Crystallization of chiral para-n-alkylphenyl glycerol ethers: phase

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Crystallization of chiral para-n-alkylphenyl glycerol ethers: phase diversity and impressive predominance of homochiral guaifenesin-like supramolecular motif Alexander A Bredikhin, Dmitry V. Zakharychev, Aidar T. Gubaidullin, Robert R. Fayzullin, Aida I Samigullina, and Zemfira A. Bredikhina Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b00321 • Publication Date (Web): 04 Jun 2018 Downloaded from http://pubs.acs.org on June 4, 2018

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Crystal Growth & Design

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Crystallization of chiral para-n-alkylphenyl glycerol ethers: phase diversity and impressive predominance of homochiral guaifenesin-like supramolecular motif Alexander A. Bredikhin*, Dmitry V. Zakharychev, Aidar T. Gubaidullin, Robert R. Fayzullin, Aida I. Samigullina, and Zemfira A. Bredikhina A.E. Arbuzov Institute of Organic and Physical Chemistry of Kazan Scientific Center of Russian Academy of Sciences, Arbuzov St., 8, Kazan 420088, Russian Federation

When studying the crystallization in a monotonously varying series of chiral glycerol ethers para-Alk-C6H4-OCH2CH(OH)CH2OH [Alk = Me (1), Et (2), n-Pr (3) and n-Bu (4)] it was established that all except one members form stable crystalline homo- or heterochiral α-phase, depending on the enantiomeric composition (racemic or close to enantiopure) of the feed medium. Propyl derivative 3 falls out of the series and invariably forms stable homochiral crystals. Regardless of the enantiomeric composition, the last two members of the set can form a stable (4) or metastable (3) liquid-crystalline β-phase. For the entire set, regardless of enantiomeric composition, the formation of metastable γ-phase was registered in supercooled melts; according a number of evidences the phase is close to an ideal solid solution of enantiomers. It is shown by X-ray diffraction analysis that in crystals of 1-4 samples with high enantiomeric purity, as well as in racemic 3 and 4 samples, a common homochiral guaifenesinlike supramolecular motif is realized. Some considerations are given on the reasons for this behavior.

*

Corresponding author: Phone/fax: +7 843 2727393/ +7 843 2731872. E-mail: [email protected].

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Crystallization of chiral para-n-alkylphenyl glycerol ethers: phase diversity and impressive predominance of homochiral guaifenesin-like supramolecular motif Alexander A. Bredikhin*, Dmitry V. Zakharychev, Aidar T. Gubaidullin, Robert R. Fayzullin, Aida I. Samigullina, and Zemfira A. Bredikhina A.E. Arbuzov Institute of Organic and Physical Chemistry of Kazan Scientific Center of Russian Academy of Sciences, Arbuzov St., 8, Kazan 420088, Russian Federation ABSTRACT When studying the crystallization in a monotonously varying series of chiral glycerol ethers para-Alk-C6H4-OCH2CH(OH)CH2OH [Alk = Me (1), Et (2), n-Pr (3) and n-Bu (4)] it was established that all except one members form stable crystalline homo- or heterochiral α-phase, depending on the enantiomeric composition (racemic or close to enantiopure) of the feed medium. Propyl derivative 3 falls out of the series and invariably forms stable homochiral crystals. Regardless of the enantiomeric composition, the last two members of the set can form a stable (4) or metastable (3) liquid-crystalline β-phase. For the entire set, regardless of enantiomeric composition, the formation of metastable γ-phase was registered in supercooled melts; according a number of evidences the phase is close to an ideal solid solution of enantiomers. It is shown by X-ray diffraction analysis that in crystals of 1-4 samples with high enantiomeric purity, as well as in racemic 3 and 4 samples, a common homochiral guaifenesinlike supramolecular motif is realized. Some considerations are given on the reasons for this behavior.

INTRODUCTION Crystallization is a multifaceted phenomenon, attractive from the aesthetic, intellectual and practical points of view.1-5 And although the existence of a relationship between the molecular structure and the structure of (molecular) crystal is not in doubt, revealing the nature of this relationship is one of the important tasks of modern natural science.6-9 Molecular structure is a multi-level concept, which includes the chemical composition, connectivity, the arrangement of atoms in space and much more.10 Chirality is responsible for the appearance of such an apparently insignificant element of the structure of the molecule as its configuration. But both the chirality and the crystal lattice are generated and controlled by the laws of symmetry common to both entities. Therefore, the configuration and enantiomeric ACS Paragon Plus Environment

