LUMO involved with the color change corresponding to Fig. 17 (b): (i) HOMO-1 to LUMO+1 of zwitterionic trihydrate phase (colorless), (ii) HOMO-1 to LUMO of non-zwitterionic anhydrous A phase (yellow), and (iii) HOMO to LUMO of nonzwitterionic anhydrous A phase (yellow), which cause the coloration of the crystal. HOMO-m and LUMO+m denote the (m-1)th highest occupied orbital and the (m+1)th lowest unoccupied orbital, respectively.


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CONCLUSIONS

Although vapochromic organic crystals are not common, in this study we found that a quinolone antibacterial agent, PPA, showed vapochromism. This vapochromism was achieved based on the reversible dehydration/hydration of PPA crystals upon exposure to solvent vapors. The mechanism was elucidated using ab initio powder X-ray diffraction analysis. The color changes are mainly due to the differences in the molecular structure between the zwitterionic and non-zwitterionic form (i.e., difference in the electronic states), which was successfully confirmed using theoretical calculations. The intramolecular H+ transfer is caused by the rearrangement of the hydrogen bonds. The crystal structures of all PPA phases have a common 2D sheet structure, which is maintained during the dehydration/hydration process and polymorphic phase transformation. Thus the phase transformations are easy to induce under relatively mild conditions such as solvent vapor exposure. On the other hand, ENX did not show the color change because the H+ transfer did not occur upon hydration/dehydration because the hydrogen bonding environment did not change (Fig. 19). Structural investigations of dynamic behaviors such as vapochromism utilizing ab initio powder X-ray diffraction analysis can shed light on mechanisms behind phase transformations related to physicochemical properties such as color. Ab initio powder X-ray diffraction has a big advantage in obtaining three dimensional structures in case single crystals are not obtained because of grinding, solid state reactions, desolvation, or polymorphic transformations, including chromism. Applying such strategy to further examples will facilitate the discovery of new vapochromic materials and the systematic understanding of vapochromism.


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Figure 19. A summary of the vapochromic behavior of PPA and phase transformation of ENX.


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ASSOCIATED CONTENT Supporting Information. Molecular structures of vapochromic organic crystals, tables summarizing phase transformations upon exposure to solvent vapors, crystallographic data, FTIR spectra (PDF), and X-ray crystallographic information files (CIF). These materials are available free of charge via the Internet at http://pubs.acs.org. Crystallographic information files are also available from the Cambridge Crystallographic Data Center (CCDC) upon request (http://www.ccdc.cam.ac.uk, CCDC deposition numbers 1447069, 1447070 and 1447072).

AUTHOR INFORMATION Corresponding Author. *E-mail: [email protected]. Telephone and Fax: +81-3-57343529.

ACKNOWLEDGMENT This work was supported by a Grant-in-Aid for JSPS Fellows. We are grateful to Dr. Shinji Ando and Dr. Shigeki Kuroki for measurements and helpful discussions about 13C-SSNMR, and to Dr. Shinji Ando for help with theoretical calculations. The synchrotron radiation experiments were performed on a BL15XU at SPring-8 with the approval of the Japan Synchrotron Radiation Research Institute (JASRI) (Proposal No. 2013A4906 / 2013B4907 / 2014B4907) and on BL04B2 at PF with the approval of the High Energy Accelerator Research Organization, KEK (Proposal No. 2011G551 / 2013G575 / 2015G660).


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For Table of Contents Use Only Powder Structure Analysis of Vapochromic Quinolone Antibacterial Agent Crystals Aya Sakon, Akiko Sekine, and Hidehiro Uekusa

Table of Contents Graphic

Synopsis Pipemidic acid crystals were found to undergo a reversible color change upon exposure to acetonitrile vapor via dehydration/hydration transformations. The mechanistic aspects of these transformations and the color change were revealed using X-ray analysis and theoretical calculations.


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Powder Structure Analysis of Vapochromic Quinolone Antibacterial

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