Chemometric contributions to the evolution of metabonomics: mathematical solutions to characterising and interpreting complex biological NMR spectra

The pharmaceutical industry has embraced emerging technologies such as genomics, proteomics and metabonomics over the past decade with a view to minimizing attrition and expanding drug development pipelines. Metabonomic technology, based on the multivariate analysis of complex biological profiles generated from spectroscopic instruments, has enabled the construction of successful expert systems for toxicity screening and disease diagnosis. Here we describe the evolution of chemometric and bioinformatic methodologies to accommodate the multi- and megavariate data generated by high resolution NMR spectroscopy of biofluids, tissues and cell cultures and explore their potential role in mining, modeling and predicting metabolic data.     

Quantum chemical study of the hydrogen-bonded HXeOH–H2O complex

A combined MP2 and DFT/B3LYP study of the HXeOH–H₂O complex is presented. These computational methods have been used to extract information on the structural, energetical and vibrational properties of the complex. Additionally, we have applied anharmonic vibrational calculations based on the MP2-computed intermolecular potential energy surface. Large perturbations both on the subunit structures and their fundamental vibrational modes are found upon complexation. Large changes of anharmonicity of the HXeOH subunit reflects the perturbation of the molecule's electronic structure. The computed BSSE-corrected interaction energies are −40.23 and −38.94 kJ mol⁻¹ at the CCSD(T)//MP2 and CCSD(T)//B3LYP levels of theory, respectively. The estimated deformation energy contribution to the interaction energy is about 5%, which is very large compared with classical hydrogen-bonded complexes. The topological analysis of the Electron Localization Function (ELF) was applied to study further the hydrogen-bonded interaction between the two complex partners. The obtained interaction pattern suggests that the interaction between HXeOH and H₂O is a typical hydrogen bond interaction driven mainly by electrostatic interactions.     

Bromine Pentafluoride BrF5, the Formation of [BrF6]− Salts,and the Stereochemical (In)activity of the Bromine Lone Pairs

BrF₅ can be prepared by treating BrF₃ with fluorine under UV light in the region of 300 to 400 nm at room temperature. It was analyzed by UV-Vis, NMR, IR and Raman spectroscopy. Its crystal structure was redetermined by X-ray diffraction, and its space group was corrected to Pnma. Quantum-chemical calculations were performed for the band assignment of the vibrational spectra. A monoclinic polymorph of BrF₅ was quantum chemically predicted and then observed as its low-temperature modification in space group P2₁/c by single crystal X-ray diffraction. BrF₅ reacts with the alkali metal fluorides AF (A=K, Rb) to form alkali metal hexafluoridobromates(V), A[BrF₆] the crystal structures of which have been determined. Both compounds crystallize in the K[AsF₆] structure type (R , no. 148, hR24). For the species [BrF₆]⁺, BrF₅, [BrF₆]⁻, and [IF₆]⁻, the chemical bonds and lone pairs on the heavy atoms were investigated by means of intrinsic bond orbital analysis.     

Crosslinked poly(ester anhydride)s based on poly(ε‐caprolactone) and polylactide oligomers

Resorbable poly(ester anhydride) networks based on ε‐caprolactone, L ‐lactide, and D,L ‐lactide oligomers were synthesized. The ring‐opening polymerization of the monomers yielded hydroxyl telechelic oligomers, which were end‐functionalized with succinic anhydride and reacted with methacrylic anhydride to yield dimethacrylated oligomers containing anhydride bonds. The degree of substitution, determined by ¹³C NMR, was over 85% for acid functionalization and over 90% for methacrylation. The crosslinking of the oligomers was carried out thermally with dibenzoyl peroxide at 120 °C, leading to polymer networks with glass‐transition temperatures about 10 °C higher than those of the constituent oligomers. In vitro degradation tests, in a phosphate buffer solution (pH 7.0) at 37 °C, revealed a rapid degradation of the networks. Crosslinked polymers based on lactides exhibited high water absorption and complete mass loss in 4 days. In ε‐caprolactone‐based networks, the length of the constituent oligomer determined the degradation: PCL5‐AH, formed from longer poly(ε‐caprolactone) (PCL) blocks, lost only 40% of its mass in 2 weeks, whereas PCL10‐AH, composed of shorter PCL blocks, completely degraded in 2 days. The degradation of PCL10‐AH showed characteristics of surface erosion, as the dimensions of the specimens decreased steadily and, according to Fourier transform infrared, labile anhydride bonds were still present after 90% mass loss. © 2003 The Authors. Journal of Polymer Science Part A: Polymer Chemistry Published by Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 3788–3797, 2003     

