Crystallization of chiral compounds. 1. Spectroscopic,thermochemical, and crystallographic investigation of homochiral and racemic glycidyl p-toluenesulfonate

Crystalline specimens of homochiral and racemic glycidyl p-toluenesulfonate were studied by IR spectroscopy, differential scanning calorimetry, and X-ray diffraction analysis. The melting phase diagram of glycidyl p-toluenesulfonate was constructed. The stacking effect in the crystals of the racemic sulfonate is responsible for a more dense molecular packing, with the result that a heterochiral type of crystallization becomes more favorable.     

Solid state properties of 1,2-epoxy-3-(2-methoxyphenyloxy)-propane—valuable intermediate in non-racemic drug synthesis

Racemic 1,2-epoxy-3-(2-methoxyphenyloxy)-propane 1 undergoes spontaneous resolution upon crystallization. This fact is confirmed by coincidence of the IR spectra of racemic and scalemic crystalline samples of 1, by thermal analysis (single eutectic V-shape binary melting phase diagram), and X-ray analysis (space group P2₁2₁2₁, Z = 4). Racemic 1 could be resolved into (S)-(+)- and (R)-(−)-1 by a preferential crystallization procedure.     

Preparation of optically active (2RS,3SR)-2-amino-3-hydroxy-3-phenylpropanoic acid (threo-beta-phenylserine) via optical resolutions by replacing and preferential crystallization

To obtain optically active threo-2-amino-3-hydroxy-3-phenylpropanoic acid (1) via optical resolutions by replacing and preferential crystallization, the racemic structure of (2RS,3SR)-1 hydrochloride [(2RS,3SR)-1.HCl] was examined based on the melting point, solubility, and infrared spectrum. (2RS,3SR)-1.HCl was indicated to exist as a conglomerate at room temperature, although it forms a racemic compound at the melting point. When, in optical resolution by replacing crystallization, L-phenylalanine methyl ester hydrochloride (L-2) was used as the optically active co-solute, (2R,3S)-1.HCl was preferentially crystallized from the supersaturated racemic solution; the use of D-2 as the co-solute afforded (2S,3R)-1.HCl with an optical purity of 95%. In addition, optical resolution by preferential crystallization was successfully achieved to give successively (2R,3S)- and (2S,3R)-1.HCl with optical purities of 90-92%. The (2R,3S)- and (2S,3R)-1.HCl purified by recrystallization from 1-propanol were treated with triethylamine in methanol to give optically pure (2R,3S)- and (2S,3R)-1.     

Optical resolution by preferential crystallization of (RS)-2-benzoylamino-2-benzyl-3-hydroxypropanoic acid and its use in synthesizing optically active 2-amino-2-methyl-3-phenylpropanoic acid

To synthesize optically active 2-amino-2-methyl-3-phenylpropanoic acid (1), (RS)-2-benzoylamino-2-benzyl-3-hydroxypropanoic acid [(RS)-2] was first optically resolved using cinchonidine as a resolving agent to yield optically pure (S)- and (R)-2 in yields of about 70%, based on half of the starting amount of (RS)-2. Next, the racemic structure of (RS)-2 was examined based on melting point, solubility, IR spectrum, and binary and ternary phase diagrams, with the aim of optical resolution by preferential crystallization of (RS)-2. Results indicated that the (RS)-2 exists as a conglomerate at room temperature, although it forms a racemic compound at the melting point. The optical resolution by preferential crystallization yielded (S)- and (R)-2 with optical purities of about 90%, which were fully purified by recrystallization. After O-tosylation of (S)- and (R)-2, reduction by zinc powder and sodium iodide gave (R)- and (S)-1, respectively.     

