Volume and Pressure Effects for Solvation: The Case Study on

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Volume and pressure effects for solvation: the case study on polymorphs of neat triiodoimidazole replaced by its solvate J#drzej Marciniak, Micha# Ka#mierczak, Kacper W. Rajewski, and Andrzej Katrusiak Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.6b00483 • Publication Date (Web): 19 May 2016 Downloaded from http://pubs.acs.org on June 1, 2016

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Crystal Growth & Design

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Volume and pressure effects for solvation: the case

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study on polymorphs of neat triiodoimidazole

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replaced by its solvate

4

Jędrzej Marciniak, Michał Kaźmierczak, Kacper W. Rajewski, Andrzej Katrusiak*

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Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614 Poznań, Poland

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Keywords: solvates, halogen-halogen interactions, hydrogen bonds, high pressure, symmetry-

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property relations

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ABSTRACT: The formation of solvates in relation to the neat-crystal close packing efficiency

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and the symmetry, involving the number of independent molecules (Z’), has been investigated. In

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the Cambridge Structural Database solvates are most frequent when the corresponding neat

11

compounds have several independent molecules Z’>1. High-pressure changes the energy

12

difference between inequivalent molecules and their interactions, which can trigger phase

13

transitions, solvation, multi-component aggregation and other transformations. When

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2,4,5-triiodoimidazole (tIIm) polymorph α (Z’=3) was recrystallized above 0.2 GPa in methanol,

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a hemisolvate 2tIIm·CH3OH was obtained. Later, the hemisolvate could be obtained at normal

16

conditions and then polymorphs α and β disappeared, and new syntheses and recrystallizations at

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0.1 MPa yielded exclusively a new polymorph γ (Z’=4); when dissolved in methanol it

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precipitates as the methanol hemisolvate only. In its structure, chains are formed of NH···N and

str. 1 ACS Paragon Plus Environment


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NH···OH···N bonded molecules. These chains interact through halogen bonds, almost absent in

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much looser neat α-tIIm, but numerous in considerably more compact phases β and γ. The

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statistical distribution of the solvation effect for the crystal volume has been compared to the

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molecular volume calculated and measured in several ways for the most frequent compounds.

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INTRODUCTION

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The formation of polymorphs, solvates and multicomponent crystals is of vital importance for

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pharmaceutical and chemical industries, because chemical and physical properties of compounds

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can be adjusted to their practical applications.1,2 The solvation of active pharmaceutical

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ingredients (API's) generally increases their solubility and bioaccessibility.3,4 For these reasons

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the prediction and practical skills for inducing solvation, desolvation and co-crystallization are

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invaluable.5-9 The possible preference for the formation of solvates may be indicated by the

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number of symmetry-independent molecules, Z’, in the neat compound. The Z’ numbers larger

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than one are often regarded as an indication of inefficient packing of molecules or ions. Several

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reasons for increased Z’ are usually considered: asymmetric aggregation of molecules into

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dimers, trimers etc; interactions requiring molecular differentiation into tautomers, conformers

34

etc.; the mismatch between close packing10 of molecules and their directional interactions (e.g.

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hydrogen and halogen bonds11 as well as the matching of positive and negative electrostatic

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potentials in halogen bonds of type I or of highly polarizable atomic regions in halogen bonds of

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type II).12-14 At ambient pressure the directional interactions can considerably disrupt the

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arrangement of molecules into a closely-packed structure, which leads to the formation of voids.

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High pressure naturally reduces the voids and favors the close packing of molecules, and can

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destabilize the structures dominated by directional interactions. The elimination of voids may


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require that molecules change their conformation (e.g. in sucrose, 1,1,2-trichlorethane,

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pyrrolidine).15-17 The voids reduction can proceed as a monotonic compression, and as phase

43

transitions, reconstructing the molecular aggregation and affecting the Z’ number;18-23 for some

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compounds still denser packing can be achieved in solvates and co-crystals.24-28 Our survey of the

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crystals of unsolvated compounds, for which at least one solvate has been deposited in the

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Cambridge Structural Database (CSD),29 shows clearly that solvates are more frequently formed

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for neat compounds with Z’ larger than 1, compared with the compounds with Z’ equal or smaller

