Conformational polymorphism in inclusion crystals of cholic acid with ethyl acetate

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Abstract

Conformational polymorphism is observed in the inclusion crystals of cholic acid 1 with ethyl acetate. Direct recrystallization of host 1 from ethyl acetate gives one polymorph (monoclinic P2₁); in the presence of 1-naphthylmethylamine as a third component another polymorph (triclinic P1) is produced. The former has gauche conformation of the side chain (the dihedral angle of C17–C20–C22–C23, ψ⊕=⊕65°) while the latter has trans conformation (ψ⊕=⊕−158 and −168°), although they have similar bilayer host frameworks with the same 1∶1 host–guest stoichiometries. This results in differences between the hydrogen bond networks, the cavity shapes and the orientations of the guest molecules.

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Introduction

Polymorphism is an important phenomenon in solid state chemistry because the chemical and physical properties are dependent on polymorphs.¹ Commonly, polymorphism is divided into two types (i) packing the same molecules into different arrangements, or (ii) packing conformational isomers into similar or different arrangements, called conformational polymorphism.^2–4 Most studies of polymorphism have been applied to one-component systems. However, more recently, polymorphism of inclusion compounds has been reported for two host compounds, urea and cholic acid 1.†
These two compounds yield two types of inclusion crystals that have the same host–guest combinations and host–guest ratios.^5,6 In the crystal structures, the hosts and guests have the same conformations but different molecular arrangements. This indicates that they are classified as the former type polymorphism of a two-component system. Table 1 summarizes classification of known polymorphs. Here, we describe a rare example of conformational polymorphs of inclusion crystals. Inclusion crystals of 1 with ethyl acetate give two types of crystal structure that have different host–guest conformations resulting in different hydrogen bond networks.

Table 1 Polymorphism of organic crystals

System	(i)	(ii)
One component	Known^1	Known^2–4
Two component	Known^5,6	This work

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Results and discussion

Recrystallization of a salt of 1 and 1-naphthylmethylamine from ethyl acetate gave a 1∶1 inclusion crystal of 1 with ethyl acetate. X-Ray crystallography revealed that the crystal is triclinic P1 (form II) and does not involve 1-naphthylmethylamine. The host and guest components are in an asymmetric unit. This crystal structure is different from the reported crystal structure of a 1∶1 complex of 1 with ethyl acetate (form I).⁷ The crystallographic data are summarized in Table 2. Fig. 1 shows the crystal structures, which reveal the different conformations of the side chain. In the latter, the dihedral angle at C17–C20–C22–C23 (ψ) is 65°, referred to as gauche, but in the former, the angles are −158 and −168°, referred to as trans.⁸ This affects the hydrogen bond networks, as shown in Fig. 2. Form I has a cyclic network, but form II has cyclic and spiral networks. The difference of the side-chain conformation also changes the shape of the host channels. Fig. 3 illustrates typical cross-sections⁹ of the host cavities sliced parallel to the axis of the channel at the height that shows the cross-sections surrounded by the side chains. This shows that differences in the cavity shape affect the orientations of the guest molecules. In form I the guest molecules lie with their long molecular axes approximately perpendicular to the channel.⁷ On the other hand, in form II the guest molecules have their long molecular axes in two directions: at approximately 45 and 70° to the channel. In spite of these differences, the two polymorphs have common features in most of the known bilayer structures: cyclic and/or spiral hydrogen bonds force host molecules to arrange in a head-to-head and tail-to-tail fashion in a hydrophilic layer; a stack of lipophilic layers by van der Waals forces yields one-dimensional host cavities due to the anchored molecular shape of 1. In addition, the interdigitation characteristics of methyl groups in the lipophilic faces are the same α type.⁸ This is in good contrast with polymorphism of the inclusion compounds of 1 and nitriles. They have identical trans side-chain conformations, whereas they have completely different molecular arrangements: a crossing structure with a cage-like cavity and a bilayer structure with a channel cavity.^5,6

Fig. 1 Crystal structures of inclusion compounds of 1 with ethyl acetate: (a) form I and (b) form II. Click image or 1b.htm to access a 3D representation. Carbon, hydrogen and oxygen atoms are shown in grey, white and red, respectively.

Fig. 2 Hydrogen bond networks of inclusion compounds of 1 with ethyl acetate: (a) form I and (b) form II. The atom coding is identical to that in Fig. 1.

Fig. 3 Cross-sections of the host channels sliced parallel to the direction of the channel (carbon, hydrogen atoms are shown in grey and white, respectively) with arrays of included guest molecules (hydrogen atoms are omitted for clarity, and carbon and oxygen atoms are shown in grey and red, respectively): (a) form I and (b) form II.

Table 2 Crystal data for 1·ethyl acetate^a

Compound	1·ethyl acetate (form I)	1·ethyl acetate (form II)
a Click b009361k.txt for full crystallographic data (CCDC 1350/43).
Host∶guest	1∶1	1∶1
Formula	C28H48O7	C56H96O14
M	496.69	995.38
Crystal system	Monoclinic	Triclinic
Space group	P21	P1
a/Å	13.668(3)	12.279(1)
b/Å	7.824(4)	14.157(1)
c/Å	14.095(2)	8.2446(7)
α/°	90.0	90.408(3)
β/°	113.53(1)	94.234(3)
γ/°	90.0	105.690(5)
V/Å^3	1382(8)	1357.5(2)
Z	2	1
D c/g cm^−3	1.194	1.202
Reference	8	This work

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We now demonstrate conformational polymorphism of inclusion crystals of 1 and ethyl acetate. Recrystallization involving 1-naphthylmethylamine as the third component gave the novel polymorph. It should be noted that the polymorph of form II can be reproduced by recrystallization with seeding of salt crystals of 1 and 1-naphthylmethylamine. Moreover, the conformational polymorphism was observed in inclusion crystals of 1 with ethyl propionate on the basis of X-ray powder diffraction. The other esters did not give such polymorphs. The discovery suggests that systematic investigation of the formation of host molecules containing flexible moieties may find new conformational polymorphism.

Acknowledgements

This work was partially supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture, Japan.

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Footnote

† Polymorphism of host frameworks dependent on the guest species has been observed in many hosts.¹⁰

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