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In four of the five crystalline modifications of the muscle relaxants mephenoxalone 3 and metaxalone 2, chain supramolecular motifs of three different types are realized. The centrosymmetric cyclic dimer, which is considered typical of amides, was found only once. To clarify the nature of the emerging supramolecular synthons, the set of 119 crystal structures of 1,3-oxazolidin-2-one 1 derivatives, to which drugs 2 and 3 belong, were selected from the Cambridge Structural Database. Analysis of the sample showed that oxazolidinone fragments predominantly form closed ring synthons in racemic crystals, whereas linear chains are typical for enantiopure ones. Thus, in the case of chiral objects, the transition from racemic to enantiopure crystal serves as a powerful tool for designing crystals with a given organization of supramolecular synthon. Two earlier unidentified kryptoracemates (false conglomerates), QEFJAP and QEFJUJ, were found among the analyzed set. Apparently, these are the first representatives of oxazolidinones exhibiting this rare property.

Six regioisomeric nonracemic dimethylphenyl glycerol ethers were synthesized by asymmetric dihydroxylation of the corresponding allyl dimethylphenyl ethers. The enantioselectivity of the reaction with o-methyl derivatives was lower (down to 34% ee) than with m-methylphenyl ethers (up to 86% ee). Enantiomeric 3-(3,4-dimethylphenoxy)propane-1,2-diols were used to obtain enantiomerically pure physiologically active amino alcohols and their derivatives.

Spontaneous resolution of Pasteur&rsquo, s salt was historically the first way to obtain pure enantiomers from the racemate. The current increase in interest in the direct racemates resolution during crystallization is largely due to the opened prospects for the industrial application of this approach. The chiral 3-(3,4-dimethylphenoxy) propane-1,2-diol 1 is a synthetic precursor of practically useful amino alcohols, the enantiomers of which exhibit different biological effects. In this work, it was first discovered that racemic diol 1 is prone to spontaneous resolution. However, the crystallization process is complicated by the existence, along with the conglomerate, of two other crystalline forms. Using the differential scanning calorimetry (DSC) approach, methods have been developed to obtain individual metastable phases, and all identified modifications ((R)-1, (R+S)-1, &alpha, rac-1, &beta, rac-1) were ranked by energy. The IR spectroscopy and powder X-ray diffraction (PXRD) methods demonstrated the identity of the first two forms and their proximity to the third, while &beta, rac-1 is significantly different from the rest. The crystal structure of the forms (R)-1 and &alpha, rac-1 was established by the single crystal X-ray diffraction (SC-XRD) method. Preliminary information on the structure of &beta, rac-1 phase was obtained by the PXRD approach. Based on the information received, the experimental conditions for a successful direct resolution of racemic 1 into individual enantiomers by a preferential crystallization procedure were selected.

β-Blocker bupranolol 1, it’s hydrochloride and their precursors 1-(2-chloro-5-methylphenoxy)-2,3-epoxypropane 2 and 3-(2-chloro-5-methylphenoxy)propane-1,2-diol 3 were prepared in racemic and single-enantiomer forms. For all the studied compounds phase behavior during crystallization was established on the basis of IR, DSC and X-ray investigations. Absolute configurations were established for compounds 1 and 2. Being conglomerate, racemic oxirane 2 was resolved by direct entrainment procedure. Being anticonglomerate, in the process of recrystallization, almost enantiopure 1·HCl accumulates in the mother liquor, not in the crystalline precipitate.

In addition to the previously known A-rac and B-rac polymorphs of the chiral drug metaxalone 1, an enantiopure A-(S)-form was obtained and studied. According to X-ray analysis, the crystalline organization of this form is close to the A-rac-1 polymorph. Crystallization of metaxalone melts is accompanied by the formation of a previously unknown metastable C-phase, which in the case of both racemic and enantiomeric samples are transformed into A-rac-1 or A-(S)-1. Analysis of the PXRD and IR spectra of crystalline samples revealed a similarity of the internal structure for the A-(S)-1, A-rac-1, C-(S)-1, and C-rac-1 crystalline forms and the essential difference of all of these phases from the B-rac-1 phase. According to the thermochemical data, the dependences of the change in the Gibbs free energy for all the phases studied are plotted in the interval from the melting point to 20 °C. Under standard conditions, the crystalline modifications of metaxalone, relative to ΔG0, form such a series: B-rac-1 < A-(S)-...

