The amide rotational barriers in picolinamide and nicotinamide: NMR and ab initio studies

Pyridine carboxamides are a class of medicinal agents with activity that includes the reduction of iron-induced renal damage, the regulation of nicotinamidase activity, and radio- and chemosensitization. Such pharmacological activities, and the prevalence of the carboxamide moiety and the importance of amide rotations in biology, motivate detailed investigation of energetics in these systems. In this study, we report the use of dynamic nuclear magnetic resonance to measure the amide rotational barriers in the pyridine carboxamides picolinamide and nicotinamide. The activation enthalpies and entropies of DeltaH++ = 12.9 +/- 0.3 kcal/mol and DeltaS++ = -7.7 +/- 0.9 cal/mol K for nicotinamide and DeltaH++ = 18.3 +/- 0.4 kcal/mol and DeltaS++ = +1.3 +/- 1.0 cal/mol K for picolinamide report a substantial energetic difference for these regioisomers. Ab initio calculations of the rotational barriers are in good agreement with the experimentally determined values and help partition the 5.4 kcal/mol enthalpy difference into its major contributions. Of principal importance are the variations in steric interactions in the ground states of picolinamide and nicotinamide, superior pi electron donation from the pyridine ring in the transition state of nicotinamide, and an intramolecular hydrogen bond in the ground state of picolinamide.     

High-throughput purification of combinatorial libraries II: Automated separation of single diastereomers from a 4-amido-pyrrolidone library containing intentional diastereomer pairs

A 4-amido-pyrrolidone library that was intentionally synthesized as pairs of diastereomers was produced by solution-phase parallel syntheses and purified by an automated high-throughput purification system. A total of 2592 4-amido-pyrrolidinones were ultimately isolated as single diastereomers from a matrix of 1920 syntheses. After the four-step synthesis and HPLC purification, the average yield of a single diastereomer was 36.6%. The average chemical purity was >90%, and the average diastereomeric purity was >87%. The choice of chiral amines used to make amides with heterocyclic acid chlorides had a dramatic effect on success. Analysis of the relationship between amines used for synthesis and the diastereomeric separation showed that amides made from chiral 1,2-amino alcohols gave superior separation to amides from chiral morpholines. The presence of a hydrogen bond donor on the amide side chain seems to be required for a better diastereomeric separation.     

Silver-phosphine complexes of the highly methylated carborane monoanion [closo-1-H-CB11Me11]-

The synthesis of the silver(I) salt of the highly methylated carborane anion [closo-1-H-CB(11)Me(11)](-) is described, Ag[closo-1-H-CB(11)Me(11)] 1, which in the solid state shows close intermolecular Ag...H(3)C contacts. Addition of various monodentate phosphines to 1 results in the formation of the complexes (R(3)P)Ag[closo-1-H-CB(11)Me(11)] [R = Ph, 2; cyclohexyl (C(6)H(11)), 3; (3,5-Me(2)-C(6)H(3)), 4]. All these complexes show close intermolecular Ag.H(3)C contacts in the solid state that are considerably shorter than the sum of the van der Waals radius of methyl (2.00 A) and the ionic radius of silver(I) (1.29 A). For 2 and 3 there are other close intermolecular Ag...H(3)C contacts in the solid state, arising from proximate carborane anions in the crystal lattice. Addition of methyl groups to the periphery of the phosphine ligand (complex 4) switches off the majority of these interactions, leaving essentially a single cage interacting with the cationic silver-phosphine fragment through three CH(3) groups. In solution (CD(2)Cl(2)) Ag...H(3)C contacts remain, as evidenced by both the downfield chemical shift change and the significant line-broadening observed for the cage methyl signals. These studies also show that the metal fragment is fluxional over the surface of the cage. The Ag...H(3)C interactions in solution may be switched off by addition of a stronger Lewis base than [closo-1-H-CB(11)Me(11)](-). Thus, addition of [NBu(4)][closo-1-H-CB(11)H(5)Br(6)] to 2 affords (Ph(3)P)Ag[closo-1-H-CB(11)H(5)Br(6)], while adding Et(2)O or PPh(3) affords the well-separated ion-pairs [(Ph(3)P)(L)Ag][closo-1-H-CB(11)Me(11)] (L = OEt(2) 5, PPh(3) 6,) both of which have been crystallographically characterized. DFT calculations on 2 (at the B3LYP/DZVP level) show small energy differences between the possible coordination isomers of this compound, with the favored geometry being one in which the [(Ph(3)P)Ag](+) fragment interacts with three of the [BCH(3)] vertices on the lower surface of the cage, similar to the experimentally observed structure of 4.     

Test study on the excitation spectra of the N<Subscript>2</Subscript>–He van der Waals molecule

We have performed ab initio fourth-order Møller–Plesset perturbation theory calculations in the framework of the supermolecule approach on the vertical excitation spectra of the weakly bound van der Waals N₂–He dimer. They indicate a ``T-shaped' stablest ground N<sub>2</sub>(X<sup>1</sup><sub>g</sub><sup>+</sup>)–He(<sup>1</sup>S) electronic state with a well depth, D<sub>e</sub>, of 21.63 cm<sup>–1</sup> at a minimum distance, R<sub>e</sub>, of 3.44 Å and zero-point vibration correction, D<sub>o</sub>, of 7.07 cm<sup>–1</sup>. They also indicate a ``T-shaped' stablest excited conformer with R_e=3.25 Å, D_e=36.85 cm^–1 and D_o=17.06 cm^–1 for the N₂(B³_g)–He(¹S) triplet electronic level. In order to investigate the use of less-demanding correlation methods, test density functional theory calculations using the mPW1PW exchange–correlation functional are also presented for comparison.     