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composition of the chiral substance have a significant effect on the formation and properties of the crystal, starting from the space group to the habitus, inclusive of the nature and stability of the phases formed.11-13 Less obvious and less studied is the influence of the chirality of molecules on other levels of the preorganization of matter accompanying the destruction of the crystal upon melting and/or the reverse processes of the reconstruction of the crystal structure upon cooling of the isotropic melt. These processes can be accompanied by the formation of intermediate mesophases, such as, for example, plastic crystals,14,15 adjacent to "normal" crystals by the degree of its order, and/or liquid crystals16,17 approaching to fluids. Both the general18 and practical19 aspects of the crystallization of chiral compounds have long attracted our attention. In particular, we found that the higher representatives of paraalkylphenyl glycerol ethers, p-Alk-C6H4-OCH2-CH(OH)-CH2OH, both in racemic and enantiopure form, form a liquid-crystalline phase upon heating.20 When studying the properties of the simplest chiral low molecular weight gelator, p-tolyl glycerol ether 1, we found that in its supercooled melt some metastable phase is formed that differs in its thermodynamic characteristics from the normal crystal.21,22 It should be noted, that in the cited works the observed phenomena were demonstrated, but did not receive due discussion. In this report, we present the results of a systematic experimental study of the phase behavior of a series of chiral (racemic and scalemic) para-n-alkylphenyl glycerol ethers 1-4 (Chart 1) by differential scanning calorimetry (DSC), polarization microscopy, and single crystal X-ray analysis.

Chart 1. The objects of investigation The series presented is organized in such a way that neighboring members differ by the presence (or absence) of a single methylene unit. Besides, the crystallization of each substance was studied for racemic and scalemic samples. In the context of this work, the term scalemic denotes the samples with highest available for us enantiomeric excess, the specific value of which is given in the Experimental Section. As our research has shown, both these factors can significantly influence both the phase behavior in general and the internal crystal organization of a stable phase.



EXPERIMENTAL SECTION Instrumentation. Optical rotations were measured on a Perkin-Elmer model 341 polarimeter (concentration c is given as g/100 ml). HPLC analyses were performed on a Shimadzu LC-20AD system controller, using UV detector. The thermograms were measured on a Netzsch DSC 204 F1 Phoenix differential scanning calorimeter (τ-sensor) in aluminum pans with a rate of heating and cooling of 10 °C·min-1. The mass of the samples amounted to approximately ~1 mg and was controlled with Sartorius CPA 2P balance. Temperature scale and heat flux were calibrated against the data for indium and naphthalene. Optical anisotropy of liquid crystals was examined by hot-stage microscopy using a polarization optical microscope Polam P-312. Samples preparation. The synthesis of the racemic samples of the compounds 1-4 has been described in detail in our previous work.20 Enantiopure diols (R)-1-4 were obtained from (R)-3chloropropane-1,2-diol (98% ee) and the appropriately substituted phenol by analogy to published procedures. The single crystals of the compounds 2-4, first investigated by X-ray analysis in this paper, were prepared both in racemic and enantiopure form by slow evaporation of solutions of the corresponding samples in a mixture of n-hexane and ethyl acetate (8:2). Characteristics of the obtained crystals are shown below: rac-3-(4-Methylphenoxy)propane-1,2-diol, rac-1: mp 74-75 °С. (R)-3-(4-Methylphenoxy)propane-1,2-diol, (R)-2: mp 68 °С, [α]D20= -9.1 (c 0.8, EtOH), ee 99.0 %. rac-3-(4-Ethylphenoxy)propane-1,2-diol, rac-2: mp 68 °С. (R)-3-(4-Ethylphenoxy)propane-1,2-diol, (R)-2: mp 61-62 °С, [α]D20= -6.7 (c 1.2, EtOH), ee 99.5 %. rac-3-(4-n-Propylphenoxy)propane-1,2-diol, rac-3: mp 68 °С. (R)-3-(4-n-Propylphenoxy)propane-1,2-diol, (R)-3: mp 82 °С, [α]D20= -7.2 (c 1, EtOH), ee 99.7 %. rac-3-(4-n-Butylphenoxy)propane-1,2-diol, rac-4: mp 54 °С. (R)-3-(4-n-Butylphenoxy)propane-1,2-diol, (R)-4: mp 70 °С, [α]D20= -6.6 (c 1, EtOH), ee 99.9%. X-ray analysis. The X-ray diffraction data for the crystals of compounds 2-4 were collected on a Bruker Smart Apex II CCD diffractometer using graphite monochromated MoKα (0.71073 Å) radiation at 150 K [rac-3] and 296 K [for the other samples]. The crystal data, data collection, and the refinement parameters are given in Tables 1 and 2. The structures were solved by direct method using SHELXS and refined by the full matrix least-squares using SHELXL programs.23


