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A detailed understanding of the reaction mechanism(s) leading to stereoselective product formation is crucial to understanding and predicting product formation and driving the development of new synthetic methodology. One way to improve our understanding of reaction mechanisms is to characterize the reaction intermediates involved in product formation. Because these intermediates are reactive, they are often unstable and therefore difficult to characterize using experimental techniques. For example, glycosylation reactions are critical steps in the chemical synthesis of oligosaccharides and need to be stereoselective to provide the desired α- or β-diastereomer. It remains challenging to predict and control the stereochemical outcome of glycosylation reactions, and their reaction mechanisms remain a hotly debated topic. In most cases, glycosylation reactions take place via reaction mechanisms in the continuum between S

Hyperprolinemia type II (HPII) is an inborn error of metabolism due to genetic variants in ALDH4A1, leading to a deficiency in Δ-1-pyrroline-5-carboxylate (P5C) dehydrogenase. This leads to an accumulation of toxic levels of P5C, an intermediate in proline catabolism. The accumulating P5C spontaneously reacts with, and inactivates, pyridoxal 5’-phosphate, a crucial cofactor for many enzymatic processes, which is thought to be the pathophysiological mechanism for HPII. Here, we describe the use of a combination of LC-QTOF untargeted metabolomics, NMR spectroscopy and infrared ion spectroscopy (IRIS) to identify and characterize biomarkers for HPII that result of the spontaneous reaction of P5C with malonic acid and acetoacetic acid. We show that these biomarkers can differentiate between HPI, caused by a deficiency of proline oxidase activity, and HPII. The elucidation of their molecular structures yields insights into the disease pathophysiology of HPII.

N- Acyliminium ions are highly reactive intermediates that are important for creating CC-bonds adjacent to nitrogen atoms. Here we report the characterization of cyclic N -acyliminium ions in the gas phase, generated by collision induced dissociation tandem mass spectrometry followed by infrared ion spectroscopy using the FELIX infrared free electron laser. Comparison of the DFT calculated spectra with the experimentally observed IR spectra provided valuable insights in the conformations of the N -acyliminium ions.

Infrared ion spectroscopy is increasingly recognized as a method to identify mass spectrometry-detected analytes in many (bio)chemical areas and its integration in analytical laboratories is now on the horizon. Commercially available quadrupole ion trap mass spectrometers are attractive ion spectroscopy platforms but operate at relatively high pressures. This promotes collisional deactivation which directly interferes with the multiple-photon excitation process required for ion spectroscopy. To overcome this, infrared lasers having a high instantaneous power are required and therefore a majority of analytical studies have been performed at infrared free electron laser facilities. Proliferation of the technique to routine use in analytical laboratories requires table-top infrared lasers and optical parametric oscillators (OPOs) are the most suitable candidates, offering both relatively high intensities and reasonable spectral tuning ranges. Here, we explore the potential of a range of commercially available high-power OPOs for ion spectroscopy, comparing systems with repetition rates of 10 Hz, 20 kHz, 80 MHz and a continuous-wave (cw) system. We compare the performance for various molecular ions and show that the kHz and MHz repetition-rate systems outperform cw and 10 Hz systems in photodissociation efficiency and offer several advantages in terms of cost-effectiveness and practical implementation in an analytical laboratory not specialized in laser spectroscopy., Evaluation of four table-top IR lasers for ion spectroscopy in ion trap mass spectrometers shows high rep-rate lasers offer better photodissociation efficiency and are more cost-effective and practical compared to low rep-rate or cw alternatives.

We used next-generation metabolic screening to identify new biomarkers for improved diagnosis and pathophysiological understanding of glucose transporter type 1 deficiency syndrome (GLUT1DS), comparing metabolic cerebrospinal fluid (CSF) profiles from 12 patients to those of 116 controls. This confirmed decreased CSF glucose and lactate levels in patients with GLUT1DS and increased glutamine at group level. We identified three novel biomarkers significantly decreased in patients, namely gluconic + galactonic acid, xylose-α1-3- glucose, and xylose-α1-3-xylose-α1-3- glucose, of which the latter two have not previously been identified in body fluids. CSF concentrations of gluconic + galactonic acid may be reduced as these metabolites could serve as alternative substrates for the pentose phosphate pathway. Xylose-α1-3-glucose and xylose-α1-3- xylose-α1-3-glucose may originate from glycosylated proteins ; their decreased levels are hypothetically the consequence of insufficient glucose, one of two substrates for O- glucosylation. Since many proteins are O- glucosylated, this deficiency may affect cellular processes and thus contribute to GLUT1DS pathophysiology. The novel CSF biomarkers have the potential to improve the biochemical diagnosis of GLUT1DS. Our findings imply that brain glucose deficiency in GLUT1DS may cause disruptions at the cellular level that go beyond energy metabolism, underlining the importance of developing treatment strategies that directly target cerebral glucose uptake.

