Deuterium Perturbs the Molecular Arrangement in the Solid State

Feb 3, 2015 - For his discovery of heavy hydrogen, Harold C. Urey was granted the Nobel Prize in 1934. Following the synthesis of heavy water and afte...
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Deuterium perturbs the molecular arrangement in the solid state Klaus Merz, and Anna Kupka Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/cg5014973 • Publication Date (Web): 03 Feb 2015 Downloaded from http://pubs.acs.org on February 9, 2015

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Deuterium perturbs the molecular arrangement in the solid state Klaus Merz*and Anna Kupka

Chair of Inorganic Chemistry 1, Ruhr-University Bochum, Universitätstrasse 150, 44801 Bochum, Germany

KEYWORDS: hydrogen/deuterium exchange, isotope effect, isotopic polymorphism, influence on crystallization behavior ABSTRACT:

Hydrogen/deuterium (H/D)-exchange, is generally seen as a negligible criterion in the formation of crystal structures of chemical compounds. On the other hand, it could already be shown that the aggregation of molecules in the solid state of selected organic and inorganic compounds can be very sensitive to the small H/D-change in the isotopic substitution pattern of the considered molecules or the use of deuterated solvents during the crystallisation process. This perspective highlights the extraordinary aggregation behavior in certain cases of deuterated versus the non-deuterated small inorganic and organic compounds.

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Introduction "For his discovery of heavy hydrogen" the Nobel Prize was granted to Harold C. Urey in 1934. Following the synthesis of heavy water and after the availability of noticeable amounts of D2O, deuterated compounds became an increasingly interesting topic of fundamental research and applications. H/D-exchange as the smallest possible element substitution in the molecular structure affects the physical properties that depend directly on the proton or deuterium. Spectroscopic and spin-dependent properties change in a rather predictable way and allow the use of vibrational and NMR spectroscopies. However, the influence of H/D exchange on the thermodynamic properties of compounds is not yet properly understood which is nicely shown in the case of the simple compounds H2O and D2O1-3. Enthalpy, entropy, free energy and other thermodynamic functions of a crystal depend on the normal mode frequencies of the crystal and hence on whether it is protonated or deuterated4. A comparison of melting and boiling points of H2O and D2O shows that ordinary ice Ih melts at 273.15 K under 1 atm pressure and D2O ice at 276.97 K, while the boiling points are 373.15 K and 374.59 K for the normal and heavy water4. The most remarkable difference is the temperature of maximum density between water and heavy water (D2O 11.22 oC and H2O 4.08 oC)5. Since the discovery of D2 and D2O a large number of deuterated compounds have been prepared and the X-ray crystal structures of several of these compounds were investigated. In general, it is expected that the crystal structures of compounds containing hydrogen are not affected by the substitution of hydrogen by deuterium. However, a detailed survey of deuterated and non-deuterated compounds indicates that the assumption is wrong. Isotopic substitution can influence the molecular arrangement in the solid state. The phenomenon of crystal structure changes induced by isotopic substitution has been proposed as “isotopomeric polymorphism” by Herbstein6. Similar to Limbach et al.7 we use in this contribution the term “isotopic polymorphism” proposed by Boese et al.8 which is in better agreement with IUPAC rules9. This contribution focuses on the modified aggregation behavior where hydrogen is replaced by deuterium in small inorganic and organic compounds.

