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. Cross sections for aliphatic and aromatic protonated amino acids are larger than the average trend, suggesting these side chains do not fold efficiently. Sulfur-containing protonated amino acids have smaller than average cross sections, reflecting the mass of the S atom. Protonated amino acids that can internally hydrogen-bond have smaller than average cross sections, reflecting more extensive folding. The CRAFTI measurements correlate well with results from drift ion mobility (IMS) and traveling wave ion mobility (TWIMS) spectrometric measurements; CRAFTI results correlate with IMS values approximately as well as IMS and TWIMS values from independent measurements correlate with each other. Both CRAFTI and IMS results correlate well with the computed momentum transfer cross sections, suggesting both techniques provide accurate molecular structural information. Absolute values obtained using the various methods differ significantly; in the case of CRAFTI, this may be due to errors in measurements of collision gas pressure, measurement of excitation voltage, and/or dependence of cross sections on kinetic energy.

•Cross sections for ion dephasing can be determined from FTICR line widths.•Cross sections increase with kinetic energy due to collisional dissociation.•N2, Ar, and SF6 are all suitable neutral collision gases.•Dephasing cross sections correlate well with cross sections from ion mobility.•Ar is the preferred collision gas for dephasing cross section measurements.Cross sections for removal of ions, under pressure-limited conditions, from the coherently orbiting ion packet in a Fourier transform ion cyclotron resonance (FTICR) mass spectrometer can be measured by analysis of the FTICR line width as a function of collision gas pressure. We show that the FTICR pressure-limited line width is proportional to the square root of the collision kinetic energy (i.e., directly proportional to the ion velocity) in the center-of-mass reference frame. Cross sections increase with kinetic energy until they approach a high-energy limit, suggesting that collision-induced dissociation contributes significantly to ion dephasing. As the collision gas is varied, the cross sections are inversely proportional to the reduced mass of the collision system, and are also weakly sensitive to the physical size of the neutral collision gas. We show that N2, Ar, and SF6 are all suitable collision gases for these experiments. Analytical discrimination (the ability to detect small differences in cross sections) is greatest for the lighter collision gases, but the ease of reaching high kinetic energies in the center-of-mass reference frame increases with collision gas mass. Under the conditions of our instrument and experiments, Ar is the preferred collision gas.

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. The new method avoids problems inherent in ionization-based methods, such as those arising from differences in ionization potential or perturbations to the pressure that occur during electron ionization of the gas to be measured, and should be applicable in the trapping cells of FTICR and Orbitrap mass spectrometers.

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. These techniques complement drift ion mobility measurements obtained on dedicated instruments. They do not require a specialized instrument, but should be easily performed on any FTICR mass spectrometer equipped with a pulsed leak valve.

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

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. Further, under sustained off-resonance irradiation conditions, the ortho- and meta-phenylenediamine complexes fragment easily via losses of neutral phenylenediamine, whereas the para-phenylenediamine complex fragments at higher energies primarily via cleavage of covalent bonds in the cucurbituril. Finally, ion mobility studies show ion populations for the ortho- and meta-phenylenediamine complexes that primarily have collision cross sections consistent with external complexation, whereas the para-phenylenediamine complex has a collision cross section that is smaller, the same as that of protonated cucurbit[6]uril within experimental error. In agreement with experiment, computational studies indicate that at the HF/6-31G* and B3LYP/6-31G*//HF/6-31G* levels of theory external complexation is favored for ortho- and meta-phenylenediamine, whereas internal complexation is lower in energy for para-phenylenediamine. In contrast, MP2/6-31G*//HF-6-31G* calculations predict internal complexation for all three isomers.

