Mechanism of Optical Resolutions Via Diastereoisomeric Salt Formation. Part 6 Thermoanalytical investigation of the optical resolution of racemic mandelic acid with S-(+)-2-benzylamino-butanol

The optical resolution of racemic mandelic acid (I) by S-2-benzylamino-butanol (II) was performed in water, ethyl acetate, and water saturated ethyl acetate. It was found that the efficiency of the resolution is three times higher in water saturated ethyl acetate than in either water or ethyl acetate. The salt mixtures produced during the resolutions and the pure diastereoisomeric salts were analyzed by TG, DSC and X-ray powder diffraction measurements. The R-(-)-I×S-(+)-II salt has the higher melting point and heat of fusion value which indicates that this is the more stable salt. Though the general assumption is that diastereoisomeric salt pairs of successful optical resolutions form eutectic systems, the R-mandelic acid-S-2-benzylamino-butanol and the S-mandelic acid-S-2-benzylamino-butanol system was found to behave in a different way. Melting did not start at or near the estimated eutectic temperature. The difference can be explained either by miscibility in the solid phase (solid solution) or by a blocked interaction between the crystals of the two solid salts. This unusual behaviour of the salt pair should be responsible for the unusual difference in the efficiency of the resolutions performed in different solvents This revised version was published online in August 2006 with corrections to the Cover Date.     

Study of the mechanism of optical resolutions via diastereoisomeric salt formation

Racemic malic acid (I) was resolved by R-α-phenylethylamine(II). The S-(?)-I.R-(+)-II diastereoisomer was in excess in the precipitated salt. DSC curves and X-ray powder diffractograms proved that the diastereoisomeric salt mixture precipitated during the resolution was isomorphous with the optically pure S-(?)-I.R-(+)-II salt. The diastereoisomeric salt mixture containing the R-(?)-I.R-(+)-II salt in abundance bound crystal solvate (water or methanol) when produced by the total evaporation of the mother liquor, while the optically pure R-(?)-I.R-(+)-II salt crystallized without solvate. It is generally assumed that solid solution formation takes place when the two diastereoisomers are alike and the high similarity results in less efficient enantiomer separation. This paper demonstrates that efficient resolution can be accomplished in case of solid solution formation too. The diastereoisomeric salt mixtures can crystallize in isomorphic form even when the physico-chemical properties of the optically pure diastereoisomeric salts are quite different.     

Über die Enantiomerentrennung durch Verteilung zwischen flüssigen Phasen. 4. Mitteilung. Enantioselektivität der diastereoisomeren Weinsäure-dimenthylester gegenüber α-Aminoalkohol-Salzen

Separation of Enantiomers by Partition between Liquid Phases. Enantioselectivity of Diastereoisomeric Dimenthyl Tartarates towards α-Aminoalcohol Salts The enantioselectivity of the easily obtainable diastereoisomeric dimenthyl tartarates I and II towards the salts of a series of α-aminoalcohols 1 - 10 was investigated by partition between aqueous and lipophilic phase. The measured enantiomer distribution constants Q (=K_A/K_B) confirm the previously observed configurational relationships between the lipophilic tartarates and the preferentially extracted enantiomer of the hydrophilic ammonium slat. However, the (R,R)-ester I is appreciably more selective than its (S,S)-diastereoisomer II or other previously investigated esters. The tartarates I - III transport norephedrin salts through bulk lipophilic membranes with enantioselectivity comparable to that observed in partition experiments. The most enantioselective ester I can be used as an efficient mobile phase for preparative separation of norephedrine enantiomers by flash partition chromatography.     

Asymmetric Synthesis of Chiral Norbornenes from Polybromocyclopentadienes

Effect of the conditions on the enantiomeric purity, overall yield, isomeric composition ofchiral polybromonorbornene Diels-Alder adducts of polybromocyclopentadienes and (-)-menthyl acrylatewas studied. Enantiomerically pure polybromonorbornenecarboxylic acids were obtained by resolution of the corresponding racemates through diastereoisomeric salts with l-ephedrine. The structure of the products was confirmed by the IR and ¹H NMR spectra.     