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Deuterium isotope effects on hydrogen bonds

One of the earliest organic X-ray crystal structures to be investigated was the one of oxalic acid dihydrate10,

11

in 1933. Remarkably, only some years after the discovery of D2O,

Ubbelohde and Robertson reported the isotope effect of crystalline (COOD)2  2 D2O12. The authors supposed that the variations of the unit cells of the deuterated oxalic acid dihydrate are due to hydrogen bonds, which are elongated by the substitution of deuterium. This is perhaps the first discovery of differences in the molecular arrangements of crystalline material due to H/D exchange. Several years later, the assumption of Ubbelohde and Robertson could be confirmed by the X-ray crystal structure determination of the nondeuterated (α-form) and the deuterated (β-form) of oxalic acid dihydrate by Ahmed et al. and Iwasaki et al.13,

14

. The acid and water molecules in both forms are arranged in a

herringbone fashion. However, in comparison to the non-deuterated form (α-form), the angle between two neighboring layers of the deuterated form (β-form), is dramatically reduced from 73.2o (α-form) to 59.1o.

a b Figure 1: Molecular arrangement in the solid state of a) (COOH)2  2 H2O (α-form) and b) (COOD)2  2 D2O (β-form)13,14 (H2O and D2O molecules have been omitted for clarity)

The characteristics of isotope effects in hydrogen bonds are related to the anharmonicity of the potential for the hydrogen/deuterium vibration motion as well as tunneling effects. Kinetic isotope effects can be explained by the lower zero-point energy of deuterium which implies a smaller vibration amplitude and hence a smaller effective radius than that of

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protium15. The so-called “Ubbelohde effect” also describes the elongation of H bonds due to deuteration. This phenomenon can be ascribed to the lower zero point energy of the O-D bond vibration in comparison to the O-H bond. As a result, the O-D bond is stronger and deuterium is less likely to be abstracted from oxygen than protium12, 15, 16. Concerning low temperature structures this effect seems to be especially strong for O···O distances between 2.45-2.6 Å17. On the other hand Dunitz and Ibberson18 have shown that temperature influences the Boltzmann distribution of protonated and deuterated molecules over the energy levels of a quantized harmonic oscillator. For low-frequency oscillations with increasing temperature, the higher vibrational levels become more populated for deuterated molecules than for their proton isotopologues. Another important aspect of hydrogen bonds is the shape of the potential energy curve for hydrogen atom transfer along the hydrogen bond path. In a moderate hydrogen bond the hydrogen atom almost exclusively occupies the low energy minimum of the two distinct minima, which are separated by an energy barrier (Figure 2a). In a shortened hydrogen bond the minima become less separated, more similar in energy, and the energy barrier becomes small. Further shortening of the hydrogen bond results ultimately in a single well potential and the hydrogen atom occupies a position close to the centre in an X–H–A hydrogen bond (Figure 2b with X≠A).

Figure 2: Schematic comparison of potential energy curves in a) moderate and b) strong asymmetric single well hydrogen bonds. c) Probability density distribution for H/D in hydrogen bond with low barrier. X = hydrogen bond donor, A = hydrogen bond acceptor

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In the case of H/D-exchange, deuterium effectively occupies a lower energy state than hydrogen. These are caused by the fact that the vibrational contribution to the zero point energy is mass dependent, i.e. smaller for an X–D bond compared to that of an X–H. The H/D isotope effect leads to alterations in the geometry of hydrogen bond with an anharmonic potential12 (Figure 2c). In most of the cases the deuterated bridges are weaker than the protonated ones, but this is not generally so. In the case of harmonic or close to harmonic potentials with a single minimum, deuterated bridges are slightly stronger than protonated ones19. On the other hand, H/D-replacement in hydrogen bridges leads to an increase of the barrier and lowering of the levels of the potential energies. This situation favors a higher H/D tunneling ability. Especially in the case of short distances between bridging atoms, the square of the wave function for the proton can show one maximum and an intense deuteron tunneling19. A change from an ionic to a molecular structure, induced by H/D-exchange, was observed in the case of a hydrated trifluoroacetic acid.23 Non-deuterated trifluoroacetic acid tetrahydrate is isotypic to the low-temperature perdeuterated form, while the hightemperature perdeuterated compound has a significantly different structure. The comparable unit-cell parameters of both compounds could lead to the assumption of isotypic X-ray crystal structures, although the difference in one of the unit-cell angles of more than 6o is conspicuous. Trifluoroacectic acid tetrahydrate turned out to be ionic with the structural formula [H5O2][CF3COO)2H]  6H2O while the high-temperature perdeuterated form is molecular with the structural formula CF3COOD  4D2O. Other interesting aspects of the structures are the condensed six- and four-membered oxygen rings of the hydrogen bonded H2O and D2O molecules. In the non-deuterated structure, the four-membered rings can be classified as homodromic, and in the case of the six-membered rings, one is homodromic and the other is heterodromic. In the perdeuterated structure, the four-membered rings are heterodromic and both six-membered rings are homodromic.