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: α-cyclodextrin (α-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 α-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 α-CD complex dissociates via the simple loss of intact lysine, whereas the CB[5] complex dissociates to yield [CB[5] + H3O]+, and the CB[6] complex loses neutral NH3 and CO, the product ion remaining a doubly charged complex. These results are consistent with B3LYP/6−31G* binding energies (kJ mol−1) of D(Lys + H+−α−CD) = 281, D(Lys + H+−CB[5]) = 327, and D(Lys + 2H2+−CB[6]) = 600. B3LYP/6−31G* geometry optimizations show complexation with α-CD stabilizes the salt bridge form of protonated lysine, whereas complexation with CB[6] stabilizes doubly protonated lysine. Complexation of the larger polypeptide pentalysine with α-CD forms a nonspecific adduct: no modification of the pentalysine charge state distribution is observed, and dissociation occurs via the simple loss of α-CD. Complexation of pentalysine with the cucurbiturils is more specific: the observed charge state distribution shifts higher on complexation, and fragmentation patterns are significantly altered relative to uncomplexed pentalysine: C-terminal fragment ions appear that are consistent with charge stabilization by the cucurbiturils, and the cucurbiturils are retained on the fragment ions. Molecular mechanics calculations suggest CB[5] binds to two protonated sites on pentalysine without threading onto the peptide and that CB[6] binds two adjacent protonated sites via threading onto the peptide.

Sonic spray ionization mass spectrometry (SSI MS) is shown to be effective in characterizing metal-assembled cage structures that are not observed using conventional electrospray ionization mass spectrometry (ESI MS) techniques. A palladium-assembled resorcinarene-based cage containing nitrile ligands and a palladium(II) triazine cage were characterized and their +1 molecular ion peaks were observed using this method. An N,N-bis(pyridylmethyl)amine resorcinarene cavitand–metal ion complex was observed to yield peaks corresponding to open tetranuclear complexes and closed cage complexes depending on the metal ion. Molecular ion peaks for these complexes were not detected when ESI MS was used. The soft ionization inherent in SSI MS coupled with its relatively simple design provides a powerful tool to characterize such supramolecular assemblies, which are of current interest.

Natural abundance isotopic labeling has been employed to study the reactions of labeled LM+ complexes with L (L = triglyme, TG; 12-crown-4, C4; 15-crown-5, C5; 18-crown-6, C6; or 21-crown-7, C7; M = Li, Na, K, Rb, or Cs) in the gas phase using Fourier transform ion cyclotron resonance mass spectrometry. Reaction efficiencies for both ligand exchange and the formation of 2:1 ligand:metal “sandwich” complexes were determined. For a given ligand, self-exchange rates generally decrease with increasing metal size, while the sandwich complex formation rates show strong dependence on the relative sizes of the metal ions and ligand cavities. Acyclic TG complexes undergo self-exchange more rapidly than the analogous cyclic C4 complexes, whereas the sandwich complex formation rates are faster for the C4 complexes. Sandwich formation rates show a weak positive pressure dependence, as increased pressure leads to increased collisional stabilization of the complexes. Extrapolation of the rates to the zero pressure limits still yields significant rates, reflecting radiative stabilization. The self-exchange reactions have weak, negative pressure dependences, suggesting they are in direct competition with sandwich complex formation. Analysis of the sandwich complex formation radiative association kinetics yields estimates of binding enthalpies for attachment of the second ligand. Trends in the binding enthalpies, like the kinetics, show strong dependence on the relative sizes of the metal ions and ligand cavities. For a given metal, binding of a second TG is weaker than binding of a second C4. Binding enthalpies for the second ligand are in every case substantially less than calculated binding enthalpies for the first ligand to attach to a given metal.