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All non-hydrogen atoms were refined anisotropically. The position of the hydrogen atoms H1 and H2 (see Chart 2) were determined based on the electronic density distribution and these atoms were refined isotropically. Other hydrogen atoms were inserted at calculated positions and refined as riding atoms. Data collection: images were indexed and integrated using the APEX2 data reduction package.24 All calculations were performed on PC using WinGX suit of programs.25 Analysis of the intermolecular interactions was performed using the program PLATON.26 Mercury program package27 was used for figures preparation. Crystallographic data (excluding structure factors) for the investigated structures have been deposited in the Cambridge Crystallographic Data Centre as supplementary publication nos. CCDC 1406186-1406190 [for (R)-2, (R)-3, (R)-4, rac-2 and rac-4, respectively]. Copies of the data can be obtained free of charge upon application to the CCDC (12 Union Road, Cambridge CB2 1EZ UK. Fax: (internat.) +44-1223/336-033; E-mail: [email protected]). Table 1. Experimental crystallographic data for scalemic samples of compounds 1-4

Compound Formula Crystal class Space group Z, Z´ Cell parameters

(S)-1 a C10H14O3 Orthorhombic P212121 4, 1

(R)-2 C11H16O3 Orthorhombic P212121 4, 1

a = 4.8768(2) Å, b = 7.2147(3) Å, c = 28.520(1) Å

a = 4.8598(6) Å, b = 7.3559(9) Å, c = 31.051(4) Å

V, Ǻ3 M (g/mol) T, K Size, mm F(000) ρcalc g/cm3 µ, cm-1 θ, deg Refl. meas. Independ/ Rint Param./restr Refl. [I>2σ(I)] R1 / wR2 R1/wR2 (all refl.) Goodness-of-fit ρmax/ρmin (eǺ-3)

1003.48(7)

1.206

(R)-4 C13H20O3 Orthorhombic P212121 4, 1

1110.0(2) Å3 196.24 296(2) 0.12 x 0.18 x 0.60 424 1.174 0.84 2.62 ≤ θ ≤ 27.99 12428 2637 / 0.0327 136 / 0 2026 0.0410 / 0.0919

(R)-3 C12H18O3 Monoclinic P21 2, 1 a = 4.9300(17) Å, b = 7.480(3) Å, c = 15.899(6) Å, β = 94.656(4)° 584.3(4)Å3 210.26 296(2) 0.12x 0.32 x 0.55 228 1.195 0.84 2.57 ≤ θ ≤ 27.00 6178 2481 / 0.0252] 164 / 1 2336 0.0341 / 0.0895

0.0574 / 0.0992

0.0362 / 0.0913

0.0549/ 0.0990

1.034 0.150 / -0.113

1.082 0.114 / -0.152

1.028 0.115 / -0.127

a – Ref.22


a = 4.8518(7) Å, b = 7.5846(11) Å, c = 34.527(5) Å, 1270.6(3) 224.29 296(2) 0.11 x 0.22 x 0.68 488 1.173 0.82 2.36 ≤ θ ≤ 30.35 18369 3377 / 0.0306 215 / 0 2752 0.0417 / 0.0932


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Table 2. Experimental crystallographic data for racemic samples of compounds 1-4

Compound Formula Crystal class Space group Z, Z´ Cell parameters

V, Ǻ3 M (g/mol) T, K Size, mm F(000) ρcalc g/cm3 µ, cm-1 θ, deg Refl. meas. Independ/ Rint Param./restr Refl. [I>2σ(I)] R1 / wR2 R1/wR2 (all refl.) Goodness-of-fit ρmax/ρmin (eǺ-3)

rac-1 a C10H14O3 Monoclinic Pc 4, 2 a = 17.264(2) Å, b = 4.7225(7) Å, c = 11.901(2) Å, β = 90.091(2)о 970.3(2) Å3 1.247