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a

b

Figure 3: Differences in homodromic and heterodromic arrangements of H2O and D2O molecules in trifluoroacetic acid tetrahydrate and d9- trifluoroaectic acid tetrahydrate20. In the case of the crystalline compounds [AuCl4][(RO)2H]+ (with R = Py, Ph3As) the bridging hydrogen atom has been assumed to be located on the center of symmetry located at the midpoint of the OO moiety21. Based on the studies of the influence of H/D exchange on hydrogen order-disorder in inorganic ferroelectric compounds4, similar behavior for the hydrogen bonded cations in [AuCl4][(RO)2H]+ could be anticipated. In the case of [PyO)2H][AuCl4] (H-salt), the X-ray crystal structure determination of the deuterated compound (D-salt) confirms a striking structural difference from the H-salt. In contrast to the H-salt, the [PyO-D-PyO]+ cation is asymmetric (C1 point symmetry) and shows a slightly enlarged OO distance. These observations suggest that the position of the D atom in [(PyO)2D] may deviate from the mid-point between the two oxygen atoms to result in a hydrogen bond with an asymmetric potential well21. The influence of H/D exchange on the fine structure patterns of the νN-H and νN-D bands in polarized IR spectra could be observed in the case of non-deuterated and deuterated oxindole by Flakus et al.22. The hydrogen-bonded cyclic dimers of the isotopic polymorphs differ in their geometric parameters. These differences in the polymorph spectral properties result from the geometric relations concerning the dimers constituting the lattice structural units. In the case of the non-deuterated phase, the hydrogen bond lengths of the dimers differ by 0.18 Å. Due to geometry changes in the dimers, the primarily mutually exciton coupled hydrogen bonds in dimers of the deuterated phase decouple in the non-deuterated ACS Paragon Plus Environment

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phase dimers. For the deuterated phase, with essentially symmetric dimers in the lattice, the spectra are typical for centro-symmetric hydrogen bond systems due to the full resonance of the proton or deuteron vibrations. Crystal structure changes of hydrogen bonded systems upon deuteration of mobile proton sites have been observed in the crystalline pentachlorophenol / 4-methylpyridine complex. Spectroscopic, X-ray, and neutron crystallographic studies showed that the triclinic 1:1 complex exhibits a remarkably short intermolecular O-HN hydrogen bond in the solid state. In contrast, deuteration in the hydrogen bond gives rise to the formation of a monoclinic lattice exhibiting a longer hydrogen bond. Formally there is a high temperature molecular phase with O–H···N configuration and a low temperature ionic phase with O-···H– N+ configuration. The group of Limbach pointed out, based on NMR experiments, at increasing degrees of deuteration that the dipole−dipole interacPon between adjacent coupled O-HN hydrogen bonds, is then reduced by deuteration, and other interactions become dominant, leading to the monoclinic form7.

