Isotopic scrambling in Di-13C-labeled 2-butyl cation: evidence for a protonated cyclopropane intermediate

The (13)C NMR spectrum of 2-butyl-1,2-(13)C(2) cation (1) is unchanged on heating the sample to -78 degrees C, indicating no isomerization to another isotopomer. In contrast, the spectrum of 2-butyl-2,3-(13)C(2) cation (2) shows rapid formation of all of the other isotopomers except 1. These results are consistent with a protonated cyclopropane intermediate in the rearrangement process. In this mechanism, either C(1) and C(2) or C(3) and C(4) interchange. Only the bond between C(2) and C(3) breaks.     

Acylaminoacetyl derivatives of active methylene compounds. 2. The cyclization of the acetylaminoacetyl derivatives to α-substituted tetramic acids and the formation of N-acetyl-α-substituted tetramic acids

The reaction of aceturic acid p-nitrophenyl ester with active methylene compounds Y-CH₂-CO₂R has been found to give either the normally expected C-acylation compounds 2 (Y = -CN, -CO₂R, -COCH₃) or N-acetyl-α-Y-substituted tetramic acids 3 (Y = -CO₂R,-COCH₃), depending on the reaction conditions. Moreover, the intramolecular condensation of the C-acylation compounds 2 derived from malonic and acetoacetic esters (Y = -CO₂R, -COCH₃) to α-Y-substituted tetramic acids is shown to proceed through initial cyclization to the corresponding N-acetyl-α-Y-substituted tetramic acids 3 (Y = -CO₂R, -COCH₃).     

Electrostatics of PEGylated micelles and liposomes containing charged and neutral lipopolymers

The electrostatics of large unilamellar vesicles (LUVs) of various lipid compositions were determined and correlated with steric stabilization. The compositional variables studied include (a) degree of saturation, comparing the unsaturated egg phosphatidylcholine (EPC) and the fully hydrogenated soy phosphatidylcholine (HSPC) as liposome-forming lipids; (b) the effect of 40 mol % cholesterol; (c) the effect of mole % of three methyl poly(ethylene glycol) (mPEG)-lipids (the negatively charged mPEG-distearoyl phosphoethanolamine (DSPE) and two uncharged lipopolymers, mPEG-distearoyl glycerol (DSG) and mPEG-oxycarbonyl-3-amino-1,2-propanediol distearoyl ester (DS)); and (d) the negatively charged phosphatidyl glycerol (PG). The lipid phases were as follows: liquid disordered (LD) for the EPC-containing LUV, solid ordered (SO) for the HSPC-containing LUV, and liquid ordered (LO) for either of those LUV with the addition of 40 mol % cholesterol. The LUV zeta potential and electrical surface potential (psi(0)) were determined. It was found that progressive addition of mPEG(2k)-DSPE to liposomes increases negative surface potential and reduces surface pH to a similar extent as the addition of PG. However, due to the "hidden charge effect", zeta potential was more negative for liposomes containing PG than for those containing mPEG(2k)-DSPE. Replacing mPEG-DSPE with mPEG(2k)-DS or mPEG-DSG had no effect on surface pH and surface potential, and zeta potential was approximately zero. Addition of low concentrations of cationic peptides (protamine sulfate and melittin) to PG- or mPEG-DSPE-containing liposomes neutralized the liposome negative surface potential to a similar extent. However, only in liposomes containing PG, did liposome aggregation occur. Replacing the negatively charged lipopolymer mPEG-DSPE with the neutral lipopolymers mPEG-DS or mPEG-DSG eliminates or reduces such interactions. The relevance of this effect to the liposome performance in vivo is discussed.     

A very large diversity space of synthetically accessible compounds for use with drug design programs

We have constructed a very large virtual diversity space containing more than 10¹³ chemical compounds. The diversity space is built from about 400 combinatorial libraries, which have been expanded by choosing sizeable collections of suitable R-groups that can be attached to each link point of their scaffolds. These R-group collections have been created by selecting reagents that have drug-like properties from catalogs of available chemicals. As members of known combinatorial libraries, the compounds in the diversity space are in general synthetically accessible and useful as potential drug leads. Hence, the diversity space can be used as a vast source of compounds by a de novo drug design program. For example, we have used such a program to generate inhibitors of HIV integrase enzyme that exhibited activity in the micromolar range.     