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The interaction of organic molecules with oxonium cations within their solvation shell may lead to the emergence of dynamic supramolecular structures with recurrently changing host–guest chemical identity. We illustrate this phenomenon in benchmark proton-bonded complexes of water with polyether macrocyles. Despite the smaller proton affinity of water versus the ether group, water in fact retains the proton in the form of H3O+, with increasing stability as the coordination number increases. Hindrance in many-fold coordination induces dynamic reversible (ether)·H3O+ ⇌ (etherH+)·H2O interconversion. We perform infrared action ion spectroscopy over a broad spectral range to expose the vibrational signatures of the loose proton bonding in these systems. Remarkably, characteristic bands for the two limiting proton bonding configurations are observed in the experimental vibrational spectra, superimposed onto diffuse bands associated with proton delocalization. These features cannot be described by static equilibrium structures but are accurately modeled within the framework of ab initio molecular dynamics., Area of Physical Chemistry

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Uronic acids are carbohydrates carrying a terminal carboxylic acid and have a unique reactivity in stereoselective glycosylation reactions. Herein, the competing intramolecular stabilization of uronic acid cations by the C-5 carboxylic acid or the C-4 acetyl group was studied with infrared ion spectroscopy (IRIS). IRIS reveals that a mixture of bridged ions is formed, in which the mixture is driven towards the C-1,C-5 dioxolanium ion when the C-5,C-2-relationship is cis, and towards the formation of the C-1,C-4 dioxepanium ion when this relation is trans. Isomer-population analysis and interconversion barrier computations show that the two bridged structures are not in dynamic equilibrium and that their ratio parallels the density functional theory computed stability of the structures. These studies reveal how the intrinsic interplay of the different functional groups influences the formation of the different regioisomeric products.

Breslow intermediates (BIs) are the crucial nucleophilic amino enol intermediates formed from electrophilic aldehydes in the course of N‐heterocyclic carbene (NHC)‐catalyzed umpolung reactions. Both in organocatalytic and enzymatic umpolung, the question whether the Breslow intermediate exists as the nucleophilic enol or in the form of its electrophilic keto tautomer is of utmost importance for its reactivity and function. Herein, the preparation of charge‐tagged Breslow intermediates/keto tautomers derived from three different types of NHCs (imidazolidin‐2‐ylidenes, 1,2,4‐triazolin‐5‐ylidenes, thiazolin‐2‐ylidenes) and aldehydes is reported. An ammonium charge tag is introduced through the aldehyde unit or the NHC. ESI‐MS IR ion spectroscopy allowed the unambiguous conclusion that in the gas phase, the imidazolidin‐2‐ylidene‐derived BI indeed exists as a diamino enol, while both 1,2,4‐triazolin‐5‐ylidenes and thiazolin‐2‐ylidenes give the keto tautomer. This result coincides with the tautomeric states observed for the BIs in solution (NMR) and in the crystalline state (XRD), and is in line with our earlier calculations on the energetics of BI keto–enol equilibria., Breslow intermediates in the gas phase: In N‐heterocyclic carbene (NHC)‐catalyzed Umpolung, the reaction of the substrate aldehyde with the NHC gives the Breslow intermediate (BI) as pivotal species. The combination of IR ion spectroscopy with quantum chemical computations can determine whether the BI exists as a nucleophilic amino enol or as its keto tautomer in the gas phase, which is decisive for its reactivity both in enzymatic catalysis and in organocatalysis.