Deuterated Drugs If deuterated compounds have different crystal forms, they must also work in a different manner in the complex and sensitive biochemical processes8. Based on the mass difference between

hydrogen and deuterium, the zero point energy for the C-D bond is 1.2 - 1.5 kcal/mol lower than that of a corresponding C-H bond. This makes the C-D bond much stronger than the C-H bond and thus more resistant with respect to chemical or enzymatic cleavage. A relatively new, but at the same time very important application of deuterated compounds can be found in pharmaceutical applications. Recently, there has been a notable trend to produce well-known active pharmaceutical ingredients in their deuterated form and to apply for patents. In the 1970's, studies with deuterated active pharmaceutical ingredients were already carried out. At that time, the goal was to get a deeper insight into the metabolism of the drugs23, 24. The H/D substitution can influence the speed of drug degradation and the retention time of the drug in the blood as well as in detoxification processes25, 26. One of the most delicate problems next to synthesis in pharmaceutical industry is the purification of the active pharmaceutical ingredients (API). Here, crystallization processes play a particularly important role. Different crystallization techniques are used for the purification and ACS Paragon Plus Environment

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separation of the API.

27, 28

For example acridine finds its applications as an antimalarial

binding agent to protoporphyrin29, 30 and as antimicrobial and anticancer DNA intercalating agents31,

32

. The control on the polymorphic behavior derived from acridine as a drug

candidate is therefore crucial to develop drugs with desired properties33. The development of new instruments and techniques for controlling the polymorphic forms of organic compounds, is therefore of great importance. For many drugs, only a few of the polymorphic modifications are so far approved and patented.

Physical properties of deuterated compounds In materials which exhibit strong and short hydrogen bonds with low energy barrier, hydrogen can be disordered over the two energy minima. In case of the benzoic acid dimers, the hydrogen atom occupations are temperature dependent, and show a gradual Hdisorder-H-order transition upon cooling34. Such disorder-order transition can also lead to a polarisation of the material and result in a ferroelectric phase transition in which case the transition temperature is called the Curie temperature, Tc. Isotope effects can be observed in ferroelectric crystals with hydrogen bonds. The phase transition temperature of such compounds with ferroelectric and paraelectric phases is mostly connected with ordering of protons. The paraelectric phase possess a symmetric potential curve with a double minimum and disordered protons, while in ferro- or antiferroelectric phases the curve becomes asymmetric with localized protons at particular bridge atoms (usually oxygen atoms)19. Matsuo et al.4 investigated the proton tunneling in the deuteration-induced phase transition of A3H(XO4)2 (NH4)2MCl6, and C13H6COOH19 with A as potassium, rubidium, cesium or thallium cations, X representing sulphur, selenium, phosphorus or arsenic and M one of the tetravalent ions Te, Pd, Pt or Pb35-40. Some crystals of the A3H(XO4)2 type undergo phase transitions in the deuterated forms. The authors showed that proton tunneling is the likely mechanism of the peculiar phase behavior of these solid compounds. In the case of (NH4)2MCl6, rotational tunneling of an ammonium ion is suspected to be responsible for the deuteration-induced phase transition. Intensive investigations deal with the isotope effect on the dielectric phase transitions of 5-bromo-9-H-hydroxyphenalenone. X-ray diffraction analysis has shown that the compound contains a short isolated intramolecular hydrogen bond which is symmetric at ambient temperature. The studies ACS Paragon Plus Environment

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suggest that no geometrical effect but intramolecular tunneling motion of the protons significantly influence the structural phase transitions via a molecular tautomerization process41. The usage of H/D-exchange as a tool to modify magnetic properties is not restricted to inorganic materials or organic compounds where the properties are influenced by hydrogen bonds. The replacement of the weak coordinating co-crystal former CH2Cl2 by CD2Cl2 in a cobalt-dioxolene complex leads to a significantly different magnetic behavior, shown by the temperature dependence of χT of the complexes with non-deuterated and deuterated solvate42.