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than 1. This may indicate that Z’ larger than 1 is connected with some misfit and increased

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volume of voids in molecular packing in crystals. For example, in neat thiourea pressure induces

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a phase transition from phase III (Z’=1) phase IV with Z’=3, which coincides with the formation

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of hydrates, when the compound is recrystallized from aqueous solution.30

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As a case study, we have performed high-pressure crystallizations of 2,4,5-triiodiimidazole

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(tIIm), which forms a structure with three symmetry-independent molecules (Z’=3) at ambient

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conditions. The crystal structure of tIIm is distinctly different and less densely packed than the

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two isostructural crystals of analogous trichloroimidazole (tClIm) and tribromoimidazole

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(tBrIm), both of space-group symmetry Ama2 and Z’=0.5.31 The intermolecular contacts in these

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structures indicate that the steric hindrances between large iodine substituents prevent the

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formation of triiodoimidazole crystals isostructural with trichloro and tribromo analogs. While

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we tried to obtain tIIm polymorph similar to the structures of tClIm and tBrIm, polymorph α-tIIm

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was first transformed to high-pressure β-form, but then they disappeared, and a new γ-polymorph

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(Z’=4) could be obtained. Still, later, polymorph γ was replaced by methanol solvate

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2tIIm⋅CH3OH, even though neat tIIm had been obtained from methanol solution at ambient

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pressure before.



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EXPERIMENTAL

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The samples of 2,4,5-triiodoimidazole synthesized by us three years ago31 and now obtained

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again according to the same procedure published in the literature32 were used for this study. We

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slowly evaporated several solutions of tIIm in a series of solvents (methanol, ethanol, acetone and

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isopropanol) in order to check if tIIm forms solvates. In one of the vials of the methanol solution

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one small crystal of distinct morphology was found among neat tIIm crystals. Its single-crystal X-

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ray diffraction measurement showed that it was a new hemisolvate 2tIIm·CH3OH. The

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crystallization by evaporation of solvent from ethanol, acetone and isopropanol solutions yielded

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solely the unsolvated tIIm crystals.

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We also recrystallized tIIm at high pressure. These experiments were performed in a modified

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Merrill-Bassett diamond-anvil cell (DAC).33 A single crystal of neat tIIm was put into the DAC

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chamber, then filled up with methanol, to yield a saturated solution. The gaskets were made of

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stainless steel foil 0.3 mm thick with the aperture of 0.45 mm in diameter. Pressure was

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determined from the ruby R1 fluorescence line shifts34 by using a Photon Control spectrometer

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affording an accuracy of 0.03 GPa. Pressure was increased to 0.2 GPa and all the tIIm was

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dissolved in methanol by using a heat-gun and increasing the temperature to 366 K, and then a

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single crystal, of clearly different habit than that of neat α-tIIm, was grown by slowly cooling the

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DAC to room temperature (Figure 1).

82


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Figure 1. The DAC high-pressure chamber with a crystal of neat α-tIIm before recrystallization

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(a); the 2tIIm·CH3OH solvate (b) at 0.2GPa/296K. Several ruby chips for pressure calibration lie

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along the gasket edge.

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The sample was recovered from the chamber and studied by single-crystal X-ray diffraction on

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an Xcalibur EOS diffractometer with a MoKα X-ray tube. All diffraction data were preliminarily

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reduced with the CrysAlis software.35 The crystal grown in situ in the DAC proved to be the

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2tIIm·CH3OH hemisolvate. Its structure was solved by direct methods and refined with full-

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matrix least squares on F2 using Shelxs and Shelxl-2013 implemented in Olex2.36,37 The azole

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hydrogen atoms were located and assigned from the molecular geometry at the positions

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consistent with the bond length in the N=C-N bonds systems.

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Disappearance of the α-tIIm polymorph

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For the experiments we used the tIIm sample synthesized in our laboratory three years ago, and

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when we ran out of the crystals used for ambient and high-pressure recrystallizations from

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different solvents, we synthesized the compound again, in the same way as we had done it

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before.32 The new batch of tIIm contained a new polymorph γ,38 considerably denser than

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polymorph α (Table 1).

