Analysis of Zoledronic Acid and Its Related Substances by Ion-Pair RP-LC

A simple high-performance liquid chromatographic method – ion-pair reversed- phase high performance liquid chromatography (RPIC) has been developed and employed for the analysis of zoledronic acid and its related substances in bulk material and commercial dosage forms. The mobile phase was a mixture of methanol (20%) and 5 mmol L^–1 phosphate buffer (80%) containing 6 mmol L^–1 tetrabutylammonium bromide, adjusted to pH 7.0 with sodium hydroxide. C₈ column was used as the stationary phase. The chromatographic conditions were optimized. The active ingredient – zoledronic acid was successfully separated from its related substances, including remained imidazol-1-yiacetic acid in the synthesis of zoledronic acid and other possible impurities of oxidation and decomposition. The excipients did not interfere with the determination of zoledronic acid in commercial dosage formulations. The method was rapid, simple, accurate and reproducible. It was not only successfully employed for the assay of zoledronic acid in bulk material and pharmaceutical dosage forms but also for the determination of its related substances.     

Conductance of HCl in water-sulfolane solvents at 25, 30, and 40°C; a comparison of conductance equations

The molar conductance of solutions of HCl (concentrations from 3×10^–4 to 0.033 mol-l^–1) in water-sulfolane (tetramethylenesulfone) mixtures of mole fractions (X₂) of sulfolane of 0.25, 0.50, 0.75, and 0.85 at 25, 30, and 40°C have been determined. The dielectric constants of the solvents varied from 45 to 60 at 25°C. The data were analyzed by the full Pitts equation, the expanded Pitts equation, and the expanded Fuoss-Hsia equations, all of which give comparable results for the limiting molar conductanceA _o and for the ion-pair association constant K_A for HCl. These equations were unsuccessful for the analysis of supplemental data in pure sulfolane. At 25°C, the pK for dissociation of HCl varies from 0.4 (X₂=0.25) to 2.9 (X₂=0.85). The extent of ion pairing is apparently strongly influenced by selective ion-solvent interactions.On leave 1973–75, Technical University of Gdansk, 80-952 Gdansk Poland.On leave 1980 from Comisión Nacional de Energia Atómica, Buenos Aires, Argentina.     

A Mechanistic Study on the Formation of Dronic Acids

Dronic acid derivatives, important drugs against bone diseases, may be synthesized from the corresponding substituted acetic acid either by reaction with phosphorus trichloride in methanesulfonic acid as the solvent or by using also phosphorous acid as the P-reactant if sulfolane is applied as the medium. The energetics of the two protocols were evaluated by high-level quantum chemical calculations on the formation of fenidronic acid and benzidronic acid. The second option, involving (HO)₂P-O-PCl₂ as the nucleophile, was found to be more favorable over the first variation, comprising Cl₂P-O-SO₂Me as the real reagent, especially for the case of benzidronate.     

The conductance of tetrabutylammonium salts in water-sulfolane mixtures at 30°C

Conductance measurements are reported for Bu ₄ NCl, Bu ₄ NBr, Bu ₄ NI, and Bu ₄ NClO ₄ at 30°C in water-sulfolane mixtures over the entire solvent composition range. Experimental data were analyzed by the 1965 Fuoss-Onsager-Skinner equation. The limiting equivalent conductances in water and in sulfolane were compared with literature values. The trends of the Walden products are discussed in terms of water structural changes caused by addition of sulfolane. As expected, on the basis of previous results reported in the literature, a significant amount of association was detected for Bu ₄ NI in water. Very small association constants were also found for Bu ₄ NI and Bu ₄ NClO ₄ at 10 wt.% sulfolane.     