Z’>1 For many crystal structures, molecules arrange themselves to form crystals in a relatively simple network with Z’=1. Interestingly, less than 10% of the X-ray crystal structures listed in the CSD have Z’>1. The question is why molecules choose to crystallize in such complicated patterns. The reasons for the formation of this phenomenon are still not fully understood43. Desiraju suggested to consider structures with Z’>1 as crystals “on the way” in the sense of being frozen in some high energy kinetic forms47. If the gap between the thermodynamic and kinetic stability is energetically very small, then a phase transition of such crystal structures to thermodynamically favored arrangements are very likely and more polymorphs could be achieved by the replacement of hydrogen by deuterium atoms. First comments on such a phenomenon were found for the simple organic compound pyridine by Biswas in 195844. Extensive IR studies of pyridine and d5-pyridine by Verderamew et al. in 1969 revealed the different arrangements of the molecules in the solid state45. Pyridine crystallizes in the space group P212121 and has an unusual crystal structure with four independent molecules in the asymmetric unit (Z’=4)50. In contrast, Boese et al. (2009) discovered that the isotopic polymorph of d5-pyrinde crystallizes at about –85 °C with a crystal structure (Pna21 with Z’=1) which differs from the structure which is usually adopted by pyridine. In parallel, Parsons et al. found that non-deuterated pyridine also adopts this structure under high pressure, because it requires a smaller volume than pyridine’s usual structure8.

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Figure 4: X-ray crystal structures of pyridine (colored) and d5-pyridine (black)8 Alloxan is another example for exceptional crystallization behavior. It crystallizes in the space group P41212 with Z'=0.5. This compound has an unusually high melting point, high crystal density and the crystal structure is characterized by an absence of conventional hydrogen bonds. The crystal structure and the physical properties of alloxan have fascinated scientists since the X-ray study was published in 196446. In contrast to earlier studies, a recent neutron powder diffraction investigation47 has shown that the crystal structure of deuterated alloxan transforms to a new orthorhombic isotopic phase below 35 K. The two phases are almost superimposable. There are two main types of intermolecular interactions: quite similar COCO contacts in both phases but different NHO contacts. This observable crystallographic isotope effect of a per-deuterated organic compound immediately leads to the question whether a partial H/D-exchange results in a measurable isotope effect, and at which level of substitution such an isotope effect would start. Our own investigations of pyridine-N-oxide48 have shown that partial deuteration influences the crystal packing of pyridine-N-oxide and leads to the formation of an isotopic lowtemperature crystallographic phase. Mono-deuterated pyridine-N-oxide crystallized from an under-cooled melt and is isostructural to pyridine-N-oxide in the tetragonal space group P41212. In contrast, the tri-deuterated pyridine-N-oxide was first cooled to -50 oC, a temperature of ten degrees below the solid-solid phase transition, and then subsequently crystal growth was initiated. Following this procedure it was possible to obtain single crystals of the isotopic low temperature phase in the orthorhombic space group P212121, a nonisomorphic subgroup of the tetragonal space group P41212, with two molecules in the asymmetric unit (Z'= 2). Analysis of the crystal packing of phase I and II shows comparable ACS Paragon Plus Environment

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calculated lattice energies with a difference of 0.259 kJ·mol-1 between the two phases49. The two phases differ in weak intermolecular CHO contacts. If strong classic intermolecular interactions are absent it is difficult to analyze the role of weak intermolecular interactions in crystal packing. An approach to get deeper insight into the aggregation behavior is based on the analysis of energies of these weak intermolecular interactions in the crystal structures. In particular this approach was successfully applied for the analysis of the crystal structure of deuterated pyridine-N-oxides. A comparison of the individual interactions in non-deuterated and trideuterated pyridine-N-oxide indicates only one similar C-HO hydrogen bond that is considerably stronger in the deuterated form. In contrast, the character of the C-Hπ bonds in both polymorphs is completely different50. Recently we have shown the influence of H/D substitution on the formation of different polymorphic forms of acridine33. While acridine preferred to aggregate in form II during the crystallization from acetone solution, similar crystallization experiments on per-deuterated acridine lead exclusively to form III. The different crystallization behavior could be explained by the different ways of crystal packing in the forms II and III. The calculated effective intermolecular potentials of C-D/HN pointed out that the H/D-substitution stabilizes the CHN intermolecular interaction in form III and prevents the rearrangement into the more stable form II.

a

b

Figure 5: Intermolecular interactions in the polymorphs of acridine (a) form II, (b) form III33.