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Table 1. Selected crystallographic data of ambient-pressure 2,4,5-triiodoimidazole (tIIm) forms α

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and γ, as well as the methanol hemisolvate 2tIIm·CH3OH. Molecular volume Vm (V/Z), the

101

molecular volume of van der Waals hard spheres (VvdW – one molecule of tIIm in polymorphs α

102

and β, as well as the asymmetric unit of tIIm⋅⋅⋅tIIm⋅⋅⋅CH3OH hydrogen-bonded chain in

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2tIIm·CH3OH, with their partly superimposing spheres), the crystal packing coefficient C of neat

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α-tIIm and solvate 2tIIm·CH3OH calculated as C=Z⋅VvdW/V, are also given. Detailed information

105

are listed in Table S1 of Supporting Information (SI).



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Compound

α-tIIma

γ-tIImb

2tIIm·CH3OHc

Space group

P21/a

P21/c

P21/c

T [K]/P [MPa]

296/0.1

296/0.1

296/0.1

a [Å]

9.4594(5)

19.6205(10)

11.44976(15)

b [Å]

22.0816(12)

9.0209(3)

9.18782(10)

c [Å]

14.0795(8)

21.7969(11)

18.0734(2)

β [°]

108.218(5)

116.295(6)

94.6060(11)

Z/Z’

12/3

16/4

4/1

Vm (V/Z) [Å3]

232.8

216.17

473.8

VvdW [Å3]

134.02

134.02

302.06

Dx [g cm-3]

3.180

3.424

3.237

C

0.58

0.62

0.63

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106

a

Ref. 31,

107

b

Ref. 38,

108

c

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14/14, k -11/11, l -22/22, reflections collected 25482, unique 3842; Parameters 166; Rall 0.030;

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Robs [I>2σI] 0.024; wR2all 0.043; wR2obs 0.042; GOF 1.179; ∆ρmax,min 0.79/-0.96 e Å-3.

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Polymorph γ is of the same space group symmetry, P21/c, as polymorph α-tIIm, but its number of

112

symmetry independent molecules Z’ increased to 4. Most importantly, the subsequent repeated

113

syntheses yielded polymorph γ only, while polymorph α disappeared. The next attempts to obtain

114

the high-pressure solvates could be carried out only with the γ polymorph of tIIm. In a series of

115

ambient and high-pressure recrystallizations, where polymorph γ was used for preparing the

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aqueous, methanol, ethanol, acetone and isopropanol solutions as well as of water:ethanol (1:1,

This study: FW 1846.11 g mol-1; µ 9,83 mm-1; F(000) 1606; 2Θ range 6.33-53.54; min/max. h -


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4:1 and 9:1 vol.) solutions, either the same hemisolvate with methanol or the neat tIIm in the

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γ-form could be obtained.

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RESULTS AND DISCUSSION

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Initially, at ambient conditions and of methanol solution, tIIm preferentially crystallized in the

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unsolvated form α (Table 1). Of all the recrystallizations by slowly evaporating methanol at

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ambient conditions, only one 2tIIm·CH3OH parallelepiped crystal was found among needle-

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shaped α-tIIm crystals. In turn, all isothermal and isochoric recrystallizations of α-tIIm from

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methanol at 0.2 GPa exclusively yielded the 2tIIm·CH3OH hemisolvate. Subsequent ambient and

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high-pressure recrystallizations of the γ-tIIm polymorph from methanol yield the 2tIIm·CH3OH

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hemisolvate. It shows that high pressure changed the crystallization preference of α-tIIm

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dissolved in methanol to crystallize as the hemisolvate, where the asymmetric unit contains two

128

tIIm molecules and one methanol molecule (Figure 2).

129



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Figure 2. NH···N bonded chains in (a) neat α-tIIm; (b) neat γ-tIIm38 and (c) NH···N and

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NH···OH···N bonded chains in 2tIIm·CH3OH. Atoms and independent molecules are labeled and

132

H-bonds are marked as cyan lines.