1.206

rac-2 C11H16O3 Monoclinic P21/c 16, 4 a = 7.9990(6) Å, b = 48.208(4) Å, c = 10.7882(8) Å, β = 90.565(5)° 4159.9(5) Å3 784.95 296(2) 0.10 x 0.24 x 0.35 1696 1.253 0.90 1.69 ≤ θ ≤ 32.78 50063 13576 / 0.1094 536 / 1 5942 0.0914 / 0.1926

rac-3 C12H18O3 Monoclinic P21 2, 1 a = 4.947(10) Å, b = 7.409(14) Å, c = 15.83(3) Å, β = 95.98(3)° 577(2)Å3 210.26 150(2) 0.07x 0.37 x 0.44 226 1.205 0.85 2.59 ≤ θ ≤ 28.91 4505 2258 / 0.0659 142 / 1 1850

rac-4 C13H20O3 Monoclinic P21/c 4, 1 a = 4.8857(6) Å, b = 7.5781(9) Å, c = 34.409(4) Å, β = 91.6860(10)° 1273.4(3) Å3 224.29 296(2) 0.10 x 0.26 x 0.47 488 1.170 0.82 2.37 ≤ θ ≤ 26.99 7239 2711 / 0.0235 225 / 0 1920 0.0429 / 0.1002

0.2198 / 0.2424

0.0657 / 0.1111

1.012 0.391 / -0.387

1.037 0.160 / -0.145

a – Ref.22


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RESULTS AND DISCUSSION Thermotropic phase transitions in the investigated compounds. Figures 1a-d show DSC

traces of racemic (red curves) and scalemic (blue curves) samples of compounds 1-4. Comparison of the these thermograms allows us to conclude that, depending on the conditions and prehistory of the sample, the crystallization of the systems under consideration can lead to the formation of three types of phases, for the indexing of which we subsequently use the notations α, β and γ. Each of them has specific properties common to all systems in which it is observed.

Figure 1. DSC thermograms of scalemic (blue curves) and racemic (red curves) samples of the compounds 1 (a), 2 (b), 3 (c), 4 (d). The arrows indicate the direction of the temperature scanning. The lower curve of the corresponding color refers to the heating of the sample obtained by crystallization from the solution. The upper curves are obtained in additional cycles of cooling and heating of a previously melted sample. Other details are discussed in the text. When the samples 1-4 are crystallized from solutions under equilibrium conditions, a thermodynamically stable α-phase is formed. On DSC thermograms of racemic as well as enantiopure samples, obtained under these conditions, a single endothermic peak corresponding



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to its melting is observed upon heating. The thermochemical characteristics of this phase are given in Table 3 (lines 1,4). Table 3. Experimental values of thermochemical parameters of compounds 1-4 Alk Parameter

Tf, oC

∆HfTf, kJ·mole–1

phase α

1

β

2

γ

3

α

4

β

5

γ

6

sample scal rac scal rac scal rac scal rac scal rac scal rac

Ме (1)

Et (2)

n-Pr (3)

n-Bu (4)

66.4 74.9 45.8 45.6 28.6 32.9 14.4 13.1

61.6 68.8 56.1 58.9 26.7 29.8 16.1 17.4

82.5 65.3 64.4 64.9 42.5 43.9 36.6 36.0 3.3 3.2 9.6 10.5

70.5 52.8 74.9 75.6 42.8 35.2 34.9 31.1 3.4 3.3 14.4 8.0

At the same time, it follows from Fig. 1d that another phase manifests itself on the temperature scale between the α-phase of para-n-butylphenyl ethers of glycerol (R)-4 (Figure 1d, curve 1) and rac-4 (Figure 1d, curve 3) and their isotropic melts. The temperature of the transformation of this phase into an isotropic melt (Table 3, line 2) practically coincides with the clarification temperature registered by us earlier for compound 4 by thermomicroscopic study.20 In the cited paper such a phase was discovered for all studied higher para-alkylphenyl ethers of glycerol (Alk = n-CnH2n+1; n = 5-9). By analogy with the literature,28 the liquid-crystal nature was ascribed to this β-phase. It can be seen from Figure 1c that the β-phase reproducibly emerges upon cooling of isotropic melts of compound 3 samples and exists for a long time at temperatures much lower than the melting points of their α-phases. The process of the transformation of the β-phase to the isotropic melt and the inverse process of the recovery of the β-phase from the liquid are characterized by high reversibility and absence of temperature hysteresis on the DSC thermograms (Figure 1c,d). The enthalpy of this process (Table 3, line 5) is an order of magnitude lower than for the melting of the corresponding crystalline α-phases (Table 1, line 4). The kinetic stability of the β-phase (thermodynamically stable for 4 and metastable for 3) made it possible to study it with the help of polarization microscopy. When a β-phase originates from an isotropic melt, in all cases the appearance and growth of characteristic anisotropic nuclei, the so-called bâtonnets, is observed. The latter, increasing in size and merging together, provide a confocal texture (Figure 2), which is practically the same ACS Paragon Plus Environment

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for all investigated compounds and is characteristic of smectic liquid crystals SmA and SmA* (for rac- and scal-samples, respectively).29 Thus, all the data obtained are consistent with the fact that the β-phase has a liquid-crystalline nature.