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 member 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 to a number of evidence, 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 guaifenesin-like supra...

Based on the features of its crystallization, racemic 3-(2,3-dimethylphenoxy)propane-1,2-diol 2 , the synthetic precursor of the chiral drug xibenolol 1 , was resolved into pure enantiomers by the direct method of entrainment. The enantiomers of diol 2 through a Mitsunobu reaction were converted into the nonracemic 1,2-epoxy-3-(2,3-dimethylphenoxy)propanes ( S )- and ( R )- 3 , and then into the xibenolol enantiomers. Single crystals of (+)- and (−)- 1 ·HCl were studied by X-ray diffraction. On the basis of the Flack parameter, the absolute ( R )- and ( S )-configurations were assigned to these compounds and to the other intermediate chiral substances.

Phase behavior of 3-(2,6-dimethoxyphenoxy)propane-1,2-diol 1 was investigated by IR spectroscopy, X-ray diffraction, and DSC methods. Racemic diol 1 prone to spontaneous resolution and has been resolved into (S)- and (R)-enantiomers by a preferential crystallization procedure. Separation takes place, but it gives crystalline precipitates with moderate (60–70%) enantiomeric excess values. The plausible reason is the formation of metastable phase of solid solution during the crystallization.

Depending on the conditions of crystallization from solutions, racemic 3-(2,3-dimethylphenoxy)propane-1,2-diol 1 forms three relatively stable crystalline modifications. Each of the crystalline forms, namely, two polymorphic racemic compounds and a racemic conglomerate, has been characterized by single-crystal X-ray diffraction. Two more metastable racemic compounds crystallized from the racemic melt have been found by differential scanning calorimetry method. Additional thermochemical investigations allowed to plot the dependence of the free Gibbs energy on temperature for all the phases found. With the help of slurrying experiments, the nature of the transitions between solid phases has been specified. It has been found that even a slight predominance of one of the enantiomers in almost racemic 1 samples ensures the crystallization of the conglomerate. The revealed features of rac-1 crystallization have been taken into account during the realization of its resolution into individual enantiomers by the e...

In the XXI century, single enantiomeric chiral active pharmaceutical ingredients (APIs) prevail among new drugs. Their preparation is made easier by using direct methods for the separation of racemates. This review summarises the history of the issue, provides information about new and updated methods of conglomerate identification and practical implementation options for direct resolutions. Examples are given of the use of direct methods for obtaining enantiopure APIs by the resolution of their racemic synthetic precursors, using a slight modification of the target product and finally by direct resolution of the racemic chiral drugs as such.

Racemic 3-(4-indolyloxy)-1,2-propanediol 2 has been effectively resolved into (S)- and (R)-enantiomers by a preferential crystallization procedure. Non-racemic (S)-2 was converted into (S)-4-(2,3-epoxypropoxy)-1H-indole (S)-4 via a Mitsunobu reaction and then into (S)-pindolol (S)-1. The crystalline (S)-1 was studied by single crystal X-ray diffraction. A large number of symmetry independent molecules (Z′ = 6) led to a weakening of the system of strong intermolecular hydrogen bonds, which combined with a loose packing (PI = 64.6%), may be the cause of the abnormally low melting point of (S)-1 as compared with rac-1.

Heterogeneous equilibria, crystallization, and polymorphism of chiral para-methoxyphenyl glycerol ether 1 have been inspected, and, as a result, the binary phase diagram and the Gibbs free energy vs temperature plot were constructed and analyzed. This enantiomeric system forms a stable racemic compound, which turns into an almost ideal continuous solution of the enantiomers in the crystalline phase at elevated temperatures. At room temperature the system represents a stoichiometric racemic compound and two symmetrical eutectoid invariants with partial solid solutions based on the enantiomers. Crystal structures of the true racemate, the pseudoracemate, and the pure enantiomer were investigated by single crystal X-ray diffraction. The true racemate crystallizes in the Pc space group with Z′ = 2. The pseudoracemate was solved in the Pbcn group with the only independent molecule equally disordered into two mirror-related positions. The enantiomeric crystals belong to the P21212 group and are characterized by...