Understanding the conformational dependence of spin-spin coupling constants: through-bond and through-space J(31P,31P) coupling in tetraphosphane-1,4-diides [M(L)x]2[P4R4

The characteristic dependence of J(31P,31P) spin-spin coupling constants of alkali metal tetraphosphane-1,4-diides on structure and composition has been analyzed by density functional methods. The computations confirm that the structure of the contact ion pairs is conserved in solution. Calculations on model systems M2P4H4, on naked P4H4(2-) anions, and on models including point charges, show that the role of the cations is mainly structural and to a smaller extent electrostatic. Three of the four J(P,P) coupling constants depend characteristically on the conformation of the anion, which in turn is determined by the substituents R and by cation-anion interactions. Several couplings exhibit a large through-space component and are thus strongly dependent on the relative orientation of nonbonding electron pairs on the phosphorus atoms involved. This is shown by visualization of coupling pathways using the recently introduced coupling energy density (CED), in combination with the electron localization function (ELF).     

Separation and identification of organic acid-coenzyme A thioesters using liquid chromatography/electrospray ionization-mass spectrometry

A method has been developed for the direct determination of coenzyme A (CoA) and organic acid-CoA thioesters in mixtures using directly combined liquid chromatography/electrospray ionization-mass spectrometry (LC/ESI-MS). Mixtures of CoA and organic acid-CoA thioesters were analyzed by LC/ESI-MS with detection of protonated molecular ions and characteristic fragment ions for each compound. The identities of the CoA-thioesters were established based on LC retention times and simultaneously recorded mass spectra. Monitoring of the CoA specific fragment ion at m/z 428 throughout the chromatogram provides a unique fingerprint for CoA content in the samples that corroborates the identification of organic acid-CoA thioesters in the mixtures. Furthermore, fragment ions arising from the ester linkage portion of the molecule allow unambiguous identification of the CoA esters in the samples. A second LC elution system was developed that allows the simultaneous separation and identification of 2-hydroxypropionyl-CoA (lactyl-CoA) and 3-hydroxypropionyl CoA (3HP-CoA), which have the same mass and identical MS fragmentation behavior. The utility of LC/ESI-MS employing this elution system is demonstrated by the determination of 3HP-CoA and lactyl-CoA (converted to CoA-thioesters from their corresponding free acids using CoA-transferase) in fermentation broths from Escherichia coli strains engineered for the production of 3-hydroxypropionic acid (3HP). External calibration employing a purified 3HP-CoA standard allowed indirect quantification of 3HP content in the broth with a precision of 1% (RSD). The feasibility of extending the method described above to perform LC/selected reaction monitoring-tandem mass spectrometry for direct determination of organic acid-CoA thioesters in cells was also demonstrated.     

Effect of hydrodynamic interactions on the evolution of chemically reactive ternary mixtures

We investigate the structural evolution of an A/B/C ternary mixture in which the A and B components can undergo a reversible chemical reaction to form C. We developed a lattice Boltzmann model for this ternary mixture that allows us to capture both the reaction kinetics and the hydrodynamic interactions within the system. We use this model to study a specific reactive mixture in which C acts as a surfactant, i.e., the formation of C at the A/B interface decreases the interfacial tension between the A and B domains. We found that the dynamics of the system is different for fluids in the diffusive and viscous regimes. In the diffusive regime, the formation of a layer of C at the interface leads to a freezing of the structural evolution in the fluid; the values of the reaction rate constants determine the characteristic domain size in the system. In the viscous regime, where hydrodynamic interactions are important, interfacial reactions cause a slowing down of the domain growth, but do not arrest the evolution of the mixture. The results provide guidelines for controlling the morphology of this complex ternary fluid.     