Solvent effects on acid-base behavior: Five uncharged acids in water-sulfolane solvents

An electrometric titration method utilizing glass electrodes and silver-silver bromide electrodes in a cell without liquid junction has been applied to a determination of the dissociation constants of five uncharged weak acids (HA) in four mixtures of water and sulfolane (tetramethylene sulfone) at 25°C. The acids studied were monochloroacetic, formic, benzoic, and acetic acids andp-nitrophenol, and the mole fractions (x ₂) of sulfolane in the mixed solvents were 0.2, 0.4, 0.6, and 0.8. All measurements were made at a constant ionic strength of 0.02 mole-kg^–1 in a solution containing NaBr at a molality of 0.01 mole-kg^–1. The cell was standardized by measurements of HClO₄ at molalities from 0.002 to 0.01 mole-kg^–1 and, in subsequent measurements, a solution of NaA was titrated with HClO₄. To obtain the thermodynamic pK, an activity correction derived from the Debye-Hückel theory was applied. The pK of all five acids was found to vary linearly withx ₂ in the range 0 to 0.8. By comparison of data for acetic acid in water-methanol, water-dioxane, and water-sulfolane solvents, it was shown that the results are consistent with the known properties of sulfolane (low acidity, basicity, and solvating power), but the linear variation of pK with solvent composition remains unexplained.On leave 1973–1975 from the University of Gdansk, Poland.     

Selective conversion of cellulose to levulinic acid and furfural in sulfolane/water solvent

Direct conversion of cellulose into levulinic acid and furfural in sulfolane media with the aid of water and H₂SO₄ was performed at 140–220 °C under the pressures of 0–1.5 MPa. This approach could obtain 72.5 mol% levulinic acid and 11.5 mol% furfural formation under an optimal condition in which the mass ratio of sulfolane, water and H₂SO₄ was 90:10:1. It was found that the decrease of water content led to an increasing yield of furfural and that the maximum furfural yield (51.1 mol%) could be obtained in the absence of water. The synergism of sulfolane and water in the selective liquefied system was demonstrated to be responsible for not only reinforced effect of optimizing and isolating the target products but also for reducing re-polymerization and side reactions. Furthermore, sulfolane in our case could be recycled and re-used for the conversion of cellulose with the same yield, which shed light on the remarkable potential for future industrial application.     

Free Phosphoric Acid of Diatomite-Phosphate Solid Acid and its Catalytic Performance for Propylene Oligomerization

Free phosphoric acid in the diatomite-phosphate solid acid catalysts was characterized by means of ion chromatography (IC), Hammett pH indicators and chemical titration. The results show that the free phosphoric acid is composed of 535 wt.% H₃PO₄, 17 wt.% H₄P₂O₇ and < 1 wt.% polyphosphoric acid, and its composition determines the acid strength distribution of the catalyst. When the total amount of free phosphoric acid containing >3 wt.% H₄P₂O₇ is within 9 26 wt.% (in P₂O₅), the catalyst shows higher catalytic activity for propylene oligomerization with propylene conversion >75wt.%. Besides, free phosphoric acid has an important effect on the catalytic selectivity. The relationship between them is discussed.     

Measuring the solubility of CO2 and H2S in sulfolane and the density and viscosity of saturated liquid binary mixtures of (sulfolane + CO2) and (sulfolane + H2S)

The density and viscosity of liquid sulfolane saturated (loaded) with single CO₂ and H₂S gases were measured simultaneously with the solubility of the single CO₂ and H₂S gases in sulfolane at temperatures ranging from (303.15 to 363.15) K and pressures of up to about 2.4 MPa using a new experimental set-up developed in our laboratory. The experimental density and viscosity values were correlated using a modified Setchenow-type equation. It was observed that the density and viscosity of mixtures decrease by increasing temperature and acid gas solubility (loading) in sulfolane. Acid gas loading has a much profounder effect on the viscosity of solutions than on their density, i.e. at a concentration of 1 mol CO₂/H₂S per kg of sulfolane the density decreases by less than 3%, but viscosity decreases by more than 30%. Results show that at fixed temperature and pressure H₂S is more than four times as soluble as CO₂ in sulfolane. The measured solubility and density values were respectively used to obtain Henry’s law constants and partial molar volumes at infinite dilution for dissolution of CO₂ and H₂S gases in the liquid sulfolane at the temperatures studied. The Henry’s law constants obtained at different temperatures were used to determine infinite dilution partial molar thermodynamic functions (Gibbs free energy, enthalpy and entropy) of solution. The measured solubility data were correlated by using a model comprised of the extended Henry’s law and the Pitzer’s virial expansion for the excess Gibbs free energy.     