MALDI mass spectrometry is used for the first time for the rapid assessment of the binding of thiacalix[4]arene-monocrown-ethers with metal cations (Li, Na, K, Cs, Cu, Ag). The work is performed on examples of thiacalix[4]arene-monocrown-ethers in 1,3-alternate conformation with various numbers (m) of ethylene oxide units and various substituents in phenol groups. It is shown that thiacalix[4]arene-monocrown- ethers with m = 3, 4, 5, and 6 bind lithium, sodium, potassium, and cesium cations, respectively; in addition, the binding of cesium cations is stronger in the presence of aromatic substituents in the lower rim of thiacalix[4]arene-monocrown-ethers. Silver cations bind with calixarenes under study more intensely than copper ions. When aromatic substituents are present, the binding of silver cations is stronger than that of alkali metal ions with the studied thiacalix[4]arene-monocrown-ethers.

Using a set of simple tests, based on the properties of ideal conglomerate phase diagrams, it has been suggested to the conglomerate-formative nature of 3-(2,6-dichlorophenoxy)-propane-1,2-diol 1 . Additional arguments have been drawn during the study of a single crystal X-ray diffraction study of the compound. The crystal packing details have been evaluated and discussed. Racemic 1 have been resolved into individual ( S )- and ( R )-components by a preferential crystallization procedure.

Racemic 3-(2-ethylphenoxy)propane-1,2-diol 2 has been effectively resolved into ( S )- and ( R )-enantiomers by a preferential crystallization procedure. Non-racemic diols 2 , obtained via a Mitsunobu reaction, have been converted into the non-racemic 1,2-epoxy-3-(2-ethylphenoxy)propanes ( S )- and ( R )- 5 and then into non-racemic 3-(2-ethylphenoxy)-1(1,2,3,4-tetrahydronaphth-1-ylamino)-2-propanols 1 . The characteristics of all four stereoisomers, ( S , S )- 1 (SR 59230), ( R , R )- 1 (SR 59483), ( R , S )- 1 and ( S , R )- 1 (SR 59231) and their hydrogen oxalates with a 1:1 composition have been presented. The crystalline oxalates ( S , S )- 1 ·C 2 H 2 O 4 (SR 59230A) and ( R , S )- 1 ·0.5C 2 H 2 O 4 were studied by single crystal X-ray diffraction.

The solubility of the chiral drug bevantolol hydrochloride 1 in water and the azeotropic mixture ethanol–water has been investigated. It was found that rac-1 meets the requirements of Meyerhoffer’s rule, so it was possible to reduce the ternary diagram, describing the solubility of 1, to a pseudo binary form, which facilitates the analysis of crystallization processes caused by temperature changes. On this basis, the effective and robust resolution procedure of racemic bevantolol hydrochloride by a preferential crystallization approach has been realized successfully.

Spontaneous resolution of rac-3-(4-hydroxyphenoxy)propane-1,2-diol has been successfully used in the synthesis of both enantiomers of chiral drug prenalterol.

The ability of [(2-cyanophenoxy)methyl]-15-crown-5 lariat ether enantiomers to diastereomeric discrimination with respect to hydrochlorides of 1-phenylethylamine and methyl esters of alanine, phenylalanine, and phenylglycine was studied by electrospray ionization mass spectrometry. The mentioned crown ether is available in non-racemic form owing to the procedure of preferential crystallization of enantiomers of its precursor. The quantitative estimation of the differences in the formation of diastereomeric complexes between the crown ether and the guests was performed by two independent methods: application of the guests with isotopic markers and using an additive of achiral amine-displacer. Both approaches indicate the existence of a moderate chiral discrimination: The (S)-enantiomer of the crown ether binds prevailingly the (S)-enantiomer of the guest, and vice versa.

The synthesis for a single enantiomer timolol maleate based on an initial Jacobsen hydrolytic kinetic resolution of racemic epichlorohydrin and on the stereochemistry of the subsequent chemical transformations has been proposed. The feature of this synthesis is that both products of the kinetic resolution, ( R )-epichlorohydrin ( R )- 4 and ( S )-3-chloropropane-1,2-diol ( S )- 5 , have been utilized in the synthesis of the target, ( S )-timolol. The mirror stereochemical results can be obtained with the use of ( R , R )-salen Co(III) catalyst instead of ( S , S )-salen Co(III).

