Francisco Ros

Experimental and Computational Thermochemical Study and Solid-Phase Structure of 5,5-Dimethylbarbituric Acid

This paper reports an experimental and computational thermochemical study on 5,5-dimethylbarbituric acid and the solid-phase structure of the compound. The value of the standard (p(o) = 0.1 MPa) molar enthalpy of formation in the gas phase at T = 298.15 K has been determined. The energy of combustion was measured by static bomb combustion calorimetry, and from the result obtained, the standard molar enthalpy of formation in the crystalline state at T = 298.15 K was calculated as -(706.4 +/- 2.2) kJ x mol(-1). The enthalpy of sublimation was determined using a transference (transpiration) method in a saturated NB(2) stream, and a value of the enthalpy of sublimation at T = 298.15 K was derived as (115.8 +/- 0.5) kJ x mol(-1). From these results a value of -(590.6 +/- 2.3) kJ x mol(-1) for the gas-phase enthalpy of formation at T = 298.15 K was determined. Theoretical calculations at the G3 level were performed, and a study on molecular and electronic structure of the compound has been carried out. Calculated enthalpies of formation are in reasonable agreement with the experimental value. 5,5-Dimethylbarbituric acid was characterized by single crystal X-ray diffraction analysis. In the crystal structure, N-H...O=C hydrogen bonds lead to the formation of ribbons connected further by weak C-H...O=C hydrogen bonds into a three-dimensional network. The molecular and supramolecular structures observed in the solid state were also investigated in the gas phase by DFT calculations.

Experimental and computational thermochemical study of barbituric acids: structure-energy relationship in 1,3-dimethylbarbituric acid.

This paper reports an experimental and computational thermochemical study on 1,3-dimethylbarbituric acid. The value of the standard (p° = 0.1 MPa) molar enthalpy of formation in the gas phase at T = 298.15 K has been determined. The energy of combustion was measured by static bomb combustion calorimetry, and from the result obtained, the standard molar enthalpy of formation in the crystalline state at T = 298.15 K was calculated as -639.6 ± 1.9 kJ·mol(-1). The enthalpy of sublimation was determined using a transference (transpiration) method in a saturated N(2) stream and a value of the enthalpy of sublimation at T = 298.15 K was derived as 92.3 ± 0.6 kJ·mol(-1). From these results a value of -547.3 ± 2.0 kJ·mol(-1) for the gas-phase enthalpy of formation at T = 298.15 K was determined. Theoretical calculations at the G3 and G4 levels were performed, and a study on molecular and electronic structure of the compound has been carried out. Calculated enthalpies of formation are in very good agreement with the experimental value.

Thermochemistry of uracils. experimental and computational enthalpies of formation of 5,6-dimethyl-, 1,3,5-trimethyl-, and 1,3,5,6-tetramethyluracils

We describe in the current paper an experimental and computational study of three methylated uracils, in particular, the 5,6-dimethyl-, 1,3,5-trimethyl-, and 1,3,5,6-tetramethyl derivatives. The values of the standard (p(0) = 0.1 MPa) molar enthalpies of formation in the gas phase at T = 298.15 K have been determined. The energies of combustion were measured by static bomb combustion calorimetry, and from the results obtained, the standard molar enthalpies of formation in the crystalline state at T = 298.15 K were calculated. The enthalpies of sublimation were determined using the transpiration method in a saturated N(2) stream. Values of -(376.2 ± 2.6), -(355.9 ± 3.0), and -(381.7 ± 2.8) kJ·mol(-1) for the gas-phase enthalpies of formation at T = 298.15 K of 5,6-dimethyluracil, 1,3,5-trimethyluracil, and 1,3,5,6-tetramethyluracil, respectively, were obtained from the experimental thermochemical study. An extended theoretical study with the G3 and the G4 quantum-chemical methods has been carried out for all the possible methylated uracils. There is a very good agreement between experimental and calculated enthalpies of formation for the three derivatives studied. A Free-Wilson analysis on G4-calculated enthalpies of formation has been carried out, and the contribution of methylation in the different positions of the uracil ring has been estimated.