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Deuterated solvents affect crystallization behavior

Most intermolecular interactions in crystal structures are relatively weak and their formation is related to and affected by small changes in the molecular structure and the crystallization conditions. The choice of the solvent can have a huge impact on the crystallization process. However, it is almost unknown that in selected cases, deuterated solvents can influence the crystallization behavior. Deuterium isotope effect on solvation dynamics was studied in bulk water51, 52, aqueous suspension of ZrO2 nanoparticles51 and methanol53, 54. The studies showed that the solvation dynamics are ~25% slower in D2O compared to H2O55. Schwartz and Rossky proposed that deuterium substitution slows down solvation dynamics by modifying the intermolecular libration frequencies56. The important role of deuterium on the density, kinematic viscosity and surface tension of bulk water was pointed out in a study of light, normal and heavy water57. With the increase of deuterated water molecules in the range of 19-97 ppm the kinematic viscosity decreases from 1.5145 to 1.4627 mm2/s. Substantial deviations of the surface tension and kinematic viscosity are observed in water samples with a D/H ratio of 146 ppm. Furthermore, deuterated water can also affect the crystal domain structures of room temperature ionic liquid (RTIL)-water system. Beside the reported example of oxaclic acid dihydrate12-14, a comparable effect was reported in a series of RTIL-water mixtures with different amounts of H2O and D2O58. This phenomenon is not only observed in RTIL-water mixtures or hydrates. Continuing our investigations on aggregation of substituted aromatic molecules in the solid state, we studied the influence of deuterated solvents on the aggregation of small molecules. In the case of acridine and deuterated acridine, the crystallization experiments from solution revealed both, the influence of the selected solvent, and the H/D substitution on the formation of different polymorphic forms33. Another remarkable example is glycine, the simplest of all amino acids, which showed response to partial deuteration as well. In 1961 Iitaka reported the observation that the γform crystallized more likely from heavy water solution, while usually additives were needed to achieve this particular form from water solutions59. Typically the α-form aggregates much faster than γ and γ can be obtained by changing the pH or by adding electrolytes to the solution65. Later in 2009 Hughes and Harris confirmed Iitakas first observations and

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suggested a subsequent solution mediated transformation from α to γ in sufficiently deuterated solution systems 67.

Conclusion We show that the aggregation of molecules in the solid state is very sensitive to small changes within the substitution pattern of the molecules. Deuterium substitution as a weak directing substituent may have quite an influence on the molecular arrangement. This phenomenon is not only restricted to compounds with absence of strong specific intermolecular interactions in crystal structures, like acridine, pyridine, pyridine-N-oxide or alloxane. H/D-exchange can influence hydrogen bonds, and as result the crystal structure, which is shown in the cases of oxalic acid dihydrate or trifluoroaectic acid tetrahydrate. Particularly striking in the last example is the rearrangement of the condensed six- and fourmembered oxygen rings of the hydrogen bonded H2O and D2O molecules. Another interesting fact is that an isotopic effect can also be observed in the usage of solvents in crystallization procedures. The formation of polymorphic forms and the amount of water/heavy water can be controlled in the cases of acridine, glycine and ionic liquids.

AUTHOR INFORMATION

Corresponding Author *Klaus Merz, aChair of Inorganic Chemistry 1, Ruhr-University Bochum, Universitätstrasse 150, 44801 Bochum, Germany, [email protected]

Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

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ACKNOWLEDGMENT We are grateful to the Cluster of Excellence RESOLV (EXC 1069) funded by the Deutsche Forschungsgemeinschaft (DFG) for financial support.

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8.

9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32.