Figure 2. Textures of liquid-crystalline beta phases of rac-3 (a), scal-3 (b), rac-4 (c) and scal-4 (d), obtained during investigations of the supercooled melts by polarization microscopy

For compounds 1 and 2, the formation of the β-phase is not observed, but when cooling the melts of all the compounds studied, in the temperature range 35-60 °C, a characteristic exothermic peak appears, the enthalpy of which is approximately 2-3 times lower than the enthalpy of melting of the α-phase, but approximately three times higher than for the liquidcrystalline β-phase. If the sample is heated immediately after the completion of the crystallization peak of this γ-phase, it is possible to observe a complementary melting peak with coincident enthalpy, but with a pronounced temperature hysteresis (3-5 °C), which distinguishes this state from the liquid-crystalline one (Figure. 1a, curves 2,4,5; Figure 1b, curves 2,4; Figure 1c, curves 3,5,6; Figure 1d, curves 2 and 4). The thermochemical characteristics of the γ-phase (Table 3, lines 3,6) are close for all the samples studied. In all systems γ-phase is detected in the



metastable region, at temperatures well below the melting point of the α-phase. A characteristic feature of the γ-phase is the similarity of the temperature of its destruction in racemic and scalemic samples. In samples of systems 1-4 with an intermediate enantiomeric composition, the crystallization of their melts also results in the formation of a similar phase with very similar thermochemical characteristics. This behavior suggests that this phase is represented by a close to an ideal metastable solid solution of individual enantiomers. Concluding this section of our study, we turn again to the melting characteristics of a stable equilibrium crystalline α-phase (Table 3, line 1,4). It is well known that such information for racemic and enantiopure samples allows one to judge the type of crystallization of a chiral substance and, in particular, to estimate the energy gain ∆G 0 accompanying the formation of a solid racemic compound from enantiomers (Ref. 18 and references there). Negative in sign and significant in modulus ∆G 0 value for methyl and ethyl derivatives (-2760 and -2560 J·mole–1, respectively) indicates the formation of quite stable racemic compound during the equilibrium crystallization of racemates 1 and 2. On the contrary, the close to zero value for compounds 3 and 4 (-180 and -80 J·mole-1) forces to take into account the possibility of crystallization of the corresponding racemates in the form of a normal conglomerate. Comparison of the vibrational spectra of crystalline samples rac.vs.scal does not contradict this assumption.20 On the other hand, the solubility studies, carried out in the same work, indicates that the n-propyl derivative 3 is indeed a normal conglomerate, at that time as the n-butyl analog 4 forms a solid racemic compound. This, at first glance, contradictory information will find its explanation in the next section. Single crystal X-ray investigations. For all alkylphenyl glycerol ethers 1-4, a uniform

numbering is used in the work, illustrated in Chart 2. The crystal structure of compound 1 was investigated earlier,21,22 however, to preserve the integrity of the discussion, we put crystallographic data for this compound in Table 1 and Table 2 and discuss the features of its crystalline structure in the general series.

Chart 2. The numbering scheme adopted in this paper for all the molecules studied. Crystal structure of the scalemic samples. It is easier to analyze the crystalline packing of

homochiral compounds because they crystallize only in 65 Sohncke space groups. In our case (See Table 1), it is striking that the parameters a and b of the unit cell for all scalemic samples of ACS Paragon Plus Environment

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phenyl glycerol ethers 1-4 with normal alkyl substituents vary very slightly. In the same series, the parameter c is systematically increased upon passing from the younger homologue to the senior one. If one considers that the multiplicity of group Р21 is half that for group P212121, and, for comparison purposes, parameter c for n-propyl derivative 3 should be doubled, then this compound (c × 2 = 31.798 Å) does not drop out of the general pattern, which suggests that the crystalline organization of non-racemic samples 1-4 is uniform. Subsequent analysis showed that in all these crystals the guaifenesin-like (from the name of the drug guaifenesin) crystal formative motif is realized, which is archetypal for the terminal aromatic ethers of glycerol.18 This motif was described in detail earlier,22.30 here we only mention its main features using the n-propyl derivative (R)-3 as an example (Figure 3).

