Identifying and Quantifying Relative Concentrations of Epimers in Mixtures via Cyclic Ion Mobility Mass Spectrometry: Dexamethasone and Betamethasone as a Case Study.

Epimers can show different biological activities and different pharmacological behaviors; therefore, their separation and analysis are crucial in the drug development process. Due to their similar chemical and physical properties, separation of epimers is challenging. This study demonstrates the application of cyclic ion mobility-mass spectrometry to separate, identify, and quantify dexamethasone and betamethasone in a binary mixture.

Ion Mobility and Fourier Transform Ion Cyclotron Resonance Collision Cross Section Techniques Yield Long-Range and Hard-Sphere Results, Respectively.

We determined collision cross section (CCS) values for singly and doubly charged cucurbit[]uril ( = 5-7), decamethylcucurbit[5]uril, and cyclohexanocucurbit[5]uril complexes of alkali metal cations (Li-Cs). These hosts are relatively rigid. CCS values calculated using the projection approximation (PA) for computationally modeled structures of a given host are nearly identical for +1 and +2 complexes, with weak metal ion dependence, whereas trajectory method (TM) calculations of CCS for the same structures consistently yield values 7-10% larger for the +2 complexes than for the corresponding +1 complexes and little metal ion dependence.

Prototypical Allosterism in a Simple Ditopic Ligand: Gas-Phase Topologies of Cucurbit[n]uril·-Alkylammonium Complexes Controlled by Binding in the Second Site.

We have employed mass spectrometry, ion mobility, and computational techniques to characterize complexes of -alkylammonium ions with cucurbit[5]uril (CB[5]) and cucurbit[6]uril (CB[6]) ligands in the gas phase. Nonrotaxane structures are energetically preferred and experimentally observed for all CB[5] complexes. Pseudorotaxane structures are computationally favored and experimentally observed for [CB[6]·-alkylammonium] complexes, but the addition of a second cation (proton, alkali metal ion, another alkylammonium ion, or guanidinium) on the opposite rim of CB[6] causes sufficiently unfavorable steric interactions that -pentylammonium and longer chains no longer remain threaded through the CB[6] cavity; nonrotaxane topologies are then favored.

Halide Size-Selective Binding by Cucurbit[5]uril-Alkali Cation Complexes in the Gas Phase.

We report data that suggest complexes with alkali cations capping the portals of cucurbit[5]uril (CB[5]) bind halide anions size-selectively as observed in the gas phase: Cl binds inside the CB[5] cavity, Br is observed both inside and outside, and I binds weakly outside. This is reflected in sustained off-resonance irradiation collision-induced dissociation (SORI-CID) experiments: all detected Cl complexes dissociate at higher energies, and Br complexes exhibit unusual bimodal dissociation behavior, with part of the ion population dissociating at very low energies and the remainder dissociating at significantly higher energies comparable to those observed for Cl. Decoherence cross sections measured in SF using cross-sectional areas by Fourier transform ion cyclotron resonance techniques for [CB[5] + MX] (M = Na, X = Cl or Br) are comparable to or less than that of [CB[5] + Na] over a wide energy range, suggesting that Cl or Br in these complexes are bound inside the CB[5] cavity.

Barriers for Extrusion of a Guest from the Interior Binding Cavity of a Host: Gas Phase Experimental and Computational Results for Ion-Capped Decamethylcucurbit[5]uril Complexes.

Factors affecting the extrusion of guests from metal ion-capped decamethylcucurbit[5]uril (mc5) molecular container complexes are investigated using both collision-induced dissociation techniques and molecular mechanics simulations. For guests without polar bonds, the extrusion barrier increases with increasing guest volume. This is likely because escape of larger guests requires more displacement of the metal ion caps and, thus, more disruption of the ion-dipole interactions between the ion caps and the electronegative rim oxygens of mc5.