Proton affinities of ketones, vicinal diketones and α-keto esters: a computational study

The proton affinities of seven different ketones, vicinal diketones, and α-keto esters (acetophenone, 2,2,2-trifluoroacetophenone, 2,3-butanedione, 1-phenyl-1,2-propanedione, methyl pyruvate, ethyl benzoylformate, and ketopantolactone) have been evaluated theoretically using the conventional ab initio HF and several post-HF methods (MP2, MP4, CCSD), density functional methods with the B3LYP hybrid functional, as well as some ab initio model chemistries [CBS-4M, G2(MP2), and G3(MP2)//B3LYP]. The chemical compounds studied are frequently used substrates in the asymmetric hydrogenation over chirally modified platinum catalysts where the protonation properties of the chiral modifier and the substrates are of great interest. In most cases, the proton affinities (PAs) evaluated with the CCSD/6-311+G(d,p)//B3LYP/TZVP and G2(MP2) methods are in good agreement with the existing experimental ones. However, the previously reported PA of 2,3-butanedione seems to be too high by 10-15 kJ mol⁻¹. The B3LYP/TZVP//B3LYP/TZVP and MP2/6-311+G(d,p)//B3LYP/TZVP model chemistries predict proton affinities that are systematically higher and lower than the experimental PAs, respectively. If proton affinities are evaluated as the average of the PAs calculated with these two theoretical methods a very good agreement with the experimental results is obtained. The mean absolute deviation (MAD) from experiment of this combination method for the PAs of 13 test molecules is 4.0 kJ mol⁻¹. For 9 molecules composed only of first-row atoms the MAD is 2.5 kJ mol⁻¹. The B3LYP/TZVP//B3LYP/TZVP and MP2/6-311+G(d,p)//B3LYP/TZVP methods provide significant savings in computational time and disk space compared to the CCSD/6-311+G(d,p)//B3LYP/TZVP and G2(MP2) models. Therefore, it is suggested that if no experimental or highly accurate theoretical data is available (due to computational cost), the proton affinities of similar compounds as investigated in this paper, can be evaluated with the combination method. For the studied molecules, this method gives the following PAs (in kJ mol⁻¹): 788 (2,3-butanedione, exptl 802); 798 (2,2,2-trifluoroacetophenone, exptl 799); 811 (ketopantolactone); 813 (methyl pyruvate); 825 (1-phenyl-1,2-propanedione); 862 (acetophenone, exptl 861); 865 (ethyl benzoylformate).     

Liquid chromatography/mass spectrometry in anabolic steroid analysis--optimization and comparison of three ionization techniques: electrospray ionization,atmospheric pressure chemical ionization and atmospheric pressure photoionization

The applicability of liquid chromatography/tandem mass spectrometry (LC/MS/MS) for the detection of the free anabolic steroid fraction in human urine was examined. Electrospray ionization (ESI), atmospheric pressure chemical ionization and atmospheric pressure photoionization methods were optimized regarding eluent composition, ion source parameters and fragmentation. The methods were compared with respect to specificity and detection limit. Although all methods proved suitable, LC/ESI-MS/MS with a methanol-water gradient including 5 mM ammonium acetate and 0.01% acetic acid was found best for the purpose. Multiple reaction monitoring allowed the determination of steroids in urine at low nanogram per milliliter levels. LC/MS/MS exhibited high sensitivity and specificity for the detection of free steroids and may be a suitable technique for screening for the abuse of anabolic steroids in sports.     

Physical properties of aqueous solutions of a thermo-responsive neutral copolymer and an anionic surfactant: turbidity and small-angle neutron scattering studies

Aqueous mixtures of the anionic sodium dodecyl sulfate (SDS) surfactant and thermo-responsive poly(N-vinylcaprolactam) chains grafted with omega-methoxy poly(ethylene oxide) undecyl alpha-methacrylate (PVCL-g-C11EO42) have been characterized using turbidimetry and small-angle neutron scattering (SANS). Turbidity measurements show that the addition of SDS to a dilute aqueous copolymer solution (1.0 wt %) induces an increase of the cloud point (CP) value and a decrease of the turbidity at high temperatures. In parallel, SANS results show a decrease of both the average distance between chains and the global size of the objects in solution at high temperatures as the SDS concentration is increased. Combination of these findings reveals that the presence of SDS in the PVCL-g-C11EO42 solutions (1.0 wt %) promotes the formation of smaller aggregates and, consequently, leads to a more homogeneous distribution of the chains in solution upon heating of the mixtures. Moreover, the SANS data results show that the internal structure of the formed aggregates becomes more swollen as the SDS concentration increases. On the other hand, the addition of moderate amounts of SDS (up to 4 mm) to a semidilute copolymer solution (5.0 wt %) gives rise to a more pronounced aggregation as the temperature rises; turbidity and SANS studies reveal in this case a decrease of the CP value and an increase of the scattered intensity at low q. The overall picture that emerges from this study is that the degree of aggregation can be accurately tuned by varying parameters such as the temperature, level of surfactant addition, and polymer concentration.     

High-temperature decomposition of amorphous and crystalline cellulose: reactive molecular simulations

We study the thermal decomposition of cellulose using molecular simulations based on the ReaxFF reactive force field. Our analysis focuses on the mechanism and kinetics of chain scission, and their sensitivity on the condensed phase environment. For this purpose, we simulate the thermal decomposition of amorphous and partially crystalline cellulose at various heating rates. We find that thermal degradation begins with depolymerization via glycosidic bond cleavage, and that the order of events corresponds to a randomly initiated chain reaction. Depolymerization is followed by ring fragmentation reactions that lead to the formation of a number of light oxygenates. Water is formed mainly in intermolecular dehydration reactions at a later stage. The reaction rate of glycosidic bond cleavage follows a sigmoidal reaction model, with an apparent activation energy of 166?±?4 kJ/mol. Neither the condensed phase environment nor the heating programme have appreciable effects on the reactions. We make several observations that are compatible with mechanisms proposed for cellulose fast pyrolysis. However, due to the absence of anhydrosugar forming reactions, the simulations offer limited insight for conditions of industrial interest. It remains unclear whether this is a natural consequence of the reaction conditions, or a shortcoming of the force field or its parameter set.

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Tetrazolic acid functionalized dihydroindol: rational design of a highly selective cyclopropanation organocatalyst

Herein we wish to report our development of an improved catalyst (S)-(-)-indoline-2-yl-1H-tetrazole (1) for the enantioselective organocatalyzed cyclopropanation of alpha,beta-unsaturated aldehydes with sulfur ylides. The new organocatalyst readily facilitates the enantioselective organocatalytic cyclopropanation, providing cyclized product in excellent diastereoselectivities ranging from 96% to 98% along with enantioselectivities exceeding 99% enantiomeric excess for all reacted alpha,beta-unsaturated aldehydes. The new catalyst provides the best results so far reported for intermolecular enantioselective organocatalyzed cyclopropanation.