Deamidation of asparaginyl (Asn) peptides is a spontaneous post-translational modification that plays a significant role in degenerative diseases and other biological processes under physiological conditions. In the gas phase, deamidation of protonated peptides is a major fragmentation channel upon activation by collision-induced dissociation. Here, we present a full description of the deamidation process from protonated asparagine-serine, [AsnSer+H]+, -via infrared (IR) action spectroscopy and threshold collision-induced dissociation (TCID) experiments in combination with theoretical calculations. The IR results demonstrate that deamidation proceeds via bifurcating reaction pathways leading to furanone- and succinimide-type product ion structures, with a population analysis indicating the latter product dominates. Theory demonstrates that nucleophilic attack of the peptidyl amide oxygen onto the Asn side chain leads to furanone formation, whereas nudeophilic attack by the peptidyl amide nitrogen onto the Asn side-chain carbonyl carbon leads to the formation of the succinimide product structure. TCID experiments find that furanone formation has a threshold energy of 145 +/- 12 kJ/mol and succinimide formation occurs with a threshold energy of 131 +/- 12 kJ/mol, consistent with theoretical energies and with the spectroscopic results indicating that succinimide dominates. The results provide information regarding the inductive and steric effects of the Ser side chain on the deamidation process. The other major channel observed in the TCID experiments of [AsnSer+H]+ is dehydration, where a threshold energy of 104 +/- 10 kJ/mol is determined. A complete IR and theoretical analysis of this pathway is also provided. As for deamidation, a bifurcating pathway is found with both dominant oxazoline and minor diketopiperazine products identified. Here, the Ser side chain is directly involved in both pathways.

Brown carbon (BrC) organic molecules absorb solar radiation in the visible range and thus can influence the optical properties of atmospheric aerosol particles and cloud droplets. The absorption pr...

Untargeted liquid chromatography-mass spectrometry (LC-MS)-based metabolomics strategies are being increasingly applied in metabolite screening for a wide variety of medical conditions. The long-standing "grand challenge" in the utilization of this approach is metabolite identification-confidently determining the chemical structures of m/z-detected unknowns. Here, we use a novel workflow based on the detection of molecular features of interest by high-throughput untargeted LC-MS analysis of patient body fluids combined with targeted molecular identification of those features using infrared ion spectroscopy (IRIS), effectively providing diagnostic IR fingerprints for mass-isolated targets. A significant advantage of this approach is that in silico-predicted IR spectra of candidate chemical structures can be used to suggest the molecular structure of unknown features, thus mitigating the need for the synthesis of a broad range of physical reference standards. Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is an inborn error of lysine metabolism, resulting from a mutation in the ALDH7A1 gene that leads to an accumulation of toxic levels of alpha-aminoadipic semialdehyde (alpha-AASA), piperideine-6-carboxylate (P6C), and pipecolic acid in body fluids. While alpha-AASA and P6C are known biomarkers for PDE in urine, their instability makes them poor candidates for diagnostic analysis from blood, which would be required for application in newborn screening protocols. Here, we use combined untargeted metabolomics-IRIS to identify several new biomarkers for PDE-ALDH7A1 that can be used for diagnostic analysis in urine, plasma, and cerebrospinal fluids and that are compatible with analysis in dried blood spots for newborn screening. The identification of these novel metabolites has directly provided novel insights into the pathophysiology of PDE-ALDH7A1.

The product of a revealed transformation-NHC-ethynyl coupling-was observed as a catalyst transformation pathway in the Sonogashira cross-coupling, catalyzed by Pd/NHC complexes. The 2-ethynylated azolium salt was isolated in individual form and fully characterized, including X-ray analysis. A number of possible intermediates of this transformation with common formulae (NHC)n Pd(C2 Ph) (n=1,2) were observed and subjected to collision-induced dissociation (CID) and infrared multiphoton dissociation (IRMPD) experiments to elucidate their structure. Measured bond dissociation energies (BDEs) and IRMPD spectra were in an excellent agreement with quantum calculations for coupling product π-complexes with Pd0 . Molecular dynamics simulations confirmed the observed multiple CID fragmentation pathways. An unconventional methodology to study catalyst evolution suggests the reported transformation to be considered in the development of new catalytic systems for alkyne functionalization reactions.

