One barbiturate and two solvated thiobarbiturates containing the triply hydrogen‐bonded ADA/DAD synthon,plus one ansolvate and three solvates of their coformer 2,4‐diaminopyrimidine

A path to new synthons for application in crystal engineering is the replacement of a strong hydrogen‐bond acceptor, like a C=O group, with a weaker acceptor, like a C=S group, in doubly or triply hydrogen‐bonded synthons. For instance, if the C=O group at the 2‐position of barbituric acid is changed into a C=S group, 2‐thiobarbituric acid is obtained. Each of the compounds comprises two ADA hydrogen‐bonding sites (D = donor and A = acceptor). We report the results of cocrystallization experiments of barbituric acid and 2‐thiobarbituric acid, respectively, with 2,4‐diaminopyrimidine, which contains a complementary DAD hydrogen‐bonding site and is therefore capable of forming an ADA/DAD synthon with barbituric acid and 2‐thiobarbituric acid. In addition, pure 2,4‐diaminopyrimidine was crystallized in order to study its preferred hydrogen‐bonding motifs. The experiments yielded one ansolvate of 2,4‐diaminopyrimidine (pyrimidine‐2,4‐diamine, DAPY), C₄H₆N₄, (I), three solvates of DAPY, namely 2,4‐diaminopyrimidine–1,4‐dioxane (2/1), 2C₄H₆N₄·C₄H₈O₂, (II), 2,4‐diaminopyrimidine–N,N‐dimethylacetamide (1/1), C₄H₆N₄·C₄H₉NO, (III), and 2,4‐diaminopyrimidine–1‐methylpyrrolidin‐2‐one (1/1), C₄H₆N₄·C₅H₉NO, (IV), one salt of barbituric acid, viz. 2,4‐diaminopyrimidinium barbiturate (barbiturate is 2,4,6‐trioxopyrimidin‐5‐ide), C₄H₇N₄⁺·C₄H₃N₂O₃⁻, (V), and two solvated salts of 2‐thiobarbituric acid, viz. 2,4‐diaminopyrimidinium 2‐thiobarbiturate–N,N‐dimethylformamide (1/2) (2‐thiobarbiturate is 4,6‐dioxo‐2‐sulfanylidenepyrimidin‐5‐ide), C₄H₇N₄⁺·C₄H₃N₂O₂S⁻·2C₃H₇NO, (VI), and 2,4‐diaminopyrimidinium 2‐thiobarbiturate–N,N‐dimethylacetamide (1/2), C₄H₇N₄⁺·C₄H₃N₂O₂S⁻·2C₄H₉NO, (VII). The ADA/DAD synthon was succesfully formed in the salt of barbituric acid, i.e. (V), as well as in the salts of 2‐thiobarbituric acid, i.e. (VI) and (VII). In the crystal structures of 2,4‐diaminopyrimidine, i.e. (I)–(IV), R₂²(8) N—H…N hydrogen‐bond motifs are preferred and, in two structures, additional R₃²(8) patterns were observed.     

Two polymorphs of 5‐cyclohexyl‐5‐ethylbarbituric acid and their packing relationships with other barbiturates

Polymorph (Ia) (m.p. 474 K) of the title compound, C₁₂H₁₈N₂O₃, displays an N—H...O=C hydrogen‐bonded layer structure which contains R₆⁶(28) rings connecting six molecules, as well as R₂²(8) rings linking two molecules. The 3‐connected hydrogen‐bonded net resulting from these interactions has the hcb topology. Form (Ib) (m.p. 471 K) displays N—H...O=C hydrogen‐bonded looped chains in which neighbouring molecules are linked to one another by two different R₂²(8) rings. Polymorph (Ia) is isostructural with the previously reported form II of 5‐(2‐bromoallyl)‐5‐isopropylbarbituric acid (noctal) and polymorph (Ib) is isostructural with the known crystal structures of four other barbiturates.     

New mesogenic compounds possessing a biphenyl ester and ether moiety comprising 1,3-dimethylbarbituric acid: synthesis,characterisation and mesomorphic studies

New substituted derivatives of 5-vinyl-1,3-dimethylbarbituric acid were synthesised and evaluated for liquid crystal properties. Two sets of molecules were prepared. One end of all the molecules possesses the 1,3-dimethylbarbituric core. The first set comprises biphenyl ethers, 4a–n and the second set biphenyl esters, 5a–g. Liquid crystalline properties were investigated by POM and DSC techniques. All the compounds exhibited enantiotropic smectic A and nematic mesophases. The LC properties were found to depend on the spacer and terminal alkoxy- chain and alkoxy- ester moiety of the molecules. Smaller alkyl chain members showed a smectic phase, while higher alkyl chain members showed a nematic phase.     