Thermodynamic Investigation of Dimethyl Sulfoxide Binary Mixtures at 293.15 and 313.15 K

Densities (ρ), speeds of sound (u), and isentropic compressibilities (k _S) of binary mixtures of dimethyl sulfoxide (DMSO) with water, methanol, ethanol, 1-propanol, 2-propanol, acetone and cyclohexanone have been measured over the entire composition range at 293.15 and 313.15 K. The excess molar volumes (V ^E), the deviations in speed of sound (u ^E) and the deviations in isentropic compressibility (k _S ^E) have been determined. The V ^E, u ^E and k _S ^E values were fitted by the Redlich-Kister polynomial equation and the A _k coefficients as well as the standard deviations (d) between the calculated and experimental values have been derived. The results obtained are discussed from the viewpoint of the existence of interactions between the components of the binary mixtures.     

Evaluation of an index based on van't Hoff equation to predict PEG-drug eutectic composition

Five poorly soluble drugs namely hydrochlorothiazide, menadione, propylthiouracil, quinine sulfate and sulfamerazine were used to evaluate the ability of an index (I _c) based on the van't Hoff equation to predict the eutectic composition at a higher heating rate than previously published. The term I _c is a dimensionless index which has been defined in the literature and is used to predict eutectic composition. This current work uses this study to determine if the correlation holds true at the higher heating rate of 10°C min^-1. The maximum deviation was observed for quinine sulfate, for which the predicted eutectic composition was 10% lower than what was observed with the DSC. It can be concluded that the Index developed here has a good correlation with the experimentally determined eutectic composition. This revised version was published online in July 2006 with corrections to the Cover Date.     

Self-assembly of tris(2-ureidobenzyl)amines with <Emphasis Type="Italic">C</Emphasis><Subscript>1</Subscript> symmetry

Abstract  

Tris(2-ureidobenzyl)amines bearing three differentially substituted arms have been synthesized. They possess an asymmetric nitrogen atom, the pivotal one, and thus they feature C ₁ symmetry. The self-assembly of these C ₁-symmetric tris(2-ureidobenzyl)amines may potentially lead to multiple regio- and diastereoisomeric capsules coming from the pairing of the four stereoisomeric monomers with configurations (R, P), (S, P), (R, M) and (S, M). The ¹H- and ¹⁹F{¹H}-NMR spectra confirm the presence of dimeric aggregates, as a mixture of several regio- and diastereoisomeric species.     

Optical Resolution of (RS)-Pantolactone through Amide Formation

The optical resolution of (RS)-pantolactone ( 1 ) is carried out through formation of diastereoisomeric amides. These are separated by a single hot washing with CH₂C1₂ or CHC1₃. The used asymmetric amine, (1R)-3-endo-aminoborneol ( 4 ), is readily accessible and can be recovered almost quantitatively after resolution.     

Diastereomeric 2-aminomethyl-1,4-benzodioxane mandelates: phase diagrams and resolution

The diastereomeric salts of (R)- and (S)-2-aminomethyl-1,4-benzodioxane with unichiral mandelic acid form a simple eutectic, whose binary phase melting point diagram shows the unique eutectic at 0.35 M ratio of the less soluble diastereomer. Such an eutectic composition, near to 0.5, is consistent with the modest efficiency previously reported for their separation via crystallization from ethanol/ethyl acetate. However, the ternary solubility phase diagram, obtained from solubility measurements in methanol, shifts the eutectic to a lower molar ratio (0.10) of the less soluble diastereomer, thus indicating an optimal resolvability of the diastereomeric mandelates. This was confirmed by the highly efficient resolution of racemic 2-aminomethyl-1,4-benzodioxane with (R)-mandelic acid via a single crystallization from methanol. The ready availability of both the racemic substrate and the resolving acid makes this simple and efficient resolution procedure very attractive to obtain the enantiomers of 2-aminomethyl-1,4-benzodioxane, which are important synthetic intermediates.     