Investigating the Role of Adducts in Protein Supercharging with Sulfolane

The supercharging effect of sulfolane on cytochrome c (cyt c) during electrospray ionization mass spectrometry (ESI-MS) in the absence of conformational effects was investigated. The addition of sulfolane on the order of 1 mM or greater to denaturing solutions of cyt c results in supercharging independent of protein concentration over the range of 0.1 to 10 μM. While supercharging was observed in the positive mode, no change in the charge state distribution was observed in the negative mode, ruling out polarity-independent factors such as conformational changes or surface tension effects. A series of sulfolane adducts observed with increasing intensity concurrent with increasing charge state suggests that a direct interaction between sulfolane and the charged sites of cyt c plays an important role in supercharging. We propose that charge delocalization occurring through large-scale dipole reordering of the highly polar supercharging reagent reduces the electrostatic barrier for proximal charging along the cyt c amino acid chain. Supporting this claim, supercharging was shown to increase with increasing dipole moment for several supercharging reagents structurally related to sulfolane.     

Density and excess molar volumes of binary mixtures of sulfolane with methanol,n -propanol,n -butanol,and n -pentanol at 298.15–323.15 K and atmospheric pressure

Densities, ρ and excess molar volumes, V?^E of the binary mixtures of sulfolane, +methanol, +n-propanol,?+n-butanol, and +n-pentanol were measured at temperatures 298.15, 303.15, 308.15, 313.15, and 318.15?K, respectively, covering the whole composition range except methanol at 303.15–323.15?K. The V ^E for the systems were found to be negative and large in magnitude. The values of V ^E of the sulfolane, +n-butanol and sulfolane, +n-pentanol mixtures are being positive at lower and higher mole fractions of the alkanols (x ₂). The magnitudes of the V ^E values of the mixtures are in the order sulfolane?+?methanol?>?sulfolane?+?n-propanol?>?sulfolane?+?n-butanol?>?sulfolane?+?n-pentanol. The observed values of V ^E for the mixtures have been explained in terms of (i) effects due to the differences in chain length of the alcohols, (ii) dipole–dipole interactions between the polar molecules, and (iii) geometric effect due to the differences in molar volume of the component molecules. These are more noticeable in the case of lower alcohols. All these properties have been expressed satisfactorily by appropriate polynomials.     

Preparation of 1-butyl-3-methylimidazolium dodecatungstophosphate and its catalytic performance for esterification of ethanol and acetic acid

1-Butyl-3-methylimidazolium dodecatungstophosphate catalyst ([bmim]₃PW₁₂O₄₀) with high water tolerance was prepared from 1-butyl-3-methylimidazolium bromide ([bmim]Br) and phosphotungstic acid (H₃PW₁₂O₄₀). The catalyst was characterized by means of Fourier transform infrared spectroscopy, thermogravimetry-differential scanning calorimetry, n-BuNH₂ potentiometric titration, elemental analysis and so on. Its catalytic activity for esterification of ethanol and acetic acid to ethyl acetate was measured. The results show that there were three crystal-water molecules in the [bmim]₃PW₁₂O₄₀ catalyst, and it preserved the primary Keggin structure and acid strength of H₃PW₁₂O₄₀. The acid amount of [bmim]₃PW₁₂O₄₀ catalyst was less than that of H₃PW₁₂O₄₀. The [bmim]₃PW₁₂O₄₀ catalyst exhibited higher catalytic activity and reusability in the esterification of ethanol and acetic acid to ethyl acetate. __________ Translated from Chinese Journal of Catalysis, 2008, 29(7) (in Chinese)     

The Synthesis of Pamidronic Derivatives in Different Solvents: An Optimization and a Mechanistic Study

The synthesis of pamidronic acid and sodium pamidronate dihydrate from β‐alanine and P‐reagents (phosphorus trichloride and phosphorous acid) was investigated at 75°C in different solvents, and the preparation was optimized. In sulfolane, the use of 2 equiv of phosphorus trichloride and phosphorous acid was found the optimum to lead to pamidronic acid in a yield of 63%. In methanesulfonic acid, 3.2 equiv of phosphorus trichloride was necessary without any phosphorous acid to give pamidronate dihydrate in the best yield (57%) after hydrolysis and pH adjustment. In the first case, the P‐nucleophile may be (HO)₂P–O–PCl–O–P(OH)₂ or (HO)₂P–O–PCl₂, whereas in the second case, the P‐reactant is probable Cl₂P–O–S(O)₂Me. It can be said that the mechanism proposed for the formation of pamidronic acid is highly influenced by the solvent used, as it determines the necessary P‐reagent(s). Our results promote the “on purpose” planning of the synthesis of dronates.     

Lithium Nitrate Regulated Sulfone Electrolytes for Lithium Metal Batteries

The electrolytes in lithium metal batteries have to be compatible with both lithium metal anodes and high voltage cathodes, and can be regulated by manipulating the solvation structure. Herein, to enhance the electrolyte stability, lithium nitrate (LiNO₃) and 1,1,2,2-tetrafuoroethyl-2′,2′,2′-trifuoroethyl(HFE) are introduced into the high-concentration sulfolane electrolyte to suppress Li dendrite growth and achieve a high Coulombic efficiency of >99 % for both the Li anode and LiNi_0.8Mn_0.1Co_0.1O₂ (NMC811) cathodes. Molecular dynamics simulations show that NO₃⁻ participates in the solvation sheath of lithium ions enabling more bis(trifluoromethanesulfonyl)imide anion (TFSI⁻) to coordinate with Li⁺ ions. Therefore, a robust LiN_xO_y−LiF-rich solid electrolyte interface (SEI) is formed on the Li surface, suppressing Li dendrite growth. The LiNO₃-containing sulfolane electrolyte can also support the highly aggressive LiNi_0.8Mn_0.1Co_0.1O₂ (NMC811) cathode, delivering a discharge capacity of 190.4 mAh g⁻¹ at 0.5 C for 200 cycles with a capacity retention rate of 99.5 %.     

Conformation and hydrogen bonding for the bicyclic compound 3‐thiabicyclo[3.2.0]heptane‐6,7‐dicarboxylic acid 3,3‐dioxide

The initial goal of this work was to verify the geometry of the product of a photochemical reaction, viz. the title compound, C₈H₁₀O₆S, (II). Our crystallographic study firmly establishes the cis–anti–cis nature of the substituents on the cyclobutane ring. The geometry is also designated as exo, where exo signifies that the five‐membered ring is on the opposite side of the central cyclobutane ring from the carboxylic acid substituents. The structure determination reveals two molecules, A and B, in the asymmetric unit that display substantially different conformations of the bicyclic core: the cyclobutane ring puckering angles are 22 and 3°, and the sulfolane ring conformations are twist (S‐exo) and envelope (S‐endo). Intrigued by this variation, we then compared the conformations of other molecules in the Cambridge Structural Database that have sulfolane rings fused to cyclobutane rings. In this class of compound, there are five examples of saturated cyclobutane rings, with ring puckering angles ranging from 3 to 35°. The sulfolane rings were more similar: four of the six molecules exhibit envelope conformations with S‐endo, as in molecule B of (II). Despite the conformational differences, the hydrogen‐bonding scheme for both molecules is similar: carboxyl –OH groups form hydrogen bonds with carboxyl and sulfone O atoms. Alternating A and B molecules joined by hydrogen bonds between sulfone O atoms and carboxyl –OH groups form parallel chains that extend in the ac plane. Other hydrogen bonds between the carboxyl groups link the chains along the b axis.     