Figure 3. Fragment of the packing of molecules in (R)-3 crystals. (a) Bilayered supramolecular motif, the dotted lines denote classical intermolecular H-bonds O-H ··· O; view along the 0b axis. (b) Packing of adjacent bilayers. The guaifenesin-like motif is a 2D bilayer (Figure 3a) formed by the system of classical intermolecular hydrogen bonds (IMHB) О-Н···О. As one would expect,31 the most pronounced crystal formative interactions (in this case, IMHB) are oriented along the short parameters of the unit cell; herewith all H-bonds can be divided into two types. The first type bonds, О2–Н2···О'1 ACS Paragon Plus Environment


[(-1+x,y,z), ∠ОНО = 173(2)°, d = 2.702(2) Å] are oriented along the 0a axis (in Figure 3a, such IMHBs are indicated by red dotted lines). The second type IMHBs, O1-H1···O'2 [(1-x,1/2+y,1/2-z), ∠ОНО = 172(2)°, d = 2.698(2) Å] are oriented approximately along the 0b axis (in Figure 3a they are indicated by green dotted lines). In general, the guaifenesin-like bilayer develops parallel to the 0ab plane. The sequence of oxygen and hydrogen atoms, united by a continuous IMBH system, forms a helix developing along the screw axis 0b, whose pitch coincides with the parameter b (7.480 Å in (R)-3 crystals). In the guaifenesin-like packing constructed from R enantiomers, left M-helices are always formed, and in the packings constructed from S enantiomers, right P-helices are formed. Within each bilayer, the peripheral hydrophobic and central hydrophilic zone are separated; the bilayers are retained in 3D crystalline packaging by hydrophobic interactions of peripheral hydrocarbon fragments (Figure 3b). As can be seen from the figure, the contact of the layers occurs along the 0c axis. Just in the same direction alkyl substituents are oriented in molecules 14 (Figure 3a), which causes an increase in the parameter c with the lengthening of alkyl substituents. On the whole, the guaifenesin-like packing in the series of non-racemic glycerol ethers 1-4 turns out to be quite loose, but with the increase in the size of the alkyl substituent, the packing index (PI)32 increases from 64.3% for scal-1 and scal-2, to 66.6% and 66.8% for scal-3 and scal4, respectively. Note that this trend is opposite to the previously estimated benefit of forming solid racemic compounds ( ∆G 0 ) in the same row. Crystal structure of racemic samples. Crystallographic data for the racemic samples of

para-alkyl substituted phenyl glycerol ethers 1-4 investigated in the present study are shown in Table 2. The fragment of the crystal packing of methyl derivative rac-1 is shown in Figure 4. The details of this supramolecular motif were discussed by us earlier.22 Here we only mention that it is a 2D bilayer bonded by intermolecular H-bonds O-H···O. In this case, the peripheral hydrophobic zones, surrounding the hydrophilic zone of IMHBs, are represented by either (R)-1 (A) molecules or (S)-1 (B) molecules. It is possible that, due to the increase in the number of independent molecules, the rac-1 packing density significantly exceeds that for scal-1 (PI = 67.9% vs 64.3%), and this is one of the reasons for the stability of the solid racemic compound (∆G0 = -2.76 kJ·mole-1), which crystallizes from the racemic feed material.


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Figure 4. Bilayer formed by independent molecules A (magenta, (R)-molecules) and B (green, (S)-molecules) in rac-1 crystals. The dotted lines denote the classical O-H···O intermolecular hydrogen bonds. In the asymmetric unit of the compound rac-2 there are as many as four independent molecules A-D, three of which have one configuration, and the fourth - the opposite. It should also be noted that in the independent molecule A, the ethyl substituent is disordered in two positions. In the first position with a population of 0.53, its conformation is characterized by the torsion angle C6C7C10C11 equal to 64.5°, and in the second position, with a population of 0.47, the same angle is 151.8°. In the following illustrations, the ethyl substituent is shown in a synclinal conformation.

Figure 5. Fragment of crystal packing in rac-2 crystals: bilayer formed by four independent molecules ((R)-A, green; (S)-B, blue; (S)-C, red; (S)-D, yellow). Classical intermolecular hydrogen bonds О-Н···О are indicated by light blue dotted lines. Figure 5 shows the main supramolecular motif, which again turns out to be a bilayer that includes all four independent molecules of compound 2. This bilayer develops parallel to the 0ac plane and is bonded by a system of hydrogen bonds in which all the hydroxyl groups of the A-D ACS Paragon Plus Environment


molecules participate. In the projection along the 0c axis (Figure 5), homochiral (formed by molecules B and D) and heterochiral (formed by molecules A and C) sublayers can be distinguished within the single bilayer. The sophisticated architecture of the primary crystal formative motif results in the packing of rac-2 being even more denser (PI = 68.9% compared to 64.3% for R-2 and even for 67.9% for rac-1). Apparently, this is the main reason why the formation of a solid racemic compound from the free enantiomers of 2 leads to a noticeable gain in Gibbs energy (∆G0 = -2.56 kJ.mol-1). A study of a single crystal randomly selected from a polycrystalline rac-3 sample showed that the parameters of its unit cell (Table 2) largely coincide with those of (R)-3 crystals (Table 1), which is the final proof of the crystallization of the racemic 3 in the form of a conglomerate of enantiopure crystals, which retain the prevailing in this series homochiral guaifenesin-like supramolecular motif (Figure 3). Formation of racemic conglomerates (spontaneous resolution) is observed in the series of terminal aromatic ethers of glycerol rather often.18,19 However, compound 3 turned out to be the first conglomerate with a substituent at the para position of the benzene ring. Obviously, in the case of n-propyl derivative, the resource of "multiplication of independent molecules" in the asymmetric unit of the corresponding racemic compound is exhausted, and the guaifenesin-like packing itself becomes sufficiently dense to shift the energy balance toward the formation of homochiral crystals. On the basis of the above-described thermochemical characteristics of the n-butyl derivative 4 (Table 3), spontaneous resolution could also be expected in this case. Moreover, the practical coincidence of the vibrational spectra of the crystalline samples of scal-4 and rac-4 directly indicates a common for both crystals system of hydrogen bonds, and, consequently, a crystalforming motif common to both the racemate and the scalemate.20 But if for compound 3 all tests for the nature of the crystalline state are in agreement, the enantiomeric composition of the rac-4 sample eutectic (ee = 0.04) is minor but significantly different from zero value, which agrees with the crystallization of such a sample in the form of a normal racemic compound.20 Contradictions are removed when analyzing the data of a single-crystal X-ray experiment. As it can be seen from Tables 1 and 2, the parameters of the unit cells (R)-4 and rac-4 are close to each other, and the parameters a and b are insignificantly different from those of the scalemic samples 1-3. This implies, in complete agreement with the just mentioned data of vibrational spectroscopy, detailed in our previous work,20 that both in the homochiral and heterochiral crystals of compound 4, a practically identical homochiral guaifenesin-like motif is realized. The fragment of molecular organization in rac-4 crystals is shown in Figure 6. Although the pattern is similar to Figure 3a, there is a significant difference between the packings: in Figure 3a, all primary crystal formative bilayers are constructed from molecules with the same ACS Paragon Plus Environment

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configuration, whereas in rac-4 crystals, homochiral layers, constructed either from R-molecules (red color in Figure 6) or from S-molecules (blue), alternate. While in the scalemic 1-4 crystals (space groups P212121 or P21) the adjacent bilayers are symmetrically connected by the screw axes 21, in the rac-4 crystals (group P21/c) adjacent bilayers are connected by inversion centers. As a consequence, 1D helical sequences of IMHBs, organized around screw axes 21 and connecting the 2D bilayers per se, have in rac-4 crystals M- or P-configuration and are formed either from R or S molecules, respectively.

Figure 6. Fragment of crystal packing in rac-4 crystals: two adjacent guaifenesin-like bilayers. Red color denotes (R)-molecules, (S)-molecules are marked in blue; the classical intermolecular hydrogen bonds О-Н···О are indicated by green dotted lines.

On the whole, X-ray diffraction data for single crystals grown at room temperature prove the formation of a molecular (racemic) compound in the solid phase of rac-4, as it was previously indicated by the composition of the eutectic determined under the same conditions. It should be noted that the packing density for (R)-4 (PI = 66.8%), in any case, is not inferior to the packing density for rac-4 (66.6%). This fact, in the aggregate with the identity of the supramolecular motif, allows us to conclude that their lattice energies are similar. Apparently, the last drop shifting the direction of crystallization in favor of the racemic compound is the gain in the mixing entropy Rln2, which accompanies the formation of the latter. CONCLUSIONS It has been established that the crystallization of chiral phenyl glycerol ethers, 3-(4alkylphenoxy)propane-1,2-diols, bearing linear alkyl groups in the para positions of the phenyl ring [Me (1), Et (2), n-Pr (3) and n-Bu (4)], is accompanied by the formation of stable crystalline ACS Paragon Plus Environment