Highly efficient resolutions of 1,4-benzodioxane-2-carboxylic acid with para substituted 1-phenylethylamines

The salts of (S)- and (R)-1,4-benzodioxane-2-carboxylic acid with eight (S)-1-arylethylamines were prepared. The determination of their melting points and of their solubilities in alcohol solvents revealed large differences between the diastereomeric benzodioxanecarboxylates of (S)-1-(p-nitrophenyl)ethylamine and of (S)-1-(p-methylphenyl)ethylamine. Therefore, these latter amines were selected to resolve (±)-1,4-benzodioxane-2-carboxylic acid by diastereoselective crystallization finding that both of them display a very high resolution ability for such a substrate, which contrasts with the null efficiency of unsubstituted 1-phenylethylamine. These results are consistent with DSC evidences, which indicated that the two successfully resolved diastereomeric systems are binary mixtures exhibiting a eutectic with a high content of the more soluble diastereomeric salt. The new procedures can advantageously replace the two resolutions we had previously reported, that of the same acid with dehydroabietylamine and that of glycerol acetonide, a precursor of 1,4-benzodioxane-2-carboxylic acid, with 1-phenylethylamine.     

Bestimmung des Chiralitätssinns der enantiomeren 2,6-Adamantandiole

Determination of the Chirality Sense of the Enantiomeric 2,6-Adamantanediols The enantiomers of 2,6-adamantanediol ( 1 ) are resolved via the diastereoisomeric camphanoates. The (2R,6R)-chirality sense for (?)- 1 and (2S,6S) for (+)- 1 was determined by chemical correlation with (?)-(1R,5R)-bicyclo[3.3.1]nonan-2,6-dion ((1R,5R)- 3 ) of known absolute configuration in the following way: alkylation of the bis(pyrrolidine enamine) of (?)-(1R,5R)- 3 with CD₂I₂ and hydrolysis of the product gives the enantiomer 4 of (4,4-D₂)-2,6-adamantanedione. Reduction of 4 with LiAlH₄ leads to one enantiomer (Scheme 2) of each of the three diols 5 – 7 of known absolute configuration. The three diols are themselves configurational isomers due to the presence of the CD₂ group, but correspond otherwise entirely to the enantiomeric diols 1 . Accordingly, they can also be separated by means of their diastereoisomeric camphanoates to give the diols 5 / 6 and 7 . These samples are easily distinguished and identified by their characteristic ¹H-NMR spectra (cf. Fig. 2). This allows to identify the (2R,6R)- and (2S,6S)-enantiomer of 1 on the basis of their behavior in the resolution experiment analogous to that of the diols 5 / 6 and 7 , respectively. The diol (?)- 1 must have the (2R,6R)-configuration because it forms, like the diols 5 / 6 , with (?)-camphanic acid the diastereoisomeric ester less soluble in benzene. The diol (+)- 1 has (2S,6S)-configuration, because it forms, like 7 , with (+)-camphanic acid the diastereoisomeric ester less soluble in benzene. The bis(4-methoxybenzoate) of (?)-(2R,6R)- 1 shows chiroptical properties which are in accordance with Nakanishi's rule for two chromophores having coupled electric dipol transition moments arranged with a left-handed torsion angle.     

Resolution of 1-phenyl-2-(p-tolyl)ethylamine via diastereomeric salt formation

(S)-1-Phenyl-2-(p-tolyl)ethylamine (S)-1, used for the industrial scale resolution of chrysanthemic acids, was obtained via resolution of the racemate with the hemiphthalate of (S)-isopropylidene glycerol (R)-2. The maximum experimental efficiency [69% yield and >99% e.e. of (S)-1] was achieved by a simple precipitation of (S)-1·(R)-2 from the solution of the 1:1 diastereomeric salt mixture in 93/7 isopropanol/water at saturation of the more soluble (R)-1·(R)-2 salt. Such an experimental efficiency was consistent with 0.79 maximum theoretical resolvability, derived from the solubilities of the two diastereomeric salts, and with DSC data, which indicated that the (S)-1·(R)-2/(R)-1·(R)-2 system is a binary mixture exhibiting an eutectic with composition approximately corresponding to a 0.2 molar ratio of (S)-1·(R)-2.     

A three‐dimensional hydrogen‐bonded framework in (2S*,4R*)‐7‐fluoro‐2‐exo‐[(E)‐styryl]‐2,3,4,5‐tetrahydro‐1H‐1,4‐epoxy‐1‐benzazepine

Molecules of the title compound, C₁₈H₁₆FNO, are linked into a three‐dimensional framework structure by a combination of two C—H...O hydrogen bonds and three C—H...π(arene) hydrogen bonds. Comparisons are made with the (2R,4R) diastereoisomer and with the corresponding pair of diastereoisomeric 7‐chloro analogues.     

Syntheses,Crystal Structures,and Thermal Properties of Energetic Semicarbazide Salt,Manganese(II) Salt,and Coordination Compound of 3,5‐Dinitrobenzoic Acid

Nitro compounds have been actively researched as driven by their potential to be high‐performing energetic materials. Herein, three new nitro compounds including semicarbazide 3,5‐dinitrobenzoate, (SCZ)(DNBA), manganese 3,5‐dinitrobenzoate dihydrate, [Mn(DNBA)₂(H₂O)₂]_n, and bis(semicarbazide) manganese(II) 3,5‐dinitrobenzoate, Mn(SCZ)₂(DNBA)₂, were synthesized and characterized by elemental analysis, IR spectroscopy, and single‐crystal X‐ray diffraction analysis. The results indicated that the above mentioned compounds are ionic, polymeric, and molecular in nature, respectively. Moreover, their thermal decomposition properties were assessed by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Their non‐isothermal reaction kinetics parameters, critical temperature of thermal explosion (T_bp), entropy of activation (ΔS^≠), enthalpy of activation (ΔH^≠), and free energy of activation (ΔG^≠) of the exothermic decomposition process were also calculated. Results suggest that there was a relationship between the structure and thermal stability.     

Solubility and glass transition in the system α-D-trehalose/water

Precipitation of trehalose dihydrate in water is observed at room temperature for trehalose concentrations higher than 47.5%w/w. Direct observations of crystal melting in water and measures of the solution density determine the thermal variations of trehalose saturationS(T) (mM) in water: ln(S(T))=ln(0.1223)-(1330/T) withR ² =0.9982. The glass transition (T_g) curve measured by DSC is lower at low concentrations and higher at high concentrations than previously reported.T _g is also measured as a function of the cooling/warming rates. Analysis of specific heat changes atT _g and associated activation energy leads to identify a most stable glassy state around the second eutectic concentration.     

Photocyclodimers of ‘Made‐to‐Measure’ Seven‐ and Six‐Membered Cyclic Enones

On irradiation (350 nm) in benzene as solvent, dioxepinone 6 and benzoxepinone 7 afford quantitatively mixtures of two diastereoisomeric head‐to‐head dimers, respectively. In both cases, on contact with SiO₂ the minor dimer containing trans‐ring fusions undergoes spontaneous isomerization to the (major) cis‐transoid‐cis diastereoisomer. In contrast, thiopyranone 8 is converted selectively, but in very low yield, to dimer 13 .     

Usefulness of chaotropic salt additive in RP‐HPLC of organic nonionized compounds

New synthesized 1,4‐disubstituted thiosemicarbazide derivatives were analyzed in the RP system, modified with the addition of salts; chaotropic (sodium hexafluorophosphate – Na PF₆), cosmotropic (sodium phosphate – NaH₂PO₄), and neutral (NaCl) on Zorbax XDB C18 column. The effect of the eluent composition on the analytes retention (k), system efficiency (N), peak symmetry (A_s), and LOD values were all examined and compared to unmodified organic‐aqueous mobile phase system. It was established that eluent modified with chaotropic salts addition was also the most advantageous according to other peak parameters such as the theoretical plates numbers and asymmetry factors. The lower LOD values were achieved in comparison to unmodified organic‐aqueous eluent system. Compatibility of lipophilicity parameters calculated by the use of computer software with experimental ones measured by RP‐HPLC was also the best for chaotropic modified mobile phase. To explain the observed phenomena, molecular modeling was performed for chosen representative compound in different environment representing examined mobile phase composition.     

Kinetics of the Exothermic Decomposition Reaction of N-Methyl-N-nitro-2,2,2- trinitroethanamine

The thermal behavior and kinetic parameters of the exothermic decomposition reaction of N-methyl-N-nitro-2,2,2-trinitroethanamine in a temperature-programmed mode have been investigated by means of differential scanning calorimetry (DSC).The kinetic equation of the exothermic decomposition process of the compound is proposed. The values of the apparent activation energy (Ea), pre-exponential factor (A), entropy of activation (ΔS^≠ ), enthalpy of activation (ΔH^≠ ), and free energy of activation (ΔG^≠ ) of this reaction and the critical temperature of thermal explosion of the compound are reported. Information is obtained on the mechanism of the initial stage of the thermal decomposition of the compound.     

Glass Stability and Glass Forming Ability of Ge25−xSe75Sbx (x = 12, 15, and 18) Chalcogenide Glasses Using Thermal Parameters

In the present communication glass stability (GS) and glass forming ability (GFA) of Ge_25−xSe₇₅Sb_x (x = 12, 15, and 18) chalcogenide glasses have been calculated in terms of certain thermal parameters, i.e., reduced glass transition temperature (T_rg), Hruby number (H), S-parameter (S), and ΔT. The glassy samples have been prepared by quenching of melt technique. For structure characterization, XRD technique has been used. For thermal analysis Differential Scanning Calorimetery (DSC) has been used. DSC scans have been recorded at different heating rates, i.e., 5, 10, 15, and 20 K min⁻¹. Stability of glassy samples has also been confirmed in terms of activation energy of glass transition calculated by Kissinger relation. All these parameters indicate that GS and GFA both decrease with increase of Sb content in Ge_25−xSe₇₅Sb_x (x = 12, 15, and 18) glassy series.     

Mechanism of Optical Resolutions via Diastereoisomeric Salt Formation. Part 7 Role of the solvents in the optical resolution of α-phenylethylamine by 2R,3R-tartaric acid

The optical resolution of α-phenylethylamine (1) by 2R,3R-tartaric acid (2) was studied in different solvents, the precipitated salts were subjected to thermoanalytical measurements and X-ray powder diffraction. The most efficient resolution can be accomplished by using methanol, the precipitate, an unsolvated salt containing the S-(-)-1⋅2R,3R-(+)-2 salt in abundance, is not a simple mixture of the diastereoisomeric salt pair, but a new modification. In water, ethanol and acetonitrile a reversed, but less effective resolution can be accomplished by precipitation of a hydrate which contains the R-(+)-1 in abundance. The precipitates from water and ethanol also proved to be new modifications. Only the precipitate from acetonitrile is the mixture of the diastereoisomeric salt pair, which can be expected in fractional crystallization of an eutectic forming diastereoisomeric salt pair. The number of different modifications found by changing the solvent in case of this particular salt pair seems surprisingly high, but may occur for other diastereoisomeric salt pairs, too. The existing but not investigated polymorphism can be the explanation for the sometimes very poor reproducibility of the preparative resolutions. This revised version was published online in July 2006 with corrections to the Cover Date.