Preparation of optically active threo-2-amino-3-hydroxy-3-phenylpropanoic acid (threo-beta-phenylserine) via optical resolution

To obtain optically active threo-2-amino-3-hydroxy-3-phenylpropanoic acid (1), (2RS,3SR)-2-benzoylamino-3-hydroxy-3-phenylpropanoic acid [(2RS,3SR)-2] was first optically resolved using (1S,2S)- and (1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol as the resolving agents to afford (2R,3S)- and (2S,3R)-2 in yields of 73% and 66%, based on half of the starting amount of (2RS,3SR)-2. Next, the racemic structures of ammonium and some organic ammonium salts of (2RS,3SR)-2 were examined based on melting point, solubility, and infrared spectrum, with the aim of optical resolution by preferential crystallization. The benzylammonium salt of (2RS,3SR)-2 was suggested to exist as a conglomerate at room temperature, although it forms a racemic compound at the melting point. The optical resolution by preferential crystallization of the racemic salt afforded the (2R,3S)- and (2S,3R)-salts with optical purities of 90-97%. The (2R,3S)- and (2S,3R)-2 obtained from the purified salts were hydrolyzed by reflux in hydrochloric acid to give (2R,3S)- and (2S,3R)-1.     

Solid state properties and effective resolution procedure for guaifenesin, 3-(2-methoxyphenoxy)-1,2-propanediol

Racemic expectorant guaifenesin, 3-(2-methoxyphenoxy)-1,2-propanediol 2 undergoes spontaneous resolution upon crystallization. This fact is confirmed by thermal analysis (single eutectic V-shape binary melting phase diagram, adequate entropy and free energy characteristics). Racemic 2 could be effectively resolved into (S)- and (R)-2 by a preferential crystallization procedure. Single enantiomer drugs levomoprolol and levotensin were obtained by starting from enantiomeric 2 through the sulfite route.     

The influences of α/β compound nucleating agents based on octamethylenedicarboxylic dibenzoylhydrazide on crystallization and melting behavior of isotactic polypropylene

The influences of α/β compound nucleating agents based on octamethylenedicarboxylic dibenzoylhydrazide on crystallization and melting behavior of isotactic polypropylene (iPP) were analyzed. It is found that the crystallization temperatures of nucleated iPP were increased by above 11.0°C and the relative contents of β‐crystals (K_β ) in iPP reached above 0.40 after addition of compound nucleating agents. The K_β values depend on cooling rate, crystallization temperature in isothermal crystallization, and the difference between the crystallization temperatures of iPP nucleated by two individual nucleating agents. The nonisothermal crystallization kinetics were studied by Caze method and Mo method, respectively. The effective activation energy was calculated by the Friedman's method. The results illustrate that the half crystallization time was shortened and the crystallization rate was increased obviously after addition of nucleating agents, and the effective activation energy was increased with the relative crystallinity.     

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.     

Miscibility and crystallization behavior of poly(3‐hydroxybutyrate‐co‐3‐hydroxyhexanoate) and methoxy poly(ethylene glycol) blends

Poly(3‐hydroxybutyrate‐co‐3‐hydroxyhexanoate) (PHB‐HHx) and methoxy poly(ethylene glycol) (MPEG) blends were prepared using melt blending. The single glass transition temperature, T_g, between the T_gs of the two components and the negative χ value indicated that PHB‐HHx and MPEG formed miscible blends over the range of compositions studied. The Gordon–Taylor equation proved that there was an interaction between PHB‐HHx and MPEG in their blends. FTIR supported the presence of hydrogen bonding between the hydroxyl group of MPEG and the carbonyl group of PHB‐HHx. The spherulitic morphology and isothermal crystallization behavior of the miscible PHB‐HHx/MPEG blends were investigated at two crystallization temperatures (70 and 40 °C). At 70 °C, melting MPEG acted as a noncrystalline diluent that reduced the crystallization rate of the blends, while insoluble MPEG particles acted as a nucleating agent at 40 °C, enhancing the crystallization rate of the blends. However, no interspherulitic phase separation was observed at the two crystallization temperatures. The constant value of the Avrami exponent demonstrated that MPEG did not affect the three‐dimensional spherulitic growth mechanism of PHB‐HHx crystals in the blends, although the MPEG phase, such as the melting state or insoluble state, influenced the crystallization rate of the blends. © 2006 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 44: 2852–2863, 2006     

Thermal behavior of syndiotactic E-1,2-poly(3-methyl-1,3-pentadiene)