Roettger, K.; Endriss, A.; Ihringer, J., Acta Crystallogr., Sect. B: Struct. Sci. 1994, B50, 644-648. Winkel, K.; Bauer, M.; Mayer, E.; Seidl, M.; Elsaesser, M. S.; Loerting, T., J. Phys.: Condens. Matter 2008, 20, 494212/494211-494212/494216. Whalley, E., Trans. Faraday Soc. 1957, 53, 1578-1585. Matsuo, T.; Inaba, A.; Yamamuro, O.; Onoda-Yamamamuro, N., J. Phys.: Condens. Matter 2000, 12, 8595-8606. Swift, E., Jr., J. Am. Chem. Soc. 1939, 61, 1293-1294. Zhou, J.; Kye, Y.-S.; Harbison, G. S., J. Am. Chem. Soc. 2004, 126, 8392-8393. Ip, B. C. K.; Shenderovich, I. G.; Tolstoy, P. M.; Frydel, J.; Denisov, G. S.; Buntkowsky, G.; Limbach, H.-H., J. Phys. Chem. A 2012, 116, 11370-11387. Crawford, S.; Kirchner Michael, T.; Blaser, D.; Boese, R.; David William, I. F.; Dawson, A.; Gehrke, A.; Ibberson Richard, M.; Marshall William, G.; Parsons, S.; Yamamuro, O., Angew Chem Int Ed Engl 2009, 48, 755-757. Muller, P., Pure & Appl. Chem. 1994, 66, 1077-1184. Zachariasen, W. H., J. Chem. Phys. 1933, 1, 634-639. Zachariasen, W. H., Z. Kristallogr., Kristallgeom., Kristallphys., Kristallchem. 1934, 89, 442447. Robertson, J. M.; Ubbelohde, A. R., Proc. R. Soc. London, Ser. A 1939, 170, 241-251. Ahmed, F. R.; Cruickshank, D. W. J., Acta Crystallogr. 1953, 6, 385-392. Iwasaki, F. F.; Saito, Y., Acta Crystallogr. 1967, 23, 56-63. Ubbelohde, A. R.; Gallagher, K. J., Acta Crystallogr. 1955, 8, 71-83. Steiner, T., Angew Chem Int Ed Engl 2002, 41, 49-76. Ichikawa, M., J. Mol. Struct. 2000, 552, 63-70. Dunitz, J. D.; Ibberson, R. M., Angew. Chem., Int. Ed. 2008, 47, 4208-4210. Sobczyk, L.; Obrzud, M.; Filarowski, A., Molecules 2013, 18, 4467-4476. Mootz, D.; Schilling, M., J. Am. Chem. Soc. 1992, 114, 7435-7439. Asaji, T.; Tajima, F.; Hashimoto, M., Polyhedron 2002, 21, 2207-2213. Flakus, H. T.; Hachula, B., J. Phys. Chem. A 2011, 115, 12150-12160. Blake, M. I.; Crespy, H. L.; Katz, J. J., J. Pharma, Sciences 1975, 64, 367-391. Mutlib, A. E., Chem. Res. Toxicol. 2008, 21, 1672-1689. Foster, A. B., TIPS 1984, 5, 524-527. Buteau, K. C., J. High Tech. Law 2009, 10, 22-74. Rohani, S., Front. Chem. Eng. China 2010, 4, 2-9. Lorenz, H.; Capla, F.; Polenske, D.; Elsner, M. P.; Seidel-Morgenstern, A., J. Univ. Chem. Technol. Metall. 2007, 42, 5-16. Ridley, R. G., Nature (London, U. K.) 2002, 415, 686-693. 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, 174-180. Baguley, B. C.; Wakelin, L. P. G.; Jacintho, J. D.; Kovacic, P., Curr. Med. Chem. 2003, 10, 26432649. 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, 9283-9292.

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33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59.