133

It occurs that the formation of polymorphs α and γ results from the competition between N-H···N

134

hydrogen bonds and I···I and I···π halogen bonds in their structures. The compression of

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polymorph α leads to a similar competition in its structure, triggering a discontinuous transition

136

to polymorph β. Because the structural mechanisms leading to these transformations divert from

137

the main subject of the solvate formation, we decided to describe them elsewhere. After the

138

disappearance of polymorph α and its high-pressure β-form, the preference to re-crystallize as the

139

methanol hemisolvate persisted also for polymorph γ. Thus, it can be concluded that the

140

crystallizations of tIIm dissolved in methanol yielded different products: initially, it was the neat

141

polymorph α; then again the α polymorph and one single crystal of solvate 2tIIm·CH3OH; then,

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after the solvate 2tIIm·CH3OH was obtained at 0.2 GPa, the ambient-pressure recrystallizations

143

yielded exclusively the solvate; when the repeated synthesis of tIIm yielded exclusively the

144

γ polymorph, its recrystallizations of methanol solutions yielded exclusively the methanol solvate

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2tIIm·CH3OH. It shows that the phenomenon of disappearing polymorphs of neat compounds,

146

well described in the literature,39,40 can also involve their solvates. These transformations can be

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presented as a chronological sequence of equations: ஼ுయ ைு

148

α-tIIm ሱۛۛۛሮ α-tIIm

149

α-tIIm ሱۛۛۛሮ 2tIIm·CH3OH

150

γ-tIIm ሱۛۛۛሮ 2tIIm·CH3OH

஼ுయ ைு

஼ுయ ைு


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151

It indicates that polymorph α-tIIm, and most likely also β-tIIm above 1.9 GPa,38 are metastable

152

with respect to phase γ-tIIm, and that all these polymorphs are metastable with respect to the

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2tIIm·CH3OH solvate, as schematically shown for the Gibbs free energy changes in Figure 3.

154

155 156

Figure 3. Schematic plot of Gibbs free energy changes ∆G as a function of pressure for tIIm

157

polymorphic forms and methanol solvate 2tIIm·CH3OH. The years in brackets indicate the date

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of first detection of the tIIm polymorphs and its solvate.

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The solvation that yields 2tIIm·CH3OH considerably increases the number of short

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intermolecular contacts compared to the structure of neat α-tIIm, where three NH···N hydrogen

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bonds and one I···I halogen bond (per asymmetric unit) are present. The numbers of I⋅⋅⋅I

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interactions is bonds in the solvate and in γ-tIIm are comparable.

163

Table 2. Distances (Å) shorter than the sums of van der Waals radii,41 indicating hydrogen bonds

164

and I⋅⋅⋅I bonds in α-tIIm and 2tIIm·CH3OH. The symmetry codes apply to the primed atoms.

165

Letters A, B and C denote independent tIIm molecules: three in α-tIIm, and two in 2tIIm·CH3OH. α-tIIm30

distance (Å)

symmetry code

N1A···N3B

2.734(6)

x, y, z



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N1B···N3C

2.789(5)

x, y, z

N1C···N3A’

2.774(2)

1/2+x, -y, 1+z

I3B···I3B’

3.805(4)

1-x, 1-y, 1-z

N1B···N3A’

2.906(5)

x, y, z

N1A···O’

2.730(5)

x, y, z

O···N3B’

2.798(5)

1+x, y, z

I2A···I2B’

3.8120(5)

1-x, 2-y, -z

I3A···I1B’

3.8141(4)

2-x, 1/2+y, 1/2-z

I3A···I3B’

3.8187(5)

2-x, 2-y, -z

I2A···I3B’

3.8371(5)

x, y-1, z

I1A···I3A’

3.9570(4)

x, 1+y, z

I···O’

3.087(3)

2-x, y-1/2, 1/2-z

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2tIIm·CH3OH

166 167

It is characteristic that the only NH···N bond retained in the 2tIIm·CH3OH solvate is much longer

168

than those in neat α-tIIm, while the NH···OH···N hydrogen-bonds are similar in lengths. This only

169

NH···N bond is considerably longer, by about 0.15 Å, than each of three independent NH···N

170

bonds in α-tIIm (Table 2); the NH···O bond is slightly shorter than the shortest of the independent

171

bonds; bond OH···N is slightly longer than the longest of the bonds in α-tIIm. The NH···N bond

172

present in the 2tIIm·CH3OH solvate is longer by 0.1 Å than each of three NH···N bonds in α-tIIm

173

and shorter by 0.1 Å than the longest of four independent NH···N bonds in γ-tIIm. In

174

2tIIm·CH3OH the NH···N and NH···OH···N bonded molecular chains form layers connected

175

through I···O bonds (of 3.087 Å, Figure 4) and further extend into a complex 3-dimensional

176

network involving halogen bonds I···I (Table 2, Figure S1).


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177 178

Figure 4. Single layer of the H-bonded chains of 2tIIm·CH3OH shown as an autostereogram.

179

Hydrogen bonds NH···N and NH···OH···N are shown as cyan lines, I···O bonds are marked as red

180

lines, while I···I bonds have been omitted for clarity and are shown in Figure S1.

181

The low density of neat α-tIIm crystal packing and exceptionally few (one per three

182

independent tIIm molecules) halogen-halogen bonds are related. The relatively small tIIm

183

molecule with three peripheral iodine atoms can be expected to form several I···I contacts. Only

184

one I···I contact in the neat α-tIIm may result from the C–I···I angles considerably different than

185

the values required for the X···X bonds. In contrast, the I···I bond network in the tIIm γ-polymorph

186

is much denser and comparable to the I···I bonds network in the solvate 2tIIm·CH3OH. In the

187

2tIIm·CH3OH solvate two independent tIIm molecules form ten I···I bonds, six and four per

188

independent molecules A and B, respectively (Fig. S1). None of these I···I bonds is formed

189

between NH···N and NH···OH···N bonded molecules A and B within one chain (Figure 2), but

190

bonds I···I are formed between molecules A-B’ (four I···I bonds), B-A’ (four I···I bonds) and A-

191

A’ (two bonds) of adjacent molecular chains (Table 2). The I···I distances of these bonds range

192

from 3.8120(5) to 3.9570(5) Å, and their dimensions conform to the ideal type II of halogen

193

bonds (Table S2).12-14 Iodine atoms I2A, I3A and I3B involved in these halogen bonds are

194

‘amphoteric’, i.e. they act as both donors and acceptors in halogen bonds. It can be noted that in

195

two isostructural crystals tClIm and tBrIm (both orthorhombic, space group Ama2, Z’=1) angles



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196

C-X···X considerably deviate from ideal values in X⋅⋅⋅X bonds of type I and II. It is thus plausible

197

that such significant angular deviations in much stronger I···I interactions would destabilize a

198

similar arrangement and prevent the neat tIIm from forming the crystal isostructural to tClIm and

199

tBrIm. The inclusion of methanol molecules in the hemisolvate, in turn, leads to a new

200

arrangement with numerous I···I bonds.

201

The improved packing of solvate 2tIIm·CH3OH increases its density compared to the neat

202

components of the solution, α-tIIm and CH3OH (Table 1). The methanol molecules incorporated

203

in the crystal structure significantly tighten the molecular arrangement and eliminate the large

204

voids present in the neat α-tIIm (Figure 5). This considerably denser packing of solvate

205

2tIIm·CH3OH explains this high-pressure preference for the solvation over α-tIIm.

206 207

Figure 5. Contact surfaces representing voids in the structure of (a) α-tIIm; (b) γ-tIIm; and (c)

208

methanol solvate 2tIIm·CH3OH.42 The probing radius of 1.18 Å and step of 0.2 Å have been

209

adjusted to display a minimum size of the largest voids in solvate 2tIIm·CH3OH and then the

210

same radius and step have been applied for displaying the voids in neat α-tIIm and γ-tIIm. The

211

voids calculated in this way occupy 9.4% of the neat α-tIIm volume, 1.9% in γ-tIIm and 0.6% in

212

2tIIm·CH3OH.


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213

The high-pressure crystallizations of tIIm dissolved in other solvents (see Experimental) resulted

214

in the neat α-tIIm and later in the neat γ-tIIm crystals only. It is thus plausible that methanol has

215

the shape and interactions optimal for the close packing with the tIIm molecules. However, when

216

polymorph α-tIIm disappeared and the crystallizations of solutions prepared of polymorph γ-tIIm

217

resulted either in the same solvate 2tIIm⋅CH3OH or in γ-tIIm when other solvents than methanol

218

were used.

219

It was shown recently for benzimidazole and its derivatives that their solvation can be

220

connected to the dimensions of voids in the neat compounds.43 The relation between void volume

221

and maximum void width for neat α-tIIm, γ-tIIm, 2tIIm·CH3OH solvate and selected other

222

imidazole derivatives, plotted in Figure 6, is consistent and confirms the significance of the voids

223

dimensions for the solvation of α-tIIm and γ-tIIm.

224 225

Figure 6. The maximum void width in neat α-tIIm (magenta square), γ-tIIm (magenta circle),

226

2tIIm·CH3OH cocrystal (magenta triangle) and selected imidazole derivatives (calculated by

227

Mercury using 0.1 Å grid spacing) correlated to the voids volume per one ‘host’ molecule. The



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228

voids volume was calculated for the probing-sphere radius of 0.8 Å and 0.1 Å grid. The void

229

volume in the unit cell of solvate 2tIIm·CH3OH was divided by 8, the number of tIIm molecules

230

in the unit-cell. Benzimidazole, 5,6-dimethybenzimidazole and 2-methylimidazole are coded as

231

BzIm, 5,6-dmBzIm and 2-mIm, respectively. Diamonds and squares mark 4,5-di- and 2,4,5-

232

trisubstituted haloimidazoles. Dashed lines connect solvate/neat crystal pairs.

233

The voids-size reduction in 2tIIm·CH3OH is similar to that in 2(5,6-dimethylbenzimidazole)⋅H2O

234

hemihydrates (Figure 6). Polymorph γ-tIIm has considerably smaller voids than α-tIIm, but still

235

larger than those in imidazole derivatives for which no solvates have been reported so far. The

236

voids present in neat α-tIIm are significantly larger than those in γ-tIIm and other imidazole

237

derivatives. The crystals of analogue 2,4,5-trisubstituted haloimidazoles, 2,4,5-trichloroimidazole

238

(tClIm) and 2,4,5-tribromoimidazole (tBrIm), which form more dense structures with Z’=0.5,

239

have much smaller voids. The solvation decreases the size of the voids in tIIm polymorphs: the

240

solvation of α-tIIm nearly halves the dimensions of its voids; compared to γ-tIIm the solvation

241

decreases the volume of its voids by 10%. This result is consistent with the conclusions

242

formulated previously for benzimidazole derivatives, that the voids dimensions in neat

243

compounds indicate their potential solvation in high-pressure conditions. The significant drop of

244

voids dimensions in 2tIIm·CH3OH may suggest that one methanol molecule included per two

245

tIIm molecules ‘saturates’ the solvation of this compound by methanol, despite the presence of

246

two independent tIIm molecules in this structure. It can be noted that the dimensions of voids in

247

α-tIIm, γ-tIIm and its solvate 2tIIm·CH3OH are consistent with the packing coefficient, C,

248

calculated according to the equation introduced by Kitaigorodskii44 (Table 1) for investigating the

249

close packing of molecules in molecular crystals: C=Z⋅VvdW/V, where VvdW is the molecular

250

volume calculated of superimposing atomic van der Waals spheres,41 V is the unit-cell volume


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251

and Z is the number of molecules in the unit cell. The packing factor C, of neat α-tIIm, equal to

252

0.58 is low and in 2tIIm·CH3OH it considerably increases to 0.63. The solvation marginally

253

increases the packing factor of the γ-polymorph, which is equal to 0.62.

254

Solvation effect on the crystal volume

255

In order to find the relation between crystal-packing efficiency and solvation for molecular

256

crystals we have searched the CSD for pairs of a neat compound and its solvate and then we have

257

determined the volume of one solvent molecule in the crystal. This analysis has been limited to

258

the crystals containing only one type of solvent molecules (e.g. hydrates, methanol solvates,

259

ethanol solvates). The molecular volume associated with one solvent molecule, ∆Vs, has been

260

calculated according to the following equation:

261

∆Vs=(Vs/Zs-Vu/Zu)/S

(Equation 1)

262

where Vs and Vu are the unit-cell volumes, Zs and Zu are the numbers of host molecules in the unit

263

cells of the solvated and unsolvated counterparts, respectively; S is the number of solvent

264

molecules per one host molecule in the solvated crystal. The distribution of so normalized

265

solvent-molecule volume in methanol solvates is plotted in Figure 7.



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Page 16 of 26

266 267

Figure 7. Distribution of differences in volumes of neat compounds and their methanol solvates.

268

Dashed lines indicate the solvent volumes per molecule in the liquid at normal conditions (Vl,

269

black), the volume per molecule in a selected crystalline phase (Vm, blue) and the molecule

270

volume calculated by treating atoms as hard van der Waals spheres according to Bondi (VvdW,

271

red).41 Green dashed lines show the normalized volume difference ∆Vs (Equation 1) calculated

272

for 2tIIm·CH3OH solvate in the reference to polymorphs α-tIIm and γ-tIIm.

273

Compared to α-tIIm, in the 2tIIm·CH3OH solvate one methanol molecule causes the crystal

274

volume increase ∆Vs equal to 8.2 Å. This ∆Vs is smaller than the molecular volume of methanol

275

in liquid (Vl) and that of atomic van der Waals spheres (VvdW). Of all neat-crystal/methanol-

276

solvate pairs (deposited in the CSD) in 97% the ∆Vs volume is larger than that calculated for the

277

α-tIIm/2tIIm·CH3OH pair. In 72% of methanol-solvated crystals the ∆Vs volume is larger than the

278

VvdW volume of methanol. Finally, in 32% of methanol solvates the volume difference, ∆Vs, is


Page 17 of 26

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279

larger than the volume of the methanol molecule (Vm) in its single-component crystal. Thus, the

280

volume required for methanol molecules in methanol solvates is in most cases smaller than the

281

sum of the molecular volumes of separate single-component crystals. This volume gain is a likely

282

cause of preferential solvation in high pressure. Only in 11% of methanol solvates volume ∆Vs is

283

larger than that of methanol in its liquid phase (Figure 7). The formation of such solvates in high-

284

pressure is highly unlikely. The ∆Vs calculated for the γ-tIIm/2tIIm·CH3OH pair is equal to 40.4

285

Å. This value is similar to the most frequent ∆Vs volumes for methanol solvates.

286

The ∆Vs volume distributions calculated according to Equation 1 for hydrates, as well as

287

acetone, benzene and methylene chloride solvates are plotted in Figure 8. The ∆Vs volume

288

distributions

289

N,N-dimethyl-formamide (DMF), dimethyl sulfoxide (DMSO), ethanol, methanol, pyridine and

290

toluene can be found in the Supporting Information in Figure S3. It can be observed that the

291

molecular volume of one methanol molecule is comparable with the size of the voids in α-tIIm

292

(Figure 5), which is consistent with the small ∆Vs value calculated for the solvate/neat compound

293

pair. The smaller voids in γ-tIIm increases the ∆Vs value.

of

less

frequently

represented

acetonitrile,

chloroform,

1,4-dioxane,



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Page 18 of 26

294 295

Figure8. Distribution of ∆Vs (Equation 1) of solvate/neat-crystal pairs. Dashed lines indicate the

296

solvent volumes per molecule in liquid at normal conditions (Vl, black), the volume per molecule

297

in selected crystalline phases (Vm, blue), and the molecule volume calculated by treating atoms as

298

hard van der Waals spheres according to Bondi (VvdW, red).41


Page 19 of 26

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299

The calculated VvdW volumes are in the range of (0.6-0.7) of Vm, which is consistent with the

300

typical values of Kitaigorodskii’s packing coefficient C for molecular crystals.44 The ∆Vs plots

301

show that the population maxima are close to the molecular volume values of solvents in their

302

own neat crystals at ambient pressure (and low temperature). It is plausible that the solvation in

303

the solvate/neat crystal pairs contributing to these ∆Vs values is driven by more favorable

304

interactions in the solvated crystals. The ∆Vs plots can be used for predicting the solvate

305

formation in high-pressure conditions. The ∆Vs value smaller than the Vs of pure solvent indicates

306

that combining two compounds in a single form results in a product of a smaller volume than the

307

two compounds crystallized separately. Owing to this volume gain the solvate is more favoured

308

at high pressure than the neat compound. Reversely, large ∆Vs of a compound indicates that its

309

unsolvated form can selectively crystallize at high pressure. The ∆Vs plots can be also helpful in

310

establishing the approximate number of solvent molecules in the solvate structural model.

311

Incorrect number of solvent molecules located in the structure can result in an ∆Vs significantly

312

different than the average value. This can be useful when the number and location of disordered

313

solvent molecules is difficult to establish from structural data. We have identified few apparent

314

errors in the structures deposited in the CSD and indicated their ∆Vs values in the plots in Figure

315

S4.

316

CONCLUSIONS

317

The search for new solvates can be considerably facilitated by the systematic analysis of

318

molecular volumes of constituent components and their intermolecular interactions. It appears

319

that high Z’ numbers in the neat crystals may indicate a likely high-pressure solvation of this

320

compound. The interactions and volume are interdependent elements of the thermodynamic and

321

statistical description of the solvation process. Solvates are favored when new, stronger

322

interactions are formed or the close packing of molecules is significantly improved. The solvate



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Page 20 of 26

323

formation at low pressure conditions can be attributed to favorable intermolecular interactions.

324

The types of interactions of the host molecule, e.g. hydrophobic and hydrophilic, provide

325

additional information about solvents likely to be absorbed. The statistical analysis of the

326

molecular volume can efficiently predict the effect of pressure for generating new solvates. At

327

high pressure the close packing plays a significant role, and can be a deciding factor changing the

328

course of nucleation and crystallization. High-pressure strongly increases the preference for the

329

2tIIm·CH3OH crystallization. This preference originates from the significantly tighter molecular

330

packing of 2tIIm·CH3OH than that of neat α-tIIm. The solvation in the 2tIIm·CH3OH leads to the

331

mixed NH···N and NH···OH···N hydrogen bonds and a considerable increase of halogen bonds,

332

which can be connected to the denser packing. Such a solvation (hydration) leading to the

333

structure with mixed hydrogen bonds NH+···N and NH+···OH···N was observed for 1,4-

334

diazabicyclo[2,2,2]octane hydroiodide hydrate.45 In that monohydrate a considerable increase of

335

the crystal volume (compared to the neat salt) suggested that the modified interactions mainly

336

contributed to the hydrate formation. Still, higher pressure leads to another polymorph of this

337

monohydrate with NH+···OH···N bonds only, and of considerably lower volume. Thus, such

338

different interactions NH···N and NH···OH···N may indicate a possible other form of solvation of

339

tIIm at still higher pressure. Along with theoretical methods that aim at predicting solvate

340

formation and structure,46,47 the pressure-induced solvation is a valuable tool for crystal engineers

341

and can help in producing novel materials and in improving the performance of pharmaceutical

342

ingredients.

343

ASSOCIATED CONTENT

344

Supporting Information


Page 21 of 26

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345 346 347 348


The Supporting Information is available free of charge on the ACS Publications website at DOI:xxxxxxxxxxxx Selected bond lengths and angles, symmetry operators, Gibbs’ free energy diagram of tIIm forms, extract from laboratory journal, ∆Vs plots for selected solvents.

349

Accession codes

350

CCDC 1457082 contains the supplementary crystallographic data for this paper. These data can

351

be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing

352

[email protected], or by contacting The Cambridge Crystallographic Data Centre,

353

12, Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

354

AUTHOR INFORMATION

355

Corresponding Author

356

*E-mail: [email protected]

357

Author Contributions

358

JM: recrystallizations at ambient conditions, diffraction experiments, analyzes of structures and

359

statistical data, calculated the packing coefficients, wrote the paper; MK performed the CSD

360

survey and statistical analysis. KR performed syntheses, ambient and high-pressure

361

recrystallizations. AK designed the research, supervised the project, corrected and wrote the

362

paper.

363

Notes

364

The authors declare no competing financial interest.



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Page 26 of 26

For Table of Contents Use Only

441

Volume and pressure effects for solvation: the case study on

442

polymorphs of neat triiodoimidazole replaced by its solvate

443

Jędrzej Marciniak, Michał Kaźmierczak, Kacper W. Rajewski, Andrzej Katrusiak*

444 445

446 447

Synopsis

448

Statistical change of crystal volume increase on solvation has been applied for predicting the

449

pressure effect for solvate crystallization of a neat crystal.


Volume and Pressure Effects for Solvation: The Case Study on

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