In an effort to shed light on the factors that influence the recognition of alkaline earth cations in natural systems, we have studied intrinsic recognition of these cations by well-ordered synthetic ionophores such as crown ethers (12-crown-4 [C4] and 18-crown-6 [C6]) as well as the acyclic analog of C4, triglyme (TG), in the gas phase. We have employed electrospray ionization (ESI) to generate gas phase crown and glyme alkaline earth complexes, and have used Fourier transform ion cyclotron resonance mass spectrometry to measure rate constants for displacement of the original ligands by C6. ESI of mixtures of C4 and TG with alkaline earths primarily produces sandwich complexes of the doubly charged cations, (C4)2M2+, (C4)(TG)M2+, and (TG)2M2+. We find that the ligand exchange reactions are generally very efficient, with rates approaching or exceeding the Langevin collision rate in most cases. Trends in rates as metal size varies can be understood in terms of the degree of encapsulation of the metal by the ligands when the coordination shell is partially filled (smaller metals are more thoroughly encapsulated and tend to react more slowly) and in terms of the polarizing power of the metal cation when the metals are either “bare” or completely coordinated (smaller metals have greater charge density and tend to react more rapidly). Efficiencies for most of the reactions studied fall off in the order Mg2+ > Ca2+ > Sr2+ > Ba2+, consistent with decreasing charge density as the cation radius increases. Interestingly, TG is displaced more efficiently than C4 by C6, despite the fact that the total binding energy of the glyme is greater than that of the crown. This is consistent with a mechanism wherein the rate-limiting step involves breaking O–M2+ electrostatic bonds, and where the bonds to the oxygens of TG can be broken one at a time, whereas the more rigid ring structure of C4 requires concerted breaking of multiple bonds. Molecular dynamics simulations of this process for complexes where M2+ = Ca2+ give support to this interpretation: in all observed dissociation events, TG oxygens were removed from the metal one at a time, whereas displacement of C4 oxygens occurred in pairs.

The utility of fast atom bombardment (FAB) ionization on a sector mass spectrometer, and of electrospray ionization (ESI) on a Fourier transform ion cyclotron resonance mass spectrometer, for enantiomeric excess measurements was explored. Both methods involved the same host–guest system: (R,R)- or (S,S)-dimethyldiketopyridino-18-crown-6 (host) and α-(1-naphthyl)ethylammonium (guest). Both use an achiral amine (benzylamine for the FAB experiments, cyclohexylamine for the ESI experiments) as an internal reference compound and involve competitive complexation of the achiral and chiral amines with the chiral host. The FAB experiments are shown to give stable, reproducible results, but exhibit a smaller degree of enantiodiscrimination than the ESI experiments. The ESI experiments, which involve measurement of apparent guest exchange equilibrium constants, show a linear relationship between apparent equilibrium constant and enantiomeric excess. The apparent equilibrium constant is shown to be a composition-weighted average of the equilibrium constants for the two pure enantiomers. Enantiomeric impurities as small as about 2% can currently be detected.

Cyclodextrins (CDs) are cyclic oligosaccharides composed of 6, 7, or 8 glucose molecules (α-, β-, or γ-cyclodextrin, respectively) which are used widely in industry due to their ability to form inclusion complexes with a variety of molecules in aqueous solution. Much speculation has been made as to whether inclusion complexes form as a result of hydrophobic interactions between guest molecules and the inner hydrophobic cavity of the CDs in water. Fourier transform ion cyclotron resonance (FTICR) mass spectrometry was used to study adducts of cyclodextrins with various amines in the gas phase. Protonated cyclodextrins were generated using electrospray ionization, and were allowed to react with neutral amines. Adducts of each amine studied were observed to form with all three cyclodextrins. Equilibrium constants were measured for the exchange of neutral amines on protonated CD molecules. Size and shape dependent trends, especially with bulkier amines, suggest inclusion complex formation. Molecular modeling studies also support the formation of inclusion complexes rather than nonspecific adducts, and suggest that solvation of the charged guest by the CD host provides a large driving force for the formation of inclusion complexes, which are then stabilized by van der Waals interactions between the host and the guest. A second series of experiments was performed using gas phase hydrogen/deuterium exchange of protonated cyclodextrins and cyclodextrin–amine complexes with D2O. The protonated cyclodextrins have a rapid rate of exchange that slows by more than a factor of 10 when an amino guest is added. The amino groups of the guests are expected to have significantly higher gas phase basicities than the hydroxyl sites on the cyclodextrins or the deuterating agent, accounting for the observed decrease in exchange rates for cyclodextrin–amine complexes. Observed differences in the α- versus β- versus γ-cyclodextrin exchange rates suggest an exchange mechanism dependent upon the size of the cyclodextrin ring and its gas phase conformation.

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