Experimental IR spectra in the 500-1850 cm-1 fingerprint frequency range are presented for the isolated, gaseous redox pair ions [Ru(bpy)3]2+, and [Ru(bpy)3]+, where bpy = 2,2'-bipyridine. Spectra are obtained using the FELIX free-electron laser and a quadrupole ion trap mass spectrometer. The 2+ complex is generated by electrospray ionization and the charge-reduced radical cation is produced by gas-phase one-electron reduction in an ion-ion reaction with the fluoranthene radical anion. Experimental spectra are compared against computed spectra predicted by density functional theory (DFT) using different levels of theory. For the closed-shell [Ru(bpy)3]2+ ion, the match between experimental and computed IR spectra is very good; however, this is not the case for the charge-reduced [Ru(bpy)3]+ ion, which demands additional theoretical investigation. When using the hybrid B3LYP functional, we observe that better agreement with experiment is obtained upon reduction of the Hartree-Fock exact-exchange contribution from 204 calculations using the M06 functional appear to be promising in terms of the prediction of IR spectra; however, it is unclear if the correct electronic structure is obtained. The M06 and B3LYP functionals indicate that the added electron in [Ru(bpy)3)]+ is delocalized over the three bpy ligands, while the long-range corrected LC-BLYP and the CAM-B3LYP functionals show it to be more localized on a single bpy ligand. Although these latter levels of theory fail to reproduce the experimentally observed IR frequencies, one may argue that the unusually large bandwidths observed in the spectrum are due to the fluxional character of a complex with the added electron not symmetrically distributed over the ligands. The experimental IR spectra presented here can serve as benchmark for further theoretical investigations.

Unidirectional double-hydrogen (2H) and triple-hydrogen (3H) rearrangement reactions occur upon electron-ionization-induced fragmentation of trans-2-(4-N,N-dimethylaminobenzyl)-1-indanol (1), trans-2-(4-methoxybenzyl)-1-indanol (2), 4-(4-N,N-dimethylaminophenyl)-2-butanol (3), and related compounds, as reported some 35 years ago (Kuck, D.; Filges, U. Org. Mass Spectrom. 1988, 23, 643-653). These unusual intramolecular redox processes were found to dominate the mass spectra of long-lived, metastable ions. The present report provides independent evidence for the structures of the product ions formed by the 2H and 3H rearrangement in an ion trap instrument. The radical cations 1+ and 3+ as well as ionized 1-(4-N,N-dimethylaminophenyl)-5-(4-methoxyphenyl)-3-pentanol, 5+, were generated by electrospray ionization from anhydrous acetonitrile solutions. The 2H and 3H fragment ions were obtained by collision-induced dissociation and characterized by IR ion spectroscopy and density functional theory calculations. Comparison of the experimental and calculated infrared ion spectra enabled the identification of the 2H rearrangement product ion, C9H14N+ (m/z 136), as an N,N-dimethyl-para-toluidinium ion bearing the extra proton ortho to the amino group, a tautomer which was calculated to be 31 kJ/mol less stable than the corresponding N-protonated form. The 3H rearrangement product ion, C8H13N+ (m/z 123), formerly assumed to be a distonic ammonium ion bearing a cyclohexadienyl radical, was now identified as a conventional radical cation, ionized N,N-dimethyl-2,3-dihydro-para-toluidine. Thus, the 3H rearrangement represents an intramolecular transfer hydrogenation between a secondary alcohol and an ionized aromatic ring. Based on these structural assignments, more detailed mechanisms for the unidirectional 2H and 3H rearrangement reactions are proposed.

We present the first experimental vibrational spectra of gaseous oxidized derivatives of C60 in protonated and radical cation forms, obtained through infrared multiple-photon dissociation spectroscopy using the FELIX free-electron laser. Neutral C60O has two nearly iso-energetic isomers: the epoxide isomer in which the O atom bridges a CC bond that connects two six-membered rings and the annulene isomer in which the O atom inserts into a CC bond connecting a five- and a six-membered ring. To determine the isomer formed for C60O+ in our experiment a question that cannot be confidently answered on the basis of the DFT-computed stabilities alone we compare our experimental IR spectra to vibrational spectra predicted by DFT calculations. We conclude that the annulene-like isomer is formed in our experiment. For C60OH+, a strong OH stretch vibration observed in the 3 μm range of the spectrum immediately reveals its structure as C60 with a hydroxyl group attached, which is further confirmed by the spectrum in the 400-1600 cm-1 range. We compare the experimental spectra of C60O+ and C60OH+ to the astronomical IR emission spectrum of a fullerene-rich planetary nebula and discuss their astrophysical relevance.