Quantitative Collision Cross-Sections from FTICR Linewidth Measurements: Improvements in Theory and Experiment.

Two corrections to the equation used in the cross-sectional areas by Fourier transform ion cyclotron resonance ("CRAFTI") technique are identified. In CRAFTI, ion collision cross-sections are obtained from the pressure-dependent ion linewidths in Fourier transform mass spectra. The effects of these corrections on the accuracy of the cross-sections obtained using the CRAFTI technique are evaluated experimentally using the 20 biogenic amino acids and several crown ether complexes with protonated alkyl monoamines.

Collision Cross Sections for 20 Protonated Amino Acids: Fourier Transform Ion Cyclotron Resonance and Ion Mobility Results.

We report relative dephasing cross sections for the 20 biogenic protonated amino acids measured using the cross sectional areas by Fourier transform ion cyclotron resonance (CRAFTI) technique at 1.9 keV in the laboratory reference frame, as well as momentum transfer cross sections for the same ions computed from Boltzmann-weighted structures determined using molecular mechanics. Cross sections generally increase with increasing molecular weight.

Linewidth pressure measurement: a new technique for high vacuum characterization.

Pressure measurement is often the limiting factor in the accuracy of quantitative ion-molecule experiments. We present a new method for pressure measurement based on analysis of pressure-limited Fourier transform ion cyclotron resonance (FTICR) linewidths for well-characterized collisions of Ar(+) with Ar. The kinetic energy dependence of Ar(+)/Ar collision cross sections is well-described using a single-parameter fitting procedure, which results in pressure measurements in good agreement with those from a cold cathode tube and from measurement of total ion signal following electron impact ionization.

Resorcinarene-based cavitands with chiral amino acid substituents for chiral amine recognition.

Resorcinarene-based deep cavitands alanine methyl resorcinarene acid (AMA), alanine undecyl resorcinarene acid (AUA) and glycine undecyl resorcinarene acid (GUA), which contain chiral amino acids, have been synthesized. The upper rim of the resorcinarene host is elongated with four identical substituents topped with alanine and glycine groups. The structures of the new resorcinarenes were elucidated by nuclear magnetic resonance (NMR), mass spectrometry (MS) and the sustained off-resonance irradiation collision induced dissociation (SORI-CID) technique in FTICR-MS.

Collision cross sectional areas from analysis of Fourier transform ion cyclotron resonance line width: a new method for characterizing molecular structure.

We demonstrate a technique for determining molecular collision cross sections via measuring the variation of Fourier transform ion cyclotron resonance (FTICR) line width with background damping gas pressure, under conditions where the length of the FTICR transient is pressure limited. Key features of our method include monoisotopic isolation of ions, the pulsed introduction of damping gas to a constant pressure using a pulsed leak valve, short excitation events to minimize collisions during the excitation, and proper choice of damping gas (Xe is superior to He). The measurements are reproducible within a few percent, which is sufficient for distinguishing between many structural possibilities and is comparable to the uncertainty in cross sections calculated from computed molecular structures.

Influence of charge repulsion on binding strengths: experimental and computational characterization of mixed alkali metal complexes of decamethylcucurbit[5]uril in the gas phase.

Theory and experiment demonstrate that Coulombic repulsion plays a dominant role in the strength of binding a second cation to a rigid, ditopic host.

Supramolecular modification of ion chemistry: modulation of peptide charge state and dissociation behavior through complexation with cucurbit[n]uril (n = 5, 6) or alpha-cyclodextrin.

Electrospray Fourier transform ion cyclotron resonance mass spectrometry, ion mobility spectrometry, and computational methods were utilized to characterize the complexes between lysine or pentalysine with three prototypical host molecules: alpha-cyclodextrin (alpha-CD), cucurbit[5]uril (CB[5]), and cucurbit[6]uril (CB[6]). Ion mobility measurements show lysine forms externally bound, singly charged complexes with either alpha-CD or CB[5], but a doubly charged complex with the lysine side chain threaded through the host cavity of CB[6]. These structural differences result in distinct dissociation behaviors in collision-induced dissociation (CID) experiments: the alpha-CD complex dissociates via the simple loss of intact lysine, whereas the CB[5] complex dissociates to yield [CB[5] + H(3)O](+), and the CB[6] complex loses neutral NH(3) and CO, the product ion remaining a doubly charged complex.

One ring to bind them all: shape-selective complexation of phenylenediamine isomers with cucurbit[6]uril in the gas phase.

We examined complexes between cucurbit[6]uril and each of ortho-, meta-, and para-phenylenediamine using computational methods, Fourier transform ion cyclotron resonance mass spectrometry, and ion mobility spectrometry. These fundamental gas phase studies show that the lowest energy binding sites for ortho- and meta-phenylenediamine are on the exterior of cucurbit[6]uril, whereas para-phenylenediamine preferentially binds in the interior, in a pseudorotaxane fashion. This conclusion is based on reactivity of each of the complexes with tert-butylamine, where the ortho- and meta-phenylenediamine complexes exchange with tert-butylamine, whereas the para-phenylenediamine complex undergoes two slow additions without displacement.

Isotopic compositions and accurate masses of single isotopic peaks.

This paper presents and proves an algorithm to calculate the isotopic composition of individual (nominal) isotopic peaks. From this information one can calculate the accurate masses of isotopic peaks. This opens the way to use accurate mass measurements to determine chemical compositions of compounds using non-mono-isotopic peaks.

Incorporation of a venturi device in electrospray ionization.

Electrospray ionization has grown to be one of the most commonly used ionization techniques for mass spectrometry, and efforts continue to improve its performance. Typically, the sprayer tip must be very close to the entrance orifice of the mass spectrometer in order to maximize the conduction of ions from the sprayer into the mass spectrometer. However, because of space-charge repulsion, most ions never reach the sampling orifice.

Cucurbit[6]uril pseudorotaxanes: distinctive gas-phase dissociation and reactivity.

Cucurbit[6]uril forms a doubly charged complex with 1,4-butanediammonium cation that is observed using electrospray ionization Fourier transform mass spectrometry. Such 1:1 complexes are not observed for the smaller cucurbit[5]uril, which forms a 2:1 ammonium:cucurbituril complex instead. The 1:1 complex with cucurbit[6]uril is difficult to fragment via collisional activation; when it does fragment, both breakup of the cucurbituril cage and loss of the amine are observed.

Study of gas-phase molecular recognition using Fourier transform ion cyclotron resonance mass spectrometry (FTICR/MS).

The application of Fourier transform ion cyclotron resonance (FTICR) mass spectrometry to the quantitative study of molecular recognition in the gas phase is reviewed. Because most quantitative measurements are dependent on accurate determination of the pressure of a neutral reagent, methods for accurate pressure measurement in FTICR, including gauge calibration using a reaction with known rate constants (the traditional method), exothermic proton transfer rate measurement (often the best method when accurate neutral pressures in the trapping cell are desired), and linewidth measurement (a little-used, but generally applicable method) are discussed. The use of rate constant measurements in molecular recognition is illustrated with examples employing natural abundance isotopic labeling to study self-exchange and 2 : 1 ligand:metal complex formation kinetics in crown ether-alkali cation systems.

Gas-Phase studies of valinomycin-alkali metal cation complexes: attachment rates and cation affinities.

Reactions of laser-desorbed Na(+), K(+), Rb(+), and Cs(+) with thermally vaporized valinomycin generate metal-ligand complexes in a Fourier transform ion cyclotron resonance trapping cell, proving that complexes can form via gas-phase ion-molecule reactions. Although desorption of intact pre-formed complexes cannot be ruled out, this route appears minor. Relative rate constants for the complexation reactions show strong dependence on the charge densities of the cations.