A NEW RACEMIC CONGLOMERATE AND ITS CHARACTERIZATION BY THE MELTING POINT DIAGRAM - FORMATION OF THE METASTABLE RACEMIC COMPOUND

The highly branched ester rac-1 has been prepared. It exists in the form of a conglomerate (m.p. 90–92 °C) in which the two enantiomers are present in separate crystal lattices, as indicated by the melting point diagram. Both enantiomers of 1 have been isolated by crystallization [m.p. 112–114 °C, [α]D22 = +24.4 ± 0.7 (c = 0.45, Et2O), –25.4 ± 0.8 (c = 0.44, Et2O)]; mechanical manipulation of the conglomerate provided samples enriched in one or the other enantiomer and subsequent recrystallization of these partially resolved samples furnished the isolated enantiomers. The high value of the enthalpy of fusion of enantiomers 1 (ΔHfenant = 8.8 ± 1.4 kcal mol–1) and the moderate value of the corresponding entropy (ΔSfenant = 23 ± 4 cal K–1 mol–1), both derived from the melting point diagram, are ascribed to the relative compactness of the highly branched molecule and to its reduced conformational flexibility, respectively. Ester rac-1 has been serendipitously obtained in the form of a racemic compound (m.p. 82–84 °C) by crystallization of the racemate. The racemic compound transforms into the conglomerate at 70 °C. This transformation may be regarded as a spontaneous optical resolution occurring in the solid crystalline state.

Synthesis of a series of 3-cyanopropionamides and 4-imino-γ-butyrolactams and evaluation of their function as modulators of multidrug resistance

The synthesis of the 3‐cyanopropionamides 3a and 3b, of the 2,2‐dimethyl‐3‐cyanopropionamides 4a—4c and of the 4‐imino‐γ‐butyrolactams 5a and 5b (cyclic functional isomers of 3‐cyanopropionamides) is described. The amides 3a and 3b were obtained by aminolysis of the corresponding acid chlorides, which are accessible via hydrolysis of the ethyl esters to the acids. This methodology was not used for the synthesis of the amides 4a—4c owing to steric hindrance to hydrolysis in the corresponding ethyl esters. These nonreactive esters, accesible by alkylation of 1‐cyano carbanions with ethyl bromodimethylacetate, could be directly converted into the amides 4a—4c by aminolysis with the lithium amide of 3,4‐dimethoxy‐N‐methylphenethylamine. Instead of open‐chain amides, the lactams 5a and 5b are obtained when the lithium amide of 3,4‐dimethoxyphenethylamine (i.e., of a primary rather than secondary amine) is used for the aminolysis. The synthesized compounds were tested for their ability to decrease the resistance to vincristine in a multidrug‐resistant subline of murine leukemic lymphoblasts that are 300‐fold resistant to the antiproliferative drug. The amides 4a and 4c, and lactam 5a, all of which have a highly branched carbon backbone, were active. Lactam 5a reduced the vincristine resistance by 90% at a 2‐μM concentration.

Formation of an imidosuccinimide by cyclisation of a sterically hindered β-cyanoester with the lithium salt of a primary amine

The reaction of β-cyanoester 1 with a two-fold excess of the lithium salt of homoveratrylamine in THF at 0 °C to room temperature affords the imidosuccinimide 3, which undergoes derivation to the succinimide monooxime 4 by treatment with m-chloroperoxybenzoic acid.

Use of lactamide diastereoisomers to permit resolution of a racemic modulator of cancer drug resistance

The synthesis of enantiomers of an amidic modulator of cancer multidrug resistance, the chirality of which is not prone to chromatography, has been carried out via formation of the diastereoisomeric esters of the precursor racemic acid with (S)-lactamide and separation of the esters on silica gel.

Nucleophilic Substitution in α-Functionalized Tertiary Haloalkanes by Resonance Stabilized Carbanions

Relatively few cases of C-C bond forming SRN1 substitutions at a saturated carbon atom of substrates lacking a nitro group are known. Examples of this kind are the C-alkylation of nitroalkane anions by α-chloroisobutyrophenone (1) or α-bromoisobutyronitrile (2). In relation to these reactions we have examined those of compounds 1 with nitroalkane, α-carboxyethyl-α-cyano, or α-cyanobenzylic carbanions.