The stereoselective introduction of glycosidic bonds is of paramount importance to oligosaccharide synthesis. Among the various chemical strategies to steer stereoselectivity, participation by either neighboring or distal acyl groups is used particularly often. Recently, the use of the 2,2-dimethyl-2-(ortho-nitrophenyl)acetyl (DMNPA) protection group was shown to offer enhanced stereoselective steering compared to other acyl groups. Here, we investigate the origin of the stereoselectivity induced by the DMNPA group through systematic glycosylation reactions and infrared ion spectroscopy (IRIS) combined with techniques such as isotopic labeling of the anomeric center and isomer population analysis. Our study indicates that the origin of the DMNPA stereoselectivity does not lie in the direct participation of the nitro moiety but in the formation of a dioxolenium ion that is strongly stabilized by the nitro group.

Contains fulltext : 237516.pdf (Publisher’s version ) (Open Access) BackgroundPyridoxine-dependent epilepsy (PDE-ALDH7A1) is an inborn error of lysine catabolism that presents with refractory epilepsy in newborns. Biallelic ALDH7A1 variants lead to deficiency of α-aminoadipic semialdehyde dehydrogenase/antiquitin, resulting in accumulation of piperideine-6-carboxylate (P6C), and secondary deficiency of the important cofactor pyridoxal-5'-phosphate (PLP, active vitamin B6) through its complexation with P6C. Vitamin B6 supplementation resolves epilepsy in patients, but intellectual disability may still develop. Early diagnosis and treatment, preferably based on newborn screening, could optimize long-term clinical outcome. However, no suitable PDE-ALDH7A1 newborn screening biomarkers are currently available.MethodsWe combined the innovative analytical methods untargeted metabolomics and infrared ion spectroscopy to discover and identify biomarkers in plasma that would allow for PDE-ALDH7A1 diagnosis in newborn screening.ResultsWe identified 2S,6S-/2S,6R-oxopropylpiperidine-2-carboxylic acid (2-OPP) as a PDE-ALDH7A1 biomarker, and confirmed 6-oxopiperidine-2-carboxylic acid (6-oxoPIP) as a biomarker. The suitability of 2-OPP as a potential PDE-ALDH7A1 newborn screening biomarker in dried bloodspots was shown. Additionally, we found that 2-OPP accumulates in brain tissue of patients and Aldh7a1-knockout mice, and induced epilepsy-like behavior in a zebrafish model system.ConclusionThis study has opened the way to newborn screening for PDE-ALDH7A1. We speculate that 2-OPP may contribute to ongoing neurotoxicity, also in treated PDE-ALDH7A1 patients. As 2-OPP formation appears to increase upon ketosis, we emphasize the importance of avoiding catabolism in PDE-ALDH7A1 patients.FundingSociety for Inborn Errors of Metabolism for Netherlands and Belgium (ESN), United for Metabolic Diseases (UMD), Stofwisselkracht, Radboud University, Canadian Institutes of Health Research, Dutch Research Council (NWO), and the European Research Council (ERC).

Distinguishing positional isomers, such as compounds having different substitution patterns on an aromatic ring, presents a significant challenge for mass spectrometric analyses and is a frequently encountered difficulty in, for example, drug metabolism research. Here, we demonstrate infrared ion spectroscopy (IRIS) as a promising new mass spectrometry-based technique that easily differentiates between positional isomers of disubstituted phenyl-containing compounds. By analyzing different substitution patterns over several sets of isomeric compounds, we show that IRIS produces a highly consistent and distinct pattern of IR bands, especially in the range between 650 and 900 cm-1, that are mostly independent of the specific chemical functionality contained in the substituent group. These patterns are accurately predicted by quantum-chemically computed IR spectra and correspond well with tabulated IR group-frequencies known from conventional absorption spectroscopy. Therefore, we foresee that this method will be generally applicable to disubstituted phenyl-containing compounds and that direct interpretation of experimental IRIS spectra in terms of ortho-, meta- or para-substitution is possible, even without comparison to experimental or computationally predicted reference spectra. Strategies for the analysis of larger compounds having more congested IR spectra as well as of compounds having low (electrospray) ionization efficiencies are presented in order to demonstrate the broad applicability of this methodology.

Microspheres containing radioactive 166holmium-acetylacetonate are employed in emerging radionuclide therapies for the treatment of malