CHÂ·Â·Â·N Bonds and Dynamics in Isostructural Pyrimidine Polymorphs

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CH···N bonds and dynamics in isostructural pyrimidine polymorphs Ewa Patyk, Marcin Podsiadlo, and Andrzej Katrusiak Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.5b00657 • Publication Date (Web): 24 Jun 2015 Downloaded from http://pubs.acs.org on July 7, 2015

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Crystal Growth & Design

CH···N bonds and dynamics in isostructural pyrimidine polymorphs Ewa Patyk, Marcin Podsiadło and Andrzej Katrusiak* Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614 Poznań, Poland ABSTRACT: In the crystalline pyrimidine, the most basic building block of biochemical systems, the changes of entropy and enthalpy combine into a series of discrete structural transitions that have defied detection till now. The counterintuitive fully isostructural polymorphs of pyrimidine differ mainly by entropy, while the varied space occupied by molecules in partly isostructural polymorphs can be connected to the molecular dynamics, too. The interplay of thermodynamic and structural features affects the molecular interactions and environment and is most relevant to the functions of all organic compounds in the living tissue. The single crystals of four pyrimidine polymorphs have been grown at isobaric, isothermal and isochoric conditions and their structures have been determined by X-ray diffraction.

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INTRODUCTION The molecular recognition is a leading concept of structural biology applied in the search for new active pharmaceutical ingredients (APIs), which should deactivate proteins by blocking their specific docking sites. The docking capability of API molecules is usually connected to their shape and interactions, however the molecular dynamics is seldom considered. Pyrimidine (1,3diazine) is abundant in Nature as substituents and fused-ring systems of pyrimidine and purine DNA bases, as well as in synthesized drugs used for cancer and diabetes treatment.1 The molecular recognition of pyrimidine ring involves CH···N, CH···π and π-stacking interactions, most relevant for crystal engineering, designing drugs and all molecular biology.2-4 The CH···N interactions constitute about 2.69 % of cohesion forces in all crystal structures of organic compounds determined so far5 and are increasingly considered and applied for designing and promoting co-crystallization.6 In the series of frozen benzene, pyridine and pyridazine the CH···N contacts gradually replace the CH···π interactions.7 The CH···N and CH···π interactions can be conveniently studied in C4H4N2 diazine crystals, where the double H-acceptor capacity of two N atoms corresponds to four H-atoms. Thus each potential double H-acceptor is matched by two Hdonors. The CH···N interactions are relatively weak and they have to compete with other intermolecular forces and with other effects, such as close packing8 and electrostatic matching in the crystal environment.9 Pyrimidine is also intriguing because its isolated molecule is highly symmetric, of point group C2v. Although one-fourth of the molecule could be symmetryindependent, in the crystal the molecules are located at general positions (Z' = 1), due to the CH···N contacts to other molecules around, breaking the C2v symmetry. Moreover, the crystal structure of pyrimidine first determined at 271 K10 and then at 107 K11 were consistent in the orthorhombic symmetry of space group Pna21 (one independent molecule, Z’ = 1), which suggested the same crystal phase for all temperature range investigated. However, our


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calorimetric study has revealed that solid pyrimidine frozen at ambient pressure (m.p. 293.15 K) undergoes a solid-solid transition below 227.5 K (Figure 1). It testifies that above and below 227.5 K pyrimidine exists in two distinct solid phases, hereafter denoted I and II, respectively. Phase II persists down to 107 K, at least. On heating, phase II transforms back to phase I. No significant structural differences can be found between phases I and II. The hardly distinguishable structures of phases I and II demonstrate the apparent role of dynamic effects for the occurrence of their enantiotropic transitions. Here we have employed, apart from varied temperature, also high pressure for investigating the interplay of close-packing of molecules with their CH···N interactions, as well as the effects of molecular reorientations and symmetry in the crystal. High pressure is an ideal mean for tightening the molecular packing and for changing the balance between different types of interactions.12-19

Figure 1. Differential scanning calorimetry (DSC) thermograph for pyrimidine (6.7 mg) performed in the 310–170 K range with a rate of 5 K·min-1. Arrows indicate the directions of temperature changes. The insets one expands the indicated signal range, and the other shows the structural formula of pyrimidine in Cartesian coordinates for the irreducible representation of C2v-symmetric molecule.


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We have in situ grown single crystals of pyrimidine in a capillary by cycling temperature close to the m.p. and then we have monitored the lattice and structural changes through the phase transition and down to 200 K. Both these structures are orthorhombic, space group Pna21, consistently with the previous results at 271 and 107 K.10,11 Thus phases I and II have the same space group, and although the unit cell and structural changes at the transition are hardly detectable, they cumulate into a small discontinuity of volume (Figure 2), as required for isostructural transitions.20 Pyrimidine frozen in isothermal (60 MPa/295 K) and isochoric conditions transforms through three crystal phases: phase I persists to 0.82 GPa, when it transforms to phase III, of monoclinic space group P1121/a (Z’ = 2), which at 1.16 GPa transforms to phase IV of monoclinic space group P121/n1 (Z’ = 1). Intriguingly, the crystal lattices of phases I, II, III and IV are similar, but the unit cell of phase III is doubled along [x], i.e. aIII ≈ 2aI ≈ 2aII ≈ 2aIV (Figure 2, Table 1). The high-pressure phase transition postulated recently for pyrimidine basing on Raman spectroscopy21 corresponds to the transition between phases I and III determined in our study.


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Figure 2. (a) Thermal expansion and compression of pyrimidine lattice parameters a (aIII/2 in phase III), b and c. The inset shows angles β and γ. Lines between points are for guiding the eye only. Vertical dashed lines mark the boundaries at T12, P13 and P34 between phases I/II, I/III and III/IV, respectively. (b) The molecular volume as a function of pressure (black circles) and temperature in the cooling (blue) and heating (red) runs. The liquid-phase region is highlighted blue. The inset enhances the volume change between phases I and II. EXPERIMENTAL SECTION Pyrimidine (analytical grade, from Sigma-Aldrich, m.p. 293.15 K) was loaded to a modified Merrill-Bassett22 diamond-anvil cell (DAC) equipped with 0.3 mm thick steel gaskets with holes


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0.4 mm in diameter. Pressure was calibrated by the ruby R1 fluorescence line,23 using a BETSA PRL spectrometer affording an accuracy of ca. 0.05 GPa. Several experimental procedures were applied for obtaining high-quality single crystals (Figure 3). In the first approach, pure liquid pyrimidine was loaded to the DAC. Promptly after sealing the DAC, pyrimidine froze into polycrystalline mass. Single crystals were grown isochorically by slowly heating and cooling the sample after each pressure increase. The structure of pyrimidine phase I was determined at 0.32, 0.52, 0.71 GPa. At still higher-pressure no single crystals could be grown due to the rise of melting point at high pressure, as shown in Figure 4. Therefore next high-quality single crystals were obtained from pyrimidine-methanol mixture (vol. 1:1): phase I at 0.73 GPa; phase III at 1.02 and 1.07 GPa; and phase IV at 1.26 and 1.39 GPa, respectively. The experimental details and progress in growing the single crystals of pyrimidine are shown in Figures S1-S8 in the Supplementary Information. We have noted that the crystallization of pure pyrimidine above 0.2 GPa yielded bulky crystals, of a different habit than those at 0.32 GPa and of solution: thin elongated plates (Figures 3 and S1-S8). Single-crystal diffractometers KUMA KM-4 and Xcalibur EOS CCD with the CrysAlisPro program suite were used for data collection, determination of the UB-matrices and initial data reduction.24,25 Reflection intensities were corrected for the DAC and sample absorption, the gasket shadowing26,27 and the reflections of diamond-anvils were eliminated. All structures were solved by direct methods (SHELXS-97), and refined with anisotropic displacement parameters for non-H atoms (except phase III) by program SHELXL-97.28 All hydrogen-atoms were ideally located assuming the C−H bond length of 0.93 Å. Because we found ∆F peaks located at the positions of N atoms in phases I and II, we have included these partly occupied positions into the model, as detailed in the Supplementary Information. The purpose of these refinements was to check possible disorder of H atoms resulting from the molecular rotations.


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For the low-temperature/ambient pressure studies, a 0.3 mm drop of pyrimidine was spanned across the walls of a glass capillary, 0.3 mm in diameter. It was mounted on a four-circle KUMA KM-4 CCD diffractometer equipped with an Oxford Cryosystems attachment. The sample froze into a single crystal at ca. 280 K. After collecting diffraction data at 280 K, the crystal was cooled down at the rate of 5 K·min-1 to 260, 250, 240, 235, 230, 225, 220, 210 and 200 K. At each of these temperature points the single-crystal diffraction data were measured. Then the data were measured for the sample heated to 222.5, 227.5, 232.5 and 245 K, through the transition between phases II and I. Several differential scanning calorimetry (DSC) thermographs were recorded in the 340-170 K range with a rate of 5 K·min-1 for the pyrimidine sample enclosed in aluminum capsules on a DSC XP-10 apparatus (Figure 1). They all clearly indicated a phase transition between phases I and II at T12 = 227.5 K. The compressibility measurement of pyrimidine has been performed up to ca. 2 GPa in a piston-cylinder apparatus29 for the sample of initial volume 9.8 ml (Figure S9). In the phase diagram of pyrimidine (Figure 4) the pressure dependence of the boundary between phases I and II has been determined from the Clausius-Clapeyron equation dP/dT = ∆S/∆V, where ∆S is the transition entropy equal to 3.1 Jmol-1K-1 and ∆V is the volume change, of −0.06 cm3mol-1, at the transition (see Figure 2b). The dT/dP is equal to −19.4 KGPa-1; hence the transition temperature decreases with increasing pressure. Consequently, phase II is highly unlikely to exist at 295 K and the transition to phase III observed at 0.82 GPa/295 K proceeds directly from phase I.


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Figure 3. Single crystals of pyrimidine grown in situ in the diamond-anvil cell: (a) phase I at 0.52 GPa/340 K; (b) phase I at 0.73 GPa/323 K; (c) phase III at 1.02 GPa/339 K; and (d) phase IV at 1.26 GPa/358 K. Pure pyrimidine (a) and pyrimidine:methanol 1:1 (vol.) mixture (b−d) were used.


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Figure 4. Phase diagram of pyrimidine. The boiling point at 0.1 MPa (394.95 K; b.p.), melting point at 0.1 MPa (293.15 K; m.p.) after Ref. 30; the freezing point (f.p.) at 295 K measured by us in a piston-cylinder press; the freezing line obtained from the m.p. at 0.1 MPa, f.p. at 0.06 GPa/295 K and from melting points at 0.52 GPa and 0.71 GPa (our optical observations of pyrimidine melting in the DAC − spectroscopic pressure calibration and temperature measured by a thermocouple attached to the anvil); diffractometric determinations of pyrimidine phase I (circles), phase II (stars), phase III (triangles) and phase IV (squares). The putative gas-liquid, phase I/III and phase III/IV boundaries are marked with dashed lines. The critical point ending the boundary between phases I and II has been marked tentatively to indicate the isostructural character of the transition, although a triple point with another phases boundary is also possible. Table 1. Selected crystallographic data of pyrimidine phases I, II, III and IV (details for 22 structures are listed in the Supplementary Tables S1, S2, S3 and S4). phase I

phase II

phase III

phase IV

0.0001

0.0001

1.02(5)

1.39(5)

280.0(1)

200.0(1)

295(2)

295(2)

orthorhombic

orthorhombic

monoclinic

monoclinic

Pna21

Pna21

P1121/a

P121/n1

11.7036(7)

11.6379(5)

22.096(12)

11.109(7)

b

9.5020(4)

9.4709(3)

9.507(5)

9.2258(17)

c

3.8171(3)

3.75290(18)

3.6415(15)

3.5550(18)

−

−

95.05(6)

90.73(8)

424.49(4)

413.65(3)

762.0(6)

364.3(3)

4, 1

4, 1

8, 2

4, 1

1.253

1.286

1.396

1.460

1060/56

1038/56

272/49

126/25

Pressure (GPa) Temperature (K) Crystal system Space group Unit cell: a (Å, °)

γIII/βIV Volume (Å3) Z, Z' Dx (g cm-3) Data/parameters


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R1 (I>2σ(I)) R1/wR2 (all data)

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0.0408

0.0312

0.0407

0.0392

0.0505/0.1036

0.0329/0.0880

0.0517/0.0696

0.0480/0.0574

DISCUSSION It is characteristic of all pyrimidine phases I, II, III and IV that the molecules are linked by CH···N hydrogen bonds, forming closely related patterns. The structures of all phases I-IV are very similar in the projection down axis [z] (Figure 5). Their common feature is that each molecule is involved in eight hydrogen bonds: in four of them as the H-donor and in other four as the H-acceptor. Thus there are four symmetry-independent CH···N bonds per molecule.

Figure 5. Patterns of CH···N hydrogen bonds and molecular voids (calculated by Mercury31 with the probe radius 0.55 Å and grid spacing 0.3 Å) within the crystal structure of pyrimidine phases I (0.1 MPa/280 K), III (1.02 GPa/295 K) and IV (1.39 GPa/295 K) viewed along axes c (a) and a (b). The spiral arrows indicate the handiness of C22 (6) helices in phases I/II and III (a); letters A


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and B label independent molecules in phase III (a, c). Molecules building a three-column helical motive are marked in red. (c) The Hirshfeld surfaces32,33 of pyrimidine molecules in phases I/II, III and IV, decorated with the colour scale mapping the intermolecular distances: longer than van der Waals radii are shown in shades of navy-blue, equal are white and shorter red. The main differences between 3-dimensional (3-D) CH···N bonding patterns in the pyrimidine phases can be illustrated by the H-bonds involving atoms N1/C2H and N3/C4H. In phase I they connect molecules into helices of the opposite sense along axis [z] (Figure 5). These helices are described by symbol C22 (6) , according to the graph notation of H-bonds.34,35 The isostructural transition between phases I and II retains all the 3-D H-bonding pattern, and all the C22 (6) helices. The very subtle structural changes between phases I and II contrast with the entropy change, ∆S of 3.1 Jmol-1K-1, showing that this transition is associated with different numbers of energy states in phases I and II. The measured ∆S value well agrees with Rln3/2 = 3.37 Jmol-1K-1, which for the rigid pyrimidine molecules can be caused by molecular rotations. The rotations are activated depending on the tensor of inertia, Iµν, of the molecule and its intermolecular interactions. The orthonormal tensor Iµν in the coordinates consistent with the molecular C2v symmetry (Figure 1) is diagonal:

I µν

 I xx  = 0  0 

0 I yy 0

0   27.0 0 0     0  =  0 13.7 0  ⋅10 − 46 kgm 2 , where I µν = I zz   0 0 13.3 

∑ m (r δ 2

i

i

µν

− µ iν i ) ; mi is the mass of i-

i

th atom, ri 2 is its position with respect to the centre of mass of the molecule; µ and ν are coordinates x,y,z, for example xi is the x coordinate of ri; δ µν is the Kronecker delta and the summation runs through all atoms in the molecule. The kinetic energy Ek of a rotating molecule is Ek = ½Iµνωµων, where indices µ,ν correspond to the reference-system axes x,y,z and ωµ are the


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components of angular speed vector ω. According to this Iµν tensor the energy required for activating the rotation of a given frequency about the x axis (i.e. in the molecular plane, Figure 1) is approximately twice larger than the off-plane rotations about y and z. Moreover, the in-plane rotations require breaking all eight CH···N bonds to the neighbouring molecules around, binding the molecule to its crystal environment, whereas off-plane rotations can retain two or three of the bonds. Consequently, the in-plane rotations are considerably more energetically demanding and they are most likely to be damped at 230 K. The frequency of the in-plane rotations (ω) assessed of the Ixx component ( ω xx = 2 E / I xx ) and with the Boltzmann energy (kBT for each degree of freedom, kB being the Boltzmann constant) at 230 K is 1.75·1011 Hz, which in the crystal would be considerably slower due to the intermolecular interactions. For example, the rotations of similar pyrimidinium cations in [C5H6N]+AuBr4− at 175 K/0.1 MPa are at 6.7·107 Hz.36 The elimination of one component, ωx, of rotations in the 3-dimensional space corresponds to the ∆S ≈ Rln3/2 at the transition between phases I and II. Furthermore, the lower-energy tumbling-type motion of molecules requires an extra space in their vicinity. Indeed, phases I and II contain considerable voids (Figure 5). In the structure of phases I and II there are voids located around the pyrimidine molecules, between the CH···N bonds. These voids can provide space for motions of molecules. Although it appears that there is no sufficient voids space immediately above and below the molecules for their off-plane tumbling, possibly permitted in the vibrating lattice and by the molecular translational and librational motions. In this respect the molecular rotations in confined space is similar to the concept of 'porocity without pores', demonstrated by the permeability of guest molecules into voids of the host structure without sufficiently wide connecting channels.37 In the analogous way rotations of the molecule in the average crystal environment narrower than would be required for the molecular reorientations could be called "tumbling in tight space". The dynamics of the molecules is also consistent with the difference-