homo- or heterochiral α-phases, depending on the enantiomeric composition of the feed medium. An exception is ether 3, which forms homochiral crystals both from the racemic and from the non-racemic medium. The last two members of the investigated set can form, alongside with the main α-phase, the stable (4) or metastable (3) liquid-crystalline β-phase, which is manifest itself in heating-cooling cycles. The characteristics of the β-phases depend little on the enantiomeric composition of the samples. For the entire series of compounds, regardless of the structure and the enantiomeric composition, the formation of metastable γ-phase was discovered in supercooled melts in the narrow temperature range 35-60 oC. The nature of γ-phase is not reliably established, but for a number of signs the phase was like an ideal solid solution of enantiomers. The stable α-phases of all listed compounds have been studied by single crystal X-ray diffraction analysis. It is shown that in crystals of scalemic 1-4 samples, a common, characteristic for a family of terminal aromatic ethers of glycerol, guaifenesin-like supramolecular motif is realized. Wherein, the density of crystal packing increases markedly when passing from lower terms of the series (1-2) to the higher ones (3-4). The density of crystal packing for rac-1 and rac-2 is significantly greater than the density of the scalemic analogues. This result is achieved by increasing the number of symmetry independent molecules in the unit cell to Z '= 2 for 1 and Z' = 4 for 2. A significant gain in the packing density is accompanied by a noticeable gain in Gibbs energy accompanying the formation of a solid racemic compound in crystals of rac-1 and rac-2. An increase in the volume of the substituent in the phenyl ring contributes to filling the voids and increasing the density of the guaifenesin-like packing to such an extent that other supramolecular motifs in stable crystals of compounds 3 and 4 are not realized by crystallization from the feed medium of any enantiomeric composition. In the case of rac-3 samples, this leads to the formation of a conglomerate of enantiomorphic crystals, i.e., to spontaneous resolution of the racemate into individual enantiomers. On the contrary, heterochiral crystals are formed in rac-4 samples, in the crystal lattice of which the guaifenesin-like homochiral enantiomorphic motifs, being symmetrically connected by inversion centers, alternate within the crystal space. Apparently, in the case of rac-4, the choice in favor of the racemic compound is attributable to the gain in the mixing entropy Rln2 accompanying the formation of the latter. In conclusion, let us allow ourselves two remarks. First, a homogeneous series must be constructed on a basis of substituents which change uniformly and with a minimal increment. In this work we have used the change in the length of linear alkyl residues. A natural alternative is a series in which the topology of the alkyl fragment changes, i.e. Me, Et, i-Pr, t-Bu. Phase behavior and the crystalline structure of glycerol alkylphenyl ethers (in the specific context - of ACS Paragon Plus Environment

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the last two members of the series) can hardly be predicted in advance. Secondly, the packing index is only an approximate measure of the energy of the crystalline state. One would like to have on hand a more accurate and having the experimental nature criterion, which allows to rank the energy of crystalline packings for different compounds. Both of these subjects will be presented in our subsequent works.

ASSOCIATED CONTENT Supporting Information Crystallographic information files. This information is available free of charge via the Internet at http://pubs.acs.org/.

AUTHOR INFORMATION Corresponding Author * Tel.: +7 843 2727393; fax: +7 843 2731872. E-mail address: [email protected] (A.A. Bredikhin)

Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes The authors declare no competing financial interest.



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For Table of Contents Use Only

Crystallization of chiral para-n-alkylphenyl glycerol ethers: phase diversity and impressive predominance of homochiral guaifenesin-like supramolecular motif Alexander A. Bredikhin*, Dmitry V. Zakharychev, Aidar T. Gubaidullin, Robert R. Fayzullin, Aida I. Samigullina, and Zemfira A. Bredikhina

The crystallization of chiral ethers para-Alk-C6H4-OCH2CH(OH)CH2OH [Alk = Me (1), Et (2), n-Pr (3) and n-Bu (4)] is accompanied by the formation of a stable crystalline α-phase, a liquidcrystalline β-phase, and a metastable γ-phase. Since derivative 3 is prone to spontaneous resolution, of the eight possible crystalline packings seven only are realized. In five cases, including rac-4, the packings are based on the homochiral guaifenesin-like supramolecular motif.


Crystallization of chiral para-n-alkylphenyl glycerol ethers: phase

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