Use of poly(sodium oleyl-L-leucylvalinate) surfactant for the separation of chiral compounds in micellar electrokinetic chromatography

A chiral amino acid-based monomeric and polymeric surfactant, sodium oleyl-L-leucylvalinate) (L-SOLV) and poly(sodium oleyl-L-leucylvalinate) (poly-L-SOLV) were synthesized and used for chiral separations in micellar electrokinetic chromatography (MEKC). Poly-L-SOLV was used successfully in the separation of various enantiomers of neutral, acidic, and basic analytes such as 1,1'-bi-2-napthol, 1,1'-binaphthyl-2,2'-diamine, benzoin, hydrobenzoin, benzoin methylether, warfarin, and coumachlor obtaining well-resolved peaks but with only partial separation of temazepam. In addition, the atropisomer 1,1'-binaphthyl-2, 2'-dihydrogen phosphate was chosen to study the applicability of the polymeric surfactant over a wide range of parameters such as concentration, temperature, voltage, and pH. The most striking characteristic of this new surfactant is its high hydrophobicity. It is favorable to interactions with hydrophobic chiral analytes, and thus may provide better chiral recognition for the compounds.     

Elucidation of the fragmentation pathways of azaspiracids, using electrospray ionisation, hydrogen/deuterium exchange, and multiple-stage mass spectrometry

Collision-induced dissociation (CID) mass spectra were generated for azaspiracids using electrospray ionisation (ESI), and hydrogen/deuterium (H/D) exchange was used to ascertain the number and type of replaceable hydrogens in the three predominant azaspiracid toxins. H/D exchange was conveniently achieved using deuterated solvents for liquid chromatography (LC). Using ion-trap mass spectrometry, multiple-stage CID experiments (MS(n)) on the protonated and fully exchanged ions were performed to decipher characteristic fragmentation pathways. The precursor and product ions from azaspiracids lost up to five water molecules from different regions during MS(n) experiments and it was possible to distinguish between the water losses from different molecular regions. These studies confirmed that the first water-loss ion in the spectra of azaspiracids resulted from dehydration at the vicinal diol at C20-C21. Five MS dissociation pathways were identified that resulted from fragmentation of the carbon skeleton of azaspiracids producing nitrogen-containing ions. Two pathways, involving cleavage of the E-ring and C27-C28, gave ions that were found in all azaspiracids. Three pathways, A-ring, C-ring and C19-C20 cleavages, were useful for distinguishing between azaspiracid analogues. The same product ions from backbone fragmentation were also observed using hybrid quadrupole time-of-flight mass spectrometry (QqTOFMS). The fragmentation of the A-ring was the most facile and was exploited in the development of LC/MS(n) methods for the analysis of azaspiracids.     

Interpolated potential energy surface for abstraction and exchange reactions of NH 3 + H and deuterated analogues

An ab initio interpolated potential energy surface for the hydrogen abstraction and exchange reactions between ammonia and a hydrogen atom is reported. The interpolation is constructed over a set of data points calculated at the unrestricted coupled cluster approximation, using single and double excitations, and including the triple excitations non-iteratively. New data point selection methods were used to improve the convergence and accuracy of the interpolated surface.     

Substituent,solvent and steric effects on the electrochemical reduction of aziridinium salts

The polarographic behavior of a series of N,N-dimethyl-2-arylaziridinium fluorosulfonates was investigated as another example of ring-opening reactions of this important class of compounds. Half-wave potentials showed that in water reduction was facilitated by electron-donating groups. This unusual result was explained in terms of electron transfer to an aminocarbonium ion-like species. In methylene chloride, however, two one-electron waves were observed, with the first showing a normal substituent effect (? = 0.17 ± 0.03 V). This result indicated direct electron transfer to the aziridinium ion itself to form a radical species which was detected by cyclic voltammetry. Reasons for the change in mechanism are presented, and E_1/2 values for selected aziridinium salts illustrate the importance of steric effects on the reduction process.     

Evaluation of the BAX system for detection of Listeria monocytogenes in foods: collaborative study

A multilaboratory study was conducted to compare the automated BAX system and the standard cultural methods for detection of Listeria monocytogenes in foods. Six food types (frankfurters, soft cheese, smoked salmon, raw, ground beef, fresh radishes, and frozen peas) were analyzed by each method. For each food type, 3 inoculation levels were tested: high (average of 2 CFU/g), low (average of 0.2 CFU/g) and uninoculated controls. A total of 25 laboratories representing government and industry participated. Of the 2335 samples analyzed, 1109 were positive by the BAX system and 1115 were positive by the standard method. A Chi square analysis of each of the 6 food types, at the 3 inoculation levels tested, was performed. For all foods, except radishes, the BAX system performed as well as or better than the standard reference methods based on the Chi square results.     

Computer Graphics in the Study of Metal Cluster Compounds

Polynuclear carbonylmetal compounds provide convenient molecular analogues for the reactions occurring at metal surfaces during catalytic processes. Many properties of these cluster compounds are determined by the type and distribution of the ligands covering the metal polyhedral surface. Computer simulated space-filling models of these complicated molecules provide readily assimilated information about the arrangement of surface ligands, and in many cases lead to conclusions not readily deduced from other approaches.