Catalytic hydrofunctionalization of alkynes through P-H bond addition: the unique role of orientation and properties of the phosphorus group in the insertion step

The puzzling question of alkyne insertion into Pd-P and Pd-H bonds leading to the formation of new Pd-C, C-P, and C-H bonds was explored by theoretical calculations at the CCSD(T) and B3LYP levels of theory. The key factors responsible for selectivity of catalytic hydrofunctionalization of alkynes were resolved and studied in details for the models of hydrophosphorylation, hydrophosphinylation, and hydrophospination reactions. In contrast with the generally accepted mechanistic picture, the calculations have shown that several pathways are possible depending on the nature and geometrical arrangement of the phosphorus group. It was found that the product of alkyne insertion into the metal-hydrogen bond should be easily formed under kinetic-control conditions, while the product of alkyne insertion into the metal-phosphorus bond may be formed in certain cases under thermodynamic control. For the first time, the calculations have revealed the role of the oxygen atom in the reactivity of P=P(O)R(2) groups and the role of the interactions involving the lone pair of the P=PR(2) group in the reagent. The fundamental properties of the Pd-P, C-P, and P-H bonds were reported, and the larger bond strength upon increasing the number of oxygen atoms bound to phosphorus (P=PR(2), P(O)R(2), and P(O)(OR)(2)) have been shown. The relationship between bond energy, acidity, and reactivity of the studied phosphorus compounds has been determined.     

Overtone Mobility Spectrometry: Part 4. OMS-OMS Analyses of Complex Mixtures

A new, two-dimensional overtone mobility spectrometry (OMS-OMS) instrument is described for the analysis of complex peptide mixtures. OMS separations are based on the differences in mobilities of ions in the gas phase. The method utilizes multiple drift regions with modulated drift fields such that only ions with appropriate mobilities are transmitted to the detector. Here we describe a hybrid OMS-OMS combination that utilizes two independently operated OMS regions that are separated by an ion activation region. Mobility-selected ions from the first OMS region are exposed to energizing collisions and may undergo structural transitions before entering the second OMS region. This method generates additional peak capacity and allows for higher selectivity compared with the one-dimensional OMS method. We demonstrate the approach using a three-protein tryptic digest spiked with the peptide Substance P. The [M + 3H]³⁺ ion from Substance P can be completely isolated from other components in this complex mixture prior to introduction into the mass spectrometer.     

Overtone Mobility Spectrometry: Part 5. Simulations and Analytical Expressions Describing Overtone Limits

Mathematical expressions for the analytical duty cycle associated with different overtones in overtone mobility spectrometry are derived from the widths of the transmitted packets of ions under different instrumental operating conditions. Support for these derivations is provided through ion trajectory simulations. The outcome of the theory and simulations indicates that under all operating conditions there exists a limit or maximum observable overtone that will result in ion transmission. Implications of these findings on experimental design are discussed.      

Transition metal ‘cocktail’-type catalysis

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Temperature-dependent H/D exchange of compact and elongated cytochrome c ions in the gas phase

Isotopic exchange reactions of compact and elongated conformations of gaseous cytochrome c ions (+5 and +9 states) with D2O have been measured as a function of temperature (from 300 to approximately 440 K) using ion mobility techniques. Rate constants for those sites that exchange at high temperatures (>400 K) are about an order of magnitude smaller than rate constants for sites that exchange at 300 K. Although the exchange rates decrease, the maximum exchange levels for rapidly exchanging sites increase with temperature. At 300 K, exchange levels of 53 +/- 3 and 63 +/- 3 are measured for the compact and elongated states, respectively. From 300 to 335 K, the exchange levels increase slightly to approximately 60 to 70 hydrogens. Above 335 K, the levels increase to a value of approximately 200 for the +5 state and approximately 190 for the +9 state, near the maximum possible levels, 200 and 204 for these respective charge states. Molecular dynamics simulations have been carried out on structures having calculated cross sections that are near the experimental values in order to explore the exchange process. Overall, it appears that charge site and exchange site proximities are important factors in the exchange profiles for the elongated +9 ion and the compact +5 ion.     

Efficient route to 6-CF3-substituted nicotinic acid derivatives

A novel synthetic sequence for preparation of CF₃-pyridines is presented. Reaction of α,β-unsaturated trifluoromethylketones with α-cyanoketones leads to α-hydroxydihydropyranes 1 containing CF₃-group. α-Hydroxydihydropyranes can be easily transformed to α-hydroxytetrahydropyridines, 1,4-dihydropyridines and CF₃-pyridines. All CF₃-pyridine derivatives were obtained in good yields. This route can be applied for preparation of CF₃-pyridines containing various substituents with further possible modification on cyano-group.     

Challenges of Measuring Soluble Mn(III) Species in Natural Samples

Soluble Mn(III)–L complexes appear to constitute a substantial portion of manganese (Mn) in many environments and serve as critical high-potential species for biogeochemical processes. However, the inherent reactivity and lability of these complexes—the same chemical characteristics that make them uniquely important in biogeochemistry—also make them incredibly difficult to measure. Here we present experimental results demonstrating the limits of common analytical methods used to quantify these complexes. The leucoberbelin-blue method is extremely useful for detecting many high-valent Mn species, but it is incompatible with the subset of Mn(III) complexes that rapidly decompose under low-pH conditions—a methodological requirement for the assay. The Cd-porphyrin method works well for measuring Mn(II) species, but it does not work for measuring Mn(III) species, because additional chemistry occurs that is inconsistent with the proposed reaction mechanism. In both cases, the behavior of Mn(III) species in these methods ultimately stems from inter- and intramolecular redox chemistry that curtails the use of these approaches as a reflection of ligand-binding strength. With growing appreciation for the importance of high-valent Mn species and their cycling in the environment, these results underscore the need for additional method development to enable quantifying such species rapidly and accurately in nature.     

Regioselective synthesis of 5-trifluoromethyl-1,2,3-triazoles via CF3-directed cyclization of 1-trifluoromethyl-1,3-dicarbonyl compounds with azides

1-Trifluoromethyl-substituted 1,3-dicarbonyl compounds are shown to undergo 100% regioselective cyclization in reactions with alkyl and aryl azides to form 4-acyl-5-trifluoromethyl-1,2,3-triazoles. The reaction represents a general method for the synthesis of otherwise difficulty available 4-acyl-5-trifluoromethyl-1,2,3-triazoles. The directing role of the trifluoromethyl group is discussed in the light of stepwise and concerted mechanisms for this reaction.     

Ion Mobility Spectrometry-Hydrogen Deuterium Exchange Mass Spectrometry of Anions: Part 2. Assessing Charge Site Location and Isotope Scrambling

Ion mobility spectrometry (IMS) coupled with gas-phase hydrogen deuterium exchange (HDX)-mass spectrometry (MS) and molecular dynamic simulations (MDS) has been used for structural investigation of anions produced by electrospraying a sample containing a synthetic peptide having the sequence KKDDDDDIIKIIK. In these experiments the potential of the analytical method for locating charge sites on ions as well as for utilizing collision-induced dissociation (CID) to reveal the degree of deuterium uptake within specific amino acid residues has been assessed. For diffuse (i.e., more elongated) [M – 2H]^2– ions, decreased deuterium content along with MDS data suggest that the D4 and D6 residues are charge sites, whereas for the more diffuse [M – 3H]^3– ions, the data suggest that the D4, D7, and the C-terminus are deprotonated. Fragmentation of mobility-selected, diffuse [M – 2H]^2– ions to determine deuterium uptake at individual amino acid residues reveals a degree of deuterium retention at incorporation sites. Although the diffuse [M – 3H]^3– ions may show more HD scrambling, it is not possible to clearly distinguish HD scrambling from the expected deuterium uptake based on a hydrogen accessibility model. The capability of the IMS-HDX-MS/MS approach to provide relevant details about ion structure is discussed. Additionally, the ability to extend the approach for locating protonation sites on positively-charged ions is presented.

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Ti(IV) binds to human serum transferrin more tightly than does Fe(III)

The binding of titanium(IV) to human serum transferrin in 50 mM Tris with 20 mM bicarbonate and 10 mM citrate at pH 7.4 was studied by UV/vis kinetics and by isothermal titration calorimetry. Ti(IV) citrate, [Ti(C6H4O7)3]8-, employed in this study was previously characterized and delivers the metal to transferrin rapidly, allowing the quantification of the intrinsic binding constants for Ti(IV) to the C- and N-sites of transferrin. The results after correcting for blood plasma conditions (pH 7.4, [HCO3-] = 27 mM) reveal that Ti(IV) binds with greater affinity (log K = 26.8 and 25.7) than Fe(III) (log K = 22.5 and 21.4) to transferrin, a finding not previously observed for other examined metal ions. The strength of metal binding to transferrin correlates with the Lewis acidity of the metal. Ti(IV) is more Lewis acidic than Fe(III) and is nearly the same size. The study also reveals that Ti(IV) binds more tightly to one site than the other, and this difference is due to both entropic and enthalpic contributions. The study has implications for the role of transferrin in the anticancer activity of Ti(IV) drugs and the serum binding of Ti(IV) ions released from implants or imaging reagents.