Electronic and spatial structures of some derivatives of 5-phosphoranylidenbarbituric and 5-phosphoranylidenthiobarbituric acids

The spatial and electronic structures of some derivatives of 5-phosphoranylidenbarbituric and 5-phosphoranylidenthiobarbituric acids are investigated within the framework of the semiempirical MNDO approximation. The effect of the substituents at the phosphorus and nitrogen atoms on the geometry and distribution of electron density in the studied molecules is considered. Their pseudoaromatic -system, which is formed by diffuse lone electron pairs of the ion and two N atoms, involves alternating donor and acceptor centers. The pseudoaromatic fragment in these molecules is nearly planar, and the deviations from planarity are dependent on the size of the substituents at the phosphorus and nitrogen atoms.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1029–1034, June, 1995.     

Chromophoric Barbituric Acid Derivatives with Adjustable Hydrogen-Bonding Patterns as Component for Supramolecular Structures

Summary: The barbituric acid moiety of the presented dyes shows multifunctional properties like acidochromism, solvatochromism, and adjustable hydrogen-bonding pattern for molecular recognition. Hydrogen-bonding ability, acidity and solvatochromic effects are studied for a series of N-alkyl substituted 5-(4-nitrophenyl)-barbiturates. Solvatochromism and metal ion complexation are also investigated using chromophoric thiobarbituric acid derivatives.     

电动胶束色谱中弱酸性化合物的柱上浓缩富集技术的研究

提出一种电动胶束色谱（ＭＥＫＣ）中弱酸性化合物的柱上浓缩富集技术,并得到实验证实。以七种弱酸性巴比妥类药物的ＭＥＫＣ分离为例,考察了样品溶剂中表面活性剂浓度、ｐＨ值和离子强度等对富集作用的影响。表面活性剂浓度,ｐＨ值对富集效应的影响较大。采用低浓度（略高于ＣＭＣ点）表面活性剂、低浓度缓冲液作样品溶剂,调节溶剂ｐＨ值小于待测化合物的ｐＫａ－１,就可以对弱酸性化合物进行柱上富集。采用这种富集技术,可以压缩样品带的宽度从而提高柱效,在此基础上可通过加大进样量提高化合物的检测灵敏度。     

Mercurimetric Potentiometric Determination of Barbiturates Using a Solid-State Iodide Ion-Selective Electrode

Abstract

A simple potentiometric method is described for mercurimetric titration of barbiturates using a solid-state iodide ion-selective electrode. The optimum titration conditions involve the use of a borate buffer of pH 9–10 as a medium and mercury(II) perchlorate of pH 1.7–1.9 as a titrant. Under these conditions, titration curves with two sharp consecutive inflection breaks are obtained. The first inflection corresponds to quantitative and stoichiometric reaction of barbiturates with mercury(II) and the second break is due to the reaction of the buffer with the titrant. No interferences are caused by Cl^?, Br^?, PO₄ ^3- and many excipients and diluents commonly used in the drug formulations. Determination of barbiturates in various pharmaceutical preparations gives reproducible results with an average recovery of 99.1% of the nominal (st.dev. 0.3 %) and the method offers significant advantages over the titrimetric method of the British Pharmacopoeia.     

Determination of pK-Values of Some Barbituric Acid Derivatives

Abstract

Practical dissociation constants (μ = 0.1, 25°C) of the following barbituric acids (pK₁, pK₂) were determined spectrophotometrically: 5-pivaloyloxy-5-(1-phenylethyl) - (7.0; 12.1); 5-hydroxy-5-(1-phenyethyl) - (7.8; 12.0); N-methoxymethy 1 -5-phenyl-5-ethyl (7.3₅; -); N-methyl -5-phenyl -5-ethyl - (7.8; -); 5-phenyl-5-ethyl - (7.3₅; 12.3). Structures were attributed to individual ionic forms involved.     

Identification and quantitation of trace amounts of barbiturates with glass capillary gas chromatography

Pre-chromatographic reactions are no longer a necessary evil. Equipment such as the microrefluxer now allows reproducible 7-μl-reactions to be carried out in a short time. Thus multiple derivatisations can be used together with glass capillary GC for routine identifications. The method has been succesfully applied to barbiturates. Retention data of their methyl-, allyl- and benzyl-derivatives are given. Quantitative blood level determinations are briefly discussed.     

Calorimetry to Evaluate Inclusion Mechanism in the Complexation Between 2-hydroxypropyl-β-cyclodextrin and Barbiturates in Aqueous Solution

Two different types (structures) of inclusion complexes with a 1:1 stoichiometry between barbiturates and 2-hydroxypropyl-β-cyclodextrin (HPCyD) were realized in aqueous solution using isothermal titration calorimetry and molecular dynamics simulation. The first type of complex with a higher association constant was entropy driven and the substituent R ₂ was inserted into the HPCyD cavity by hydrophobic interaction. The barbituric acid ring contributed to the second type of complex, which was characterized by large negative values of ΔH and small positive ΔS reflecting van der Waals interaction and/or hydrogen bonding formation between the hetero atoms in the barbituric acid ring and the secondary hydroxyl groups of HPCyD. This revised version was published online in July 2006 with corrections to the Cover Date.