Molecular Structure and Conformational Composition of 1-[(Methylthio)methyl]-2-nitrobenzene (MTMNB): A Theoretical and Experimental Study

The conformational composition of gaseous MTMNB and the molecular structures of the rotational forms have been studied by electron diffraction at 130^∘C aided by results from ab initio and density functional theory calculations. The conformational potential energy surface has been investigated by using the B3LYP/6-31G(d,p) method. As a result, six minimum-energy conformers have been identified. Geometries of all conformers were optimized using MP2/6-31G(d,p), B3LYP/6-31G(d,p), and B3LYP/cc-pVTZ methods. These calculations resulted in accurate geometries, relative energies, and harmonic vibrational frequencies for all conformers. The B3LYP/cc-pVTZ energies were then used to calculate the Boltzmann distribution of conformers. The best fit of the electron diffraction data to calculated values was obtained for the six conformer model, in agreement with the theoretical predictions. Average parameter values (r_a in angstroms, angle α in degrees, and estimated total errors given in parentheses) weighted for the mixture of six conformers are r(C–C) = 1.507(5), r(C–C)_{ring, av} = 1.397(3), r(C–S)_av = 1.814(4), r(C–N) = 1.495(4), r(N–O)_av = 1.223(3), ∠(C–C–C)_ring = 116.0–122.5, ∠ C6–C4–C7 = 118.2(4), ∠ C–C–S = 113.6(6), ∠ C–S–C = 98.5(12), ∠ N–C–C4 = 121.9(3), ∠(O–N–C)_av = 116.8(3), ∠ O–N–O = 127.0(4). Torsional angles could not be refined. Theoretical B3LYP/cc-pVTZ torsional angles for the rotation about C–N bond, φ_C−N, were found to be 30.5–36.5^∘ for different conformers. As to internal rotation about C–C and C–S bonds, values of φ_C−C = 68–118^∘ and φ_C−S = 66–71^∘ were obtained for the three most stable conformers with gauche orientation with respect to these bonds. Some conclusions of this work were presented in a short communication in Russ. J. Phys. Chem. 2005, 79, 1701.     

Low-temperature destruction of carbon tetrachloride over lanthanide oxide-based catalysts: from destructive adsorption to a catalytic reaction cycle

The catalytic destruction of carbon tetrachloride in the presence of steam, CCl(4) + 2 H(2)O-->4 HCl + CO(2), was investigated at 200-350 degrees C over a series of lanthanide (La, Ce, Pr and Nd) and alkaline-earth metal (Mg, Ca, Sr and Ba) oxide-based catalysts with kinetic experiments, Raman spectroscopy, X-ray photoelectron spectroscopy, IR spectroscopy, X-ray diffraction, and DFT calculations. This new catalytic reaction was achieved by combining destructive adsorption of CCl(4) on a basic oxide surface and concurrent dechlorination of the resulting partially chlorinated solid by steam. The combination of the two noncatalytic reactions into a catalytic cycle provided a rare opportunity in heterogeneous catalysis for studying the nature and extent of surface participation in the overall reaction chemistry. The reaction is proposed to proceed over a terminal lattice oxygen site with stepwise donation of chlorine atoms from the hydrocarbon to the surface and formation of the gas-phase intermediate COCl(2), which is readily readsorbed at the catalyst surface to form CO(2). In a second step, the active catalyst surface is regenerated by steam with formation of gas-phase HCl. Depending on the reaction conditions, the catalytic material was found to transform dynamically from the metal oxide state to the metal oxide chloride or metal chloride state due to the bulk diffusion of oxygen and chlorine atoms. A catalyst obtained from a 10 wt % La(2)O(3)/Al(2)O(3) precursor exhibited the highest destruction rate: 0.289 g CCl(4) h(-1) g(-1) catalyst at 350 degrees C, which is higher than that of any other reported catalyst system.     

Carbocyclic analogues of nucleosides from bis-(Hydroxymethyl)-cyclopentane: synthesis,antiviral and cytostatic activities of adenosine,inosine and uridine analogues

Six new carbocyclic nucleosides were prepared by constructing a purine base (in compounds 9-11) or pyrimidine base (in 6-8) on the amino groups of (+/-)-(1 beta,2 alpha,4 beta)-4-amino-1,2-cyclopentanedimethanol (4) and (+/-)-(1 beta,3 alpha,4 beta)-4-amino-1,3-cyclopentanedimethanol (5), and their activities against a variety of viruses and tumour cell lines were determined.