Dielectric relaxation of sulfolane in benzene solution from microwave absorption data

The electric constant (ɛ′) and dielectric loss (ɛ″) for dilute solutions of sulfolane in benzene solution has been measured at 9.885 GHz at different temperatures (25, 30, 35, and 40°C) by using standard microwave techniques. Following the single frequency concentration variational method, the dielectric relaxation time (τ) and dipole moment (μ) have been calculated. It is found that dielectric relaxation process can be treated as the rate process, just like the viscous flow. Based on the above studies, monomer structure of sulfolane in benzene has been inferred. The presence of solute-solvent associations in benzene solution has been proposed. Energy parameters (ΔH _ɛ, ΔF _ɛ, ΔS _ɛ) for dielectric relaxation process of sulfolane in benzene at 25, 30, 35, and 40°C have been calculated and compared with the corresponding energy parameters (ΔH _η, ΔF _η, ΔS _η) for the viscous flow.     

Synthesis and characterization of poly(succinimide-co-6-aminocaproic acid) by acid-catalyzed polycondensation of L-aspartic acid and 6-aminocaproic acid

The polycondensation of L -aspartic acid ( ASP ) with 6-aminocaproic acid ( ACA ) using o-phosphoric acid produced poly(succinimide-co-6-aminocaproic acid). The yield of the MeOH-insoluble copolymer decreased from 99 to 52% and that of the MeOH-soluble one increased from 9 to 47%, with increasing molar ratio of ACA in the monomer feed. The compositions of the succinimide ( SCI ) unit in the MeOH -insoluble and -soluble copolymers tended to be higher than those of ASP in the monomer feed. The copolymers with the 35 mol % SCI units or above were soluble in DMSO , DMF , and conc- H₂SO₄ , but those with the 20 and 21 mol % SCI units were soluble only in conc-H₂SO₄. The melting temperature appeared for the copolymers with less than 76 mol % SCI units. Poly(succinimide-co-6-aminocaproic acid) was easily hydrolyzed to yield poly(aspartic acid-co-6-aminocaproic acid), and it exhibited biodegradability toward activated sludge. © 1997 John Wiley & Sons, Inc.     

Mild and Efficient Deoxygenation of Sulfoxides to Sulfides Using HfCl4/KBH4 System

HfCl₄/KBH₄ was found to be a facile, efficient, convenient, and chemoselective system for the deoxygenation of dialkyl, diaryl, and aryl alkyl sulfoxides, especially for the reduction of dibenzyl sulfoxide to the corresponding sulfides under mild conditions. In addition, the HfCl₄/KBH₄ system could be used in reduction of some other sulfur-bearing substrates to the corresponding sulfides, such as 2,2′-dibenzothiazolyl disulfide, but this reducing system could not reduce sulfolane, diphenyl sulfone, p-toluenesulfonic acid, and p-toluenesulfonyl chloride to their corresponding thiophenols.     

Synthesis and characterization of polymeric triphenyltin and cyclotetrameric tricyclohexyltin 2-(1H-imidazol-1-yl)acetates

The reaction of 2-(1H-imidazol-1-yl)acetic acid with (Ph₃Sn)₂O or Cy₃SnOH (Cy?=?cyclohexyl) yields triphenyltin 2-(1H-imidazol-1-yl)acetate (1) and tricyclohexyltin 2-(1H-imidazol-1-yl)acetate (2), respectively. 2-(1H-imidazol-1-yl)acetates in these two complexes show remarkably different coordination modes. Complex 1 forms a polymeric chain structure through intermolecular Sn–N interactions, while 2 displays a 28-membered macrocyclic tetranuclear structure by the assembly of Sn–N coordination bonds.     

Electroconductivity of Lithium Perchlorate Solutions in Sulfolane Mixtures with 1,2-Dimethoxyethane

The electroconductivity, viscosity, and density of 1 M LiClO₄solutions in sulfolane mixed with 1,2-dimethoxyethane are measured. Some of the measured quantities deviate from additivity. A maximum of LiClO₄electroconductivity in the mixture occurs at a 1 : 2 molar ratio of sulfolane to dimethoxyethane. The electroconductivity increase is presumably due to improved transport properties of the system.