Kupka, A.; Vasylyeva, V.; Hofmann, D. W. M.; Yusenko, K. V.; Merz, K., Cryst. Growth Des. 2012, 12, 5966-5971. Wilson, C. C.; Shankland, N.; Florence, A. J., Chem. Phys. Lett. 1996, 253, 103-107. Kohno, K.; Matsuo, T.; Ichikawa, M., J. Korean Phys. Soc. 1998, 32, S393-S396. Mikac, U.; Arcon, D.; Zalar, B.; Dolinsek, J.; Blinc, R., Phys. Rev. B: Condens. Matter Mater. Phys. 1999, 59, 11293-11297. Shigeta, Y.; Nagao, H.; Nishikawa, K.; Yamaguchi, K., J. Chem. Phys. 1999, 111, 6171-6179. Titze, A.; Hinze, G.; Bohmer, R., Phys. Rev. B: Condens. Matter Mater. Phys. 1998, 57, R666R669. Totsuji, C.; Matsubara, T., Solid State Commun. 1998, 105, 731-733. Totsuji, C.; Matsubara, T., Solid State Commun. 1998, 107, 741-744. Moritomo, Y.; Tokura, Y.; Mochida, T.; Izuoka, A.; Sugawara, T., J. Phys. Soc. Jpn. 1995, 64, 1892-1895. Cador, O.; Dei, A.; Sangregorio, C., Chem. Commun. (Cambridge, U. K.) 2004, 652-653. Merz, K.; Vasylyeva, V., CrystEngComm 2010, 12, 3989-4002. Biswas, S. G., Indian J. Phys. 1958, 32, 13-18. Castellucci, E.; Sbrana, G.; Verderame, F. D., J. Chem. Phys. 1969, 51, 3762-3770. Bolton, W., Acta Crystallogr. 1964, 17, 147-152. Ibberson, R. M.; Marshall, W. G.; Budd, L. E.; Parsons, S.; Pulham, C. R.; Spanswick, C. K., CrystEngComm 2008, 10, 465-468. Vasylyeva, V.; Kedziorski, T.; Metzler-Nolte, N.; Schauerte, C.; Merz, K., Cryst. Growth Des. 2010, 10, 4224-4226. Hofmann, D. W. M.; Kuleshova, L. N., Crystallogr. Rep. 2005, 50, 335-337. Shishkin, O. V.; Shishkina, S. V.; Maleev, A. V.; Zubatyuk, R. I.; Vasylyeva, V.; Merz, K., ChemPhysChem 2013, 14, 847-856. Pant, D.; Levinger, N. E., J. Phys. Chem. B 1999, 103, 7846-7852. Castner, E. W., Jr.; Chang, Y. J.; Chu, Y. C.; Walrafen, G. E., J. Chem. Phys. 1995, 102, 653-659. Reid, P. J.; Barbara, P. F., J. Phys. Chem. 1995, 99, 3554-3565. Shirota, H.; Pal, H.; Tominaga, K.; Yoshihara, K., J. Phys. Chem. 1996, 100, 14575-14577. Sasmal, D. K.; Dey, S.; Das, D. K.; Bhattacharyya, K., J. Chem. Phys. 2009, 131, 044509/044501044509/044509. Schwartz, B. J.; Rossky, P. J., J. Chem. Phys. 1996, 105, 6997-7011. Goncharuk Vladyslav, V.; Kavitskaya Alina, A.; Romanyukina Iryna, Y.; Loboda Oleksandr, A., Chem Cent J 2013, 7, 103/1-103/5. Abe, H.; Imai, Y.; Takekiyo, T.; Yoshimura, Y., J. Phys. Chem. B 2010, 114, 2834-2839. Iitaka, Y., Acta Crystallogr. 1961, 14, 1-10.

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Deuterium perturbs the molecular arrangement in the solid state Klaus Merz*and Anna Kupka

Hydrogen/deuterium (H/D)-exchange, is generally seen as a negligible criterion in the formation of crystal structures of chemical compounds. However, in this perspective we present a whole collection of different aggregation behavior shown by deuterated small inorganic and organic compounds.

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