Syndiotactic E-1,2-poly(3-methyl-1,3-pentadiene) was synthesized with the catalyst system Fe(bipy)₂Cl₂-MAO. The thermal stability and kinetic parameters of degradation were determined by thermogravimetric analysis. The isothermal crystallization kinetics were described by means of the Avrami equation, which suggested a three-dimensional growth of crystalline units, developed by heterogeneous nucleation, followed by a secondary crystallization stage. Syndiotactic E-1,2-poly(3-methyl-1,3-pentadiene) isothermally crystallizes from the melt according to regime II of crystallization described by Lauritzen-Hoffman secondary nucleation theory. Non-isothermal crystallization kinetics were elaborated using different approaches. The equilibrium melting temperature was calculated. The kinetic and thermodynamic data were compared with those obtained from syndiotactic 1,2-poly(1,3-butadiene), which is the first example of 1,2 polydienes family.     

Self-nucleation and recrystallization of isotactic polypropylene (α phase) investigated by differential scanning calorimetry

The crystallization behavior after partial or complete melting of the α phase of iPP is examined by combined differential scanning calorimetry (DSC) and optical microscopy: calorimetric results are directly correlated with corresponding morphologies of microtome sections of DSC samples. On partial melting at various temperatures (hereafter referred to as T_s) located in a narrow range (4°C) below and near T_m, the number of nuclei increases (as in classical self-nucleation experiments), by several orders of magnitude; on subsequent cooling, the crystallization peak is shifted by up to 25°C. After partial melting in the lower part of the T_s range and recrystallization, the polymers display a prominent morphology “memory effect” whereby a phantom pattern of the initial spherulite morphology is maintained. After partial melting in the upper part of the T_s range the initial morphology is erased and self-nucleation affects only the total number of nuclei. The present experimental procedures make it possible to define, under “standard” conditions, the crystallization range of the polymer and in particular, the maximum crystallization temperature achievable when “ideally” nucleated. © John Wiley & Sons, Inc.     

Crystallization kinetics and melting behavior of syndiotactic 1,2‐polybutadiene

Differential scanning calorimetry was used to investigate the isothermal crystallization, subsequent melting behavior, and nonisothermal crystallization of syndiotactic 1,2‐polybutadiene (st‐1,2‐PB) produced with an iron‐based catalyst system. The isothermal crystallization of two fractions was analyzed according to the Avrami equation. The morphology of the crystallite was observed with polarized optical microscopy. Double melting peaks were observed for the samples isothermally crystallized at 125–155 °C. The low‐temperature melting peak, which appeared approximately 5 °C above the crystallization temperature, was attributed to the melting of imperfect crystals formed by the less stereoregular fraction. The high‐temperature melting peak was associated with the melting of perfect crystals formed by the stereoregular fraction. With the Hoffman–Weeks approach, the value of the equilibrium melting temperature was derived. During the nonisothermal crystallization, the Ozawa method was limited in obtaining the kinetic parameters of st‐1,2‐PB. A new method that combined the Ozawa method and the Avrami method was employed to analyze the nonisothermal crystallization of st‐1,2‐PB. The activation energies of crystallization under nonisothermal conditions were calculated. © 2005 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 43: 553–561, 2005     

DSC analysis of isothermally melt-crystallized bacterial poly(3-hydroxybutyrate-<Emphasis Type="Italic">co</Emphasis>-3-hydroxyhexanoate) films

The multiple melting behavior of isothermally melt-crystallized poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx) from its melt was investigated using differential scanning calorimetry (DSC). PHBHHx exhibits a fourfold endothermic melting phenomenon, which were expressed as A, I, II, and III from low to high temperature, and attributed to the melting of secondary lamellae formed at room temperature, the melting of secondary lamellae at crystallization temperature, the melting of primary lamellae, and the melting of the recrystallized lamellae of different stabilities, respectively. Secondary crystallization is much slower than the primary crystallization and needs a relatively long period of time to occur. Furthermore, secondary crystallization at room temperature is heterogeneous, which depends on the presence of the primary lamellae and the secondary lamellae formation.     

Melting behavior,crystallization kinetics,and crystal structure of poly(2‐hydroxyethoxybenzoate)

The melting behavior and crystallization kinetics of poly(2‐hydroxyethoxybenzoate) (PHEBA) were investigated with differential scanning calorimetry and hot‐stage optical microscopy. The observed multiple endotherms, commonly displayed by polyesters, were influenced by the crystallization temperature. By the application of the Hoffman–Weeks method to the melting temperatures of isothermally crystallized samples, a value of 232 °C was obtained for the equilibrium melting temperature. Isothermal crystallization kinetics were analyzed according to Avrami's treatment. Values of Avrami's exponent n close to 3 were obtained, independently of the crystallization temperature, in agreement with a crystallization process originating from predetermined nuclei and characterized by three‐dimensional spherulitic growth. In fact, space‐filling banded spherulites were observed by hot‐stage optical microscopy at all crystallization temperatures explored, with the band spacing increasing with increasing crystallization temperature. The rate of crystallization became lower as the crystallization temperature increased as usual at low undercooling, with the crystallization process controlled by nucleation. The equilibrium heat of fusion was determined by differential scanning calorimetry and wide‐angle X‐ray scattering measurements. Finally, the crystal phase of PHEBA was investigated with wide‐angle X‐ray scattering, and a triclinic unit cell was hypothesized. © 2002 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 40: 1354–1362, 2002     

Effect of Y2O3 addition on viscosity and crystallization of the lithium aluminosilicate glasses

The melting and crystallization behaviors of lithium aluminosilicate (LAS) glasses containing Y₂O₃ were investigated by X-ray diffraction (XRD), scanning electron microscopy (SEM), differential thermal analysis (DTA) and viscosity test. Effects of Y₂O₃ on the viscosity of LAS glasses were investigated from the softening point temperature to melting temperature. It was indicated that the introduction of yttria effectively decreased the melting temperature and viscosity of LAS glasses. The DTA and XRD results showed that yttria controlled the crystallization of LAS glasses by increasing the crystallization peak temperature (T_p) and activation energies (E), and the main crystalline phase of glass-ceramics was β-spodumene.     

A study of phase separation of crystalline and miscible polymer blends. Poly(ε-caprolactone)/poly(styrene-co-acrylonitrile)

The phase separation of a crystalline and miscible polymer blend, poly(ε-caprolactone) /poly(styrene-co-acrylonitrile) (PCL/SAN), has been studied by differential scanning calorimetry (DSC), using a SAN containing 28.3% of acrylonitrile units. Several phenomena can be associated with the occurrence of phase separation depending upon the composition of the mixture. Following annealing at high temperatures, below and above the phase separation temperature T_c, three cases can be distinguished. In Case I, there is no sign of crystallization during quenching and DSC scanning, but a melting peak is observed at T_c, and above. In Case II, there is no crystallization on quenching but it does occur during the DSC run; the shift of the crystallization peak can then be related to T_c. In Case III, there is crystallization on quenching, and additional crystallization during the DSC run; the change of area of the crystallization peak is indicative of T_c. From these observations, the phase diagram of the system was determined. © 1993 John Wiley & Sons, Inc.     

Effect of multi-walled carbon nanotubes on crystallization behavior of poly(3-hydroxybutyrate-co-3-hydroxyvalerate)

The effect of multi-walled carbon nanotubes on the crystallization behavior of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) has been investigated. The results have shown that carbon nanotubes (CNTs) act as an effective heterogeneous nucleation agent, inducing an increase in crystallinity and crystallite sizes. Comparing with the double melting peaks in pure PHBV, there is only one peak in the melting curves of nanocomposites. The isothermal crystallization kinetics of PHBV and its nanocomposite containing 0.5% CNTs were examined based on Avrami equation, indicating that the crystallization half-time decreases while the overall crystallization rate k increases dramatically with CNTs addition. The spherulitic nucleation and growth kinetics were also discussed grounded on Lauritzen–Hoffman equation. It is found that there is a spherulitic growth rates (G) maximum within selected temperature range in our study. Also, the temperatures corresponding to G maximum shift to a high level with addition of CNTs. The parameters of the equilibrium melting temperature T_m⁰ T_m^0 , the nucleation parameter K _g , the lateral surface free energy σ, the fold surface free energy σ _e , and the work of chain folding q of PHBV and its composite containing 0.5% CNTs were all calculated. The reductions of K _g , σ _e and q values of nanocomposite are in agreement with the fact that the crystallization rate of PHBV increases greatly by addition of CNTs.     

Investigation on the dynamic crystallization and melting behavior of β‐nucleated isotactic polypropylene with different stereo‐defect distribution—the role of dual‐selective β‐nucleation agent

The selectivities of different β‐nucleating agents might be quite different from each other, which is important in determining the crystallization and properties of the obtained β‐isotactic polypropylene (β‐iPP). However, the relationship between molecular structure and dynamic crystallization behavior of β‐iPP nucleated by dual‐selective β‐nucleating agent (DS‐β‐NA) is still not clear. In this study, the dynamic crystallization and melting behavior of two β‐iPP with nearly same average isotacticity but different stereo‐defect distribution, nucleated by a DS‐β‐NA (N,N′‐dicyclohexyl‐2,6‐naphthalenedicarboxamide; trade name TMB‐5), were studied by differential scanning calorimetry, wide‐angle X‐ray diffraction, and scanning electronic microscopy. The results indicated that in the presence of TMB‐5, the dynamic crystallization and melting behavior of the samples are quite different because the joint effects of the dual selectivity of TMB‐5 and stereo‐defect distribution of the iPP under different cooling rates. Two important roles were observed: (i) slow cooling rate favors the formation of high β‐fraction; and (ii) high crystallization temperature favors the crystallization of α‐phase accelerated by TMB‐5. Generally, the dual selectivity of the DS‐β‐NA, the stereo‐defect distribution of iPP, and the cooling rate were important factors in determining the formation of β‐crystal. Copyright © 2013 John Wiley & Sons, Ltd.     

A rare case of facial selectivity inversion for Sharpless asymmetric dihydroxylation in a series of structurally homogeneous substrates: synthesis of non-racemic 3-(nitrophenoxy)-propane-1,2-diols

Asymmetric dihydroxylation of mono nitrophenyl allyl ethers leads to the corresponding non-racemic 3-(nitrophenoxy)-propane-1,2-diols 1a–c. As this takes place, regardless of the reagent used (AD-mix-α or AD-mix-β), the configuration of the predominant enantiomer for the para- and meta-nitrosubstituted products is opposite to the configuration of the ortho-nitrophenyl derivative. A correlation between the melting points and vibrational spectra of the racemic and enantiopure diols 1a–c allowed us to establish that all of the chiral substances investigated formed stable racemic compounds in the solid phase.     

High melting thermoplastic/epoxy resin blends: Influence of the curing reaction on the crystallization and melting behavior

The influence of the cure process and the resulting reaction‐induced phase separation (RIPS) on the crystallization and melting behavior of polyoxymethylene (POM) in epoxy resin diglycidylether of bisphenol A (DGEBA) blends has been studied at different cure temperatures (180 and 145 °C). The crystallization and melting behavior of POM was studied with DSC and the simultaneous blend morphology changes were studied using OM. At first, the influence of the epoxy monomer on the dynamically crystallized POM was investigated. Secondly, a cure temperature above the melting point of POM (T_cure = 180 °C) was applied for blends with curing agent to study the influence of resulting phase morphology types on the crystallization behavior of POM in the epoxy blends. Large differences between particle/matrix and phase‐inverted structures have been observed. Thirdly, the cure temperature was lowered below the melting temperature of POM, inducing isothermal crystallization prior to RIPS. As a consequence, a distinction was made between dynamically and isothermally crystallized POM. Concerning the dynamically crystallized material, a clear difference could be made between the material crystallized in the homogeneous sample and that crystallized in the phase‐separated structures. The isothermally crystallized POM was to a large extent influenced by the conversion degree of the epoxy resin. © 2007 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 45: 2456–2469, 2007