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Fourier (∆F) peaks indicating the partly occupied H-sites at N1 and N3 in phases I and II; the refinement of their structural models assuming the disorder of the H-atoms decreased the residue factors (Table S11). In phase III (Z' = 2) the symmetry-independent molecules A and B differ in their CH···N bonding and in their crystal environments (Figures 5 and 6): atoms N1/C2H and N3/C4H of molecules A form rings R22 (6) and the voids above and below the molecular plane collapse, whereas the corresponding atoms of molecules B form helices C22 (6) and the voids are retained. In phase IV (Z' = 1) atoms N1/C2H and N3/C4H of all molecules form the ring patterns R22 (6) and no voids allowing the off-plane rotations are present. Accordingly, no signs of the Hdisorder have been found. Thus the structures of phases I/II with helices C22 (6) contain considerable voids, which partly collapse in phase III where half of the helices subside into rings R22 (6) , and the voids are fully eliminated in phase IV where all N1/C2H and N3/C4H groups bind into the R22 (6) rings. This sequence of two transitions between phases I, III and IV can be classified as collapses of voids combined with reconstructions of H-bonding patterns. These reconstructions involve also other groups, C5H and C6H, however their D33 (8) patterns (D is graph descriptor R or C) are more complex than patterns D22 (6) discussed above. The collapses of voids confine the space required for off-plane molecular dynamics and increase the intermolecular interactions. Although it was in fact found that the H-disorder is present for the phases where the molecular rotations are postulated, we do realize that the significance of the partially occupied H-sites determined from X-ray diffraction data is low. The tightened crystal environment is likely to damp the rotations of molecules A in phase III and of all molecules in phase IV.


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It can be further inferred that the molecular rotations are transmitted as phonons through the crystal, and the C22 (6) helices are more suitable for this purpose than rings R22 (6) . These dynamical changes at the phase transitions combine with transformations of H-bonding patterns (Figure 6) in phases I/II, III and IV and with the crystal environment and volume occupied by the molecules, however eight CH···N contacts around each molecule are retained.

Figure 6. Increased

stacking

stages

in

pyrimidine

phases

I

(0.1 MPa/107 K),

III

(1.02 GPa/295 K) and IV (1.39 GPa/295 K). CONCLUSIONS The pyrimidine polymorphs reveal the balance between molecular dynamics and volume controlled by temperature and pressure within the constrains of transformable CH···N bonds network. The in-plane and off-plane rotations of molecules are differently demanding for volume, and in terms of energy required for CH···N bonds breaking. These factors differentiate


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the nearly identical polymorphs I and II, as well as 1-dimensional polymorphs III and IV. It is apparent that apart from the shape of the molecules (described by the space-filling model of van der Waals spheres), and the directional interactions, also the molecular dynamics of molecules at specific thermodynamic conditions can significantly affect their performance, for example in pharmaceuticals applications. The considerations of the entropy factor for the crystal structures of organic compounds are still scarce38 and further studies including the molecular dynamics in the solid state are clearly needed. It is likely that there are still quite important compounds with unnoticed phases governed by the dynamics of molecules. Calorimetric studies as well as solidstate NMR39 are most useful for their identification.

ASSOCIATED CONTENT

Supporting Information: detailed experiment and structures description. This information is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION

Corresponding Author *E-mail: [email protected] ACKNOWLEDGMENT This study was partly supported by the TEAM grant no. 2009-4/6 from the Polish National Science Foundation. The authors would like to thank Dr Kamil Dziubek, Ms. Katarzyna Maślińska and Ms. Katarzyna Dunajewska for their assistance in the high pressure experiments. REFERENCES


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For Table of Contents Use Only CH···N bonds and dynamics in isostructural pyrimidine polymorphs Ewa Patyk, Marcin Podsiadło and Andrzej Katrusiak*

The 3-dimensional CH···N bonding patterns in four highly isostructural pyrimidine phases are retained between phases I and II, but modified in one direction in phases III and IV. However, the phases clearly differ in molecular dynamics and structural voids depending on temperature and pressure.


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CHÂ·Â·Â·N Bonds and Dynamics in Isostructural Pyrimidine Polymorphs

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