Racemic 3-(2,6-dimethylphenoxy)propane-1,2-diol 8 undergoes spontaneous resolution upon crystallization. This fact is confirmed by the melting point inspection, vibration spectra and X-ray single crystal diffraction of racemic and scalemic crystalline samples of 8. Racemic 8 has been effectively resolved by a preferential crystallization procedure into (S)- and (R)-enantiomers with ee of approximately 90%. The enantiomeric purity of (S)- and (R)-8 could be increased to ee >99% through simple recrystallization. Nonracemic diols 8 were converted into nonracemic 1,2-epoxy-3-(2,6-dimethylphenoxy)propanes (S)- and (R)-7 with ee 98% via Mitsunobu reaction. The reaction proceeded without loss of enantiomeric purity, and the initial configuration of the stereogenic center was conserved. Enantiopure epoxides 7 were converted into nonracemic 1-(2,6-dimethylphenoxy)propan-2-ols 2, which are valuable intermediates in single-enantiomer mexiletine synthesis.

Solid state properties of 3-(4-N-morpholino-1,2,5-thiadiazol-3-yloxy)-propane-1,2-diol 3 , the synthetic precursor of popular drug timolol, have been investigated. The original solubility test, the data of X-ray diffraction and DSC methods indicate that the compound is prone to spontaneous resolution. Diol 3 crystallizing from both enantiopure or racemic feed material forms “guaifenesin-like” crystal packing in which the classic H-bonded bilayers, framed in both sides by hydrophobic molecular fragments, act as the basic supramolecular motif. The main chain conformation of the molecules in the crystals of diol 3 differs from that in the guaifenesin crystals, and this fact changes the absolute configuration of spiral columns formed by intermolecular hydrogen bonds in crystals of 3 as compared with guaifenesin crystals.

Chiral 4-benzoylamino-3-hydroxybutyric acid (1) was recognized in 1930 as the first example of “anomalous racemates” (correct to say, anomalous conglomerates), that is, specific addition compounds formed by different enantiomers in unequal ratio. Through the comparative (racemic against homochiral samples) inspection of the IR spectra, single crystal X-ray diffraction, PXRD analysis, and solubility data we have found that this substance forms normal racemic compound in the solid state, and must be excluded from the very short list of anomalous conglomerates. At the same time homo-1 is dissolved in 25 times better than rac-1, and this feature belongs to another interesting and rare type, namely, “anticonglomerates”. Some of the reasons for this behavior are discussed.

A series of (S)-3-(4-alkoxyphenoxy)propane-1,2-diols was prepared with the enantiomeric excess 86–92% by Sharpless asymmetric dihydroxylation of 1-alkoxy-4-allyloxybenzenes with an AD-mix-β mixture. R-Enantiomers with enantiomeric excess 97–99% and racemic samples were obtained by reaction of sodium p-substituted phenolates with (R)- and rac-3-chloropropane-1,2-diol. The phase behavior of racemates and scalemates in the produced homolog series of glycerol aryl ethers with hydrocarbon substituents of various length was examined by means of thermomicroscopy. The higher memberes of the homolog series of both racemic and scalemic diols undergo at heating an enantiotropic phase transition to a smectic liquid crystal phase.

In this work, interactions of some crown ethers, including lariat ethers bearing a side-arm methoxyphenoxymethyl substituent, with alkali metal salts were studied by matrix assisted laser desorption/ionization mass spectrometry. Peaks of cationized molecules [M + Cat]+, sandwich complexes [2M + Cat]+, [3M + Cat]+ ions, and cluster ions [2M + 2Cat + An]+ and [2M + 3Cat + 2An]+ were observed in the mass spectra; herein M is a crown ether molecule, Cat is an alkali metal cation, and An is a monobasic acid anion. The results were compared with previously obtained data for 15-crown-5, [ortho]- and [para]-methoxyphenoxymethyl-15-crown-5 ether mixtures with sodium salts. The conclusions made before, that an increase in the shielding degree of the cation in complexes with lariat ethers led to a significant decrease in the peak intensity of cluster ions [2M + 2Cat + An]+, were confirmed. For potential lariat ethers the absence or only trace amounts of such cluster ions along with the presence of an intense cluster ion peak in the mass spectrum for an unsubstituted analogue can serve a test for the involvement of the lateral fragment of the crown ether in complex formation, i.e., the lariat effect.

The ability of the crown ethers (1–4), containing the ortho- or para- methoxyphenoxy-methyl substituents in their structure, to chiral recognition in reference to amino acid esters has been investigated by electrospray ionization mass spectrometry (ESI-MS). The method allows registering the diastereomeric complexes between the studied crowns as hosts and the protonated alanine, phenylglycine and phenylalanine methyl esters as guests in the gas phase. ESI-MS experiments using isotopically labeled guests provide robust and reproducible results, indicating a moderate degree of chiral discrimination in the series of the studied crown ethers. ESI-MS experiments using achiral amine as a reference yielded the results comparable with the previous method. It has been found that (S)-enantiomers of the crowns bind predominately (S)-enantiomers of the amino acid esters, and vice-versa. It has been shown that the chiral ortho-substituted crown (S)-1 demonstrates the more pronounced values for chiral discrimination as compared with the para-substituted crown (S)-2. This fact indicates the interrelationship between the chiral recognition and the lariat nature of crown 1. Increasing the size of the cavity and the presence of a flat aromatic moiety in crowns 3 and 4 strengthens their complexing ability, simultaneously weakening the enantioselectivity of the complexation.

Oxidation of accessible (R)-3-chloropropane-1,2-diol to (R)-3-chloro-2-hydroxypropanoic acid and subsequent reaction of the latter with ortho-substituted sodium phenoxide gave a number of enantiomerically pure 3-aryloxy-2-hydroxypropanoic acid which are intermediate products in the synthesis of nonracemic 4-aminochroman-3-ols.

Mixtures of unsubstituted 15-crown-5 and its analogues containing ortho- and para-methoxyphenoxymethyl substituents with sodium salts were investigated by matrix assisted laser desorption/ionization (MALDI) mass spectrometry. Peaks of cationized molecules [M+Na]+ and cluster ions [2M+2Na+An]+, where M is the crown ether molecule and An is monobasic acid anion, were observed in the mass spectra. It was shown that an increase of the shielding degree of the sodium cation in complexes with crown ethers, i.e., the lariat effect, led to a significant decrease in the intensity of peaks of the cluster ions.

Valuable precursors of popular chiral drugs propranolol and pindolol, 3-(1-naphthyloxy)-propane-1,2-diol 3 and 3-(4-indolyloxy)-propane-1,2-diol 4 were investigated by IR spectroscopy, DSC, and X-ray diffraction methods. Both compounds, crystallizing from enantiopure feed material, form “guaifenesin-like” crystal packing in which the classic H-bonded bilayers, framed in both sides by hydrophobic fragments of the molecules, acts as the basic crystal-forming motif. Diol 4 prone to spontaneous resolution and conserves its packing pattern crystallizing from racemate. Under the same conditions, diol 3 forms weakly stable solid racemic compound. Some reasons for such a behavior are identified and discussed.

A series of enantiopure and racemic p -alkylphenyl glycerol ethers 1a – k were synthesized. A new, sensitive, and pictorial method of comparison of the IR spectra of solid enantiopure and racemic samples was developed to obtain preliminary information on the crystallization types of these compounds. In order to detect the subtle differences in the organization of the chiral solid phase, a new easily implemented approach, based on a chromatographic measuring of the relative abundance of the enantiomers in a single solution in equilibrium with a solid sample of arbitrary (0 n -Pr) and one borderline case (Alk = n -Bu) are disclosed. Higher members of the series of 1 (starting with an n -Bu derivative) are turned into liquid crystals upon melting; no significant differences between racemic and non-racemic samples were found. Only enantiopure methyl-, n -butyl, n -pentyl, n -hexyl, and n -heptyl substituted 1 were able to form supramolecular gels in hydrocarbon solvents; all racemic ethers 1 did not show such ability.

The single crystals of the NaClO 4 complexes with two potential lariat 15-crowns-5 having ortho - or para -methoxyphenoxymethyl side arms were investigated by X-ray analysis in racemic and enantiopure form. Only ortho -derivative demonstrates lariat effect, i.e. the assistance of lateral fragment in cation complexation. No one oxygen atom of para -substituted side arm takes part in guest encapsulation in the solid phase. Whereas the crystals of racemic and enantiopure ortho -substituted crown complexes differ substantially from one another in packing characteristics, racemic and enantiopure complexes of para -derivatives are almost isostructural. This fact indicates that the last chiral complex belong to the rare class of continuous solid solutions of enantiomers.

Within a single family of aryl glycerol ethers and their simplest derivatives, examples of all known types of chiral crystallization, viz. , conglomerates, racemic compounds, anomalous racemates and ideal and nonideal solid solutions have been found. A relationship was demonstrated between the crystal packing organization and chirality driven properties of organic substances, such as supramolecular gelation, capacity for enantiomeric enrichment and spontaneous resolution.

Thermochemical properties of binary mixtures of the popular chiral drug timolol maleate (TM) were investigated by differential scanning calorimetry. It was found that there are no eutectic points on the melting phase diagram, and the enantiomeric components form a continual set of solid solutions over a wide concentration range. The crystal structure of heterochiral racemic TM is essentially isostructural with that of the homochiral (S)-TM, having close cell parameters but containing a crystallographic inversion centre. The crystal structure of the homochiral TM contains two symmetry independent molecules in the unit cell. These molecules have different conformations but are approximate mirror images of each other in the crystal lattice. Within the homochiral crystals only one site of two changes its nature in the heterochiral crystals. The solid solution of TM could be treated as the solid solution of a regular racemic compound and a pure enantiomer.

According to differential scanning calorimetry data ortho-, meta-, and para-tolyl glycerol ethers 1–3 form thermodynamically most stable crystal phases during solution crystallization. For all members of the series the crystal phases formed during melt crystallization have different thermodynamic characteristics from those of the stable ones. Binary melting diagrams were constructed for the stable solid phases; on this basis it was found that 1 is prone to spontaneous resolution, and 2 and 3 form stable solid racemic compounds, the Gibbs energy of formation for which are found to be −2.70 and −2.43 kJ mol−1. Solution grown single crystals of 1–3 were investigated by an X-ray diffraction method. The principal supramolecular crystal formative motifs were revealed: 1D columns for 1 and scal-2, 2D bilayers having developed a 2D system of intermolecular hydrogen bonds (IMHB) for rac-2 and rac-3, and 2D bilayer having 1D spiral IMHB organization for scal-3. The possible reasons preventing the solid racemic compound formation in the case of 1, and the spontaneous resolution manifestation in the cases of 2 and 3 are disclosed. It was demonstrated that, from the whole family of tolyl glycerol ethers, only scal-3 samples are capable of supramolecular gels formation. This property is connected with the peculiarities of the scalemic 3 crystal packing.

Capable of spontaneous resolution rac-3-(2-methoxyphenoxy)propane-1,2-diol, guaifenesin 1 has been proposed as a cheap and readily available enantiopure precursor for the synthesis of nonracemic crown ethers having ligating OAr and OMe arms (lariat ethers). The crowns studied failed to form stable host/guest complexes with amine hydrochloride salts; the effective complexation was achieved using hexafluorophosphate salts. Moderate enantiomeric recognition of R*NH2·HPF6 was achieved with the lariat ethers 11c. As a whole, the enantioselectivity of the extraction is inversely related to the extractive power of the lariat ether.

The chiral adrenoblocker propranolol precursor 4-naphthyloxymethyl-2,2-dioxo-1,3,2-dioxathiolane, 2 , was obtained in racemic and scalemic form. It was found that sulfates 2 are practically unavailable through the standard Ru-catalyzed sulfite oxidation procedure, but could be obtained by the direct action of SO 2 Cl 2 on the corresponding vicinal diols 3 . The published properties of the sulfate were corrected. Thermodynamic characteristics and binary melting phase diagram were evaluated for compound 2 by DSC. The crystal structure of rac - and scal - 2 was established by single crystal X-ray analysis and the absolute configuration of scal - 2 was established by the Flack method. The flexible nature of the sulfur-containing cycle, and the sensitivity of the compound conformation to homo- and heterochiral crystal environment was demonstrated.

Enantiopure and racemic samples of ortho, meta, and para CN-substituted phenyl glycerol ethers 1–3 were investigated by differential scanning calorimetry and single-crystal X-ray analysis. The absolute configuration for (S)-1 was established through Flack parameter method. Whereas ortho-derivative 1 demonstrates spontaneous resolution upon crystallization, homochiral lattice for scalemic meta-derivative 2 is exceeded in stability by heterochiral lattice of racemic compound. This tendency becomes all the more evident for the para-derivative 3, in which case the difference in Gibbs free energy between rac and scal lattices amounts ΔG0 = −4.48 kJ mol−1. Most of these phenomena could be understood by reference to crystal packing details.

Three conglomerate-forming ortho -Hal (Hal = Cl, Br, I) substituted phenyl glycerol ethers 1 – 3 were investigated by single-crystal X-ray analysis, and the absolute configuration for all substances was established. The molecular structures and crystal packing details for halogen derivatives were compared with the same characteristics for ortho -OCH 3 and ortho -CH 3 analogues. Two different types of crystal packing were evaluated for these very much alike compounds. The interplay of the supramolecular crystal organization chirality sense and the single molecule absolute configuration was demonstrated. Some stabilizing and destabilizing interactions involving the ortho -substituents were revealed. The resolution of rac- 2 by entrainment procedure was successfully realized.

Spontaneous resolution of cardioselective β1-adrenergic blocker bevantolol hydrochloride 1·HCl was established by IR spectroscopy, differential scanning calorimetry, and by single crystal X-ray analysis both for enantiopure and racemic samples. The absolute configuration of 1·HCl was evaluated through Flack parameter method. The molecular structure and crystal packing details were evaluated; the symmetry independent fragment of the P1 unit cell consists of two molecules which have almost identical spatial arrangement, but differ sufficiently in the nature of nitrogen atoms: quaternary form in one case and free amine form in the other.

All ortho-substituted Cl, Br, I, and CN phenyl glycerol ethers crystallize as racemic conglomerates, whereas meta- and para-derivatives constitute racemic compounds in the solid state. Only meta-halogen-substituted phenyl glycerol ethers, alongside the thermodynamically preferential heterochiral racemic compound phase, reveal the simultaneous existence of a conglomerate phase; the last state is metastable and turns into a stable racemic compound just in the crystalline phase.

Popular chiral drugs, guaifenesin, methocarbamol, and mephenesin were investigated by single-crystal X-ray analysis both for enantiopure and racemic samples. The absolute configurations for all substances were established through Flack parameter method. The conglomerate-forming nature for the compounds was confirmed by equivalence of crystal characteristics of enantiopure and racemic samples. The molecular structures and crystal packing details were evaluated and compared with one another for all three investigated substances.

The β-adrenoblocker bunitrolol 1 as well as intermediate cyclic sulfate 6 and glycidyl ether 8 have been prepared in enantiopure form by starting from enantiopure o -cyanophenyl glycerol ether 2 by an entrainment resolution procedure. Thermal investigations reveal that 1 ·HCl forms a moderately stable racemic compound, whereas 2 , 6 and 8 are conglomerate forming substances potentially capable of entrainment resolution. Some chemical and chiroptical characteristics for bunitrolol and possible intermediates in its synthesis were corrected, and configurations were verified with the configuration of 1 ·HCl.

Five chiral arylglycerol ethers 2-R-C 6 H 4 -O-CH 2 CH(OH)CH 2 OH (R = OMe, OEt, OPr n , OPr i , OBu t ) have been prepared in racemic and enantiopure form. The melting points and enthalpies of fusion of every species were measured by differential scanning calorimetry. Binary phase diagrams were reconstructed for the whole family, the entropies of the mixing of the enantiomers in the liquid state, and Gibbs free energy of formation of the racemic compound, as well as Pettersson i -values were derived from the thermal data. The differences in the phase behavior of the investigated compounds were associated with the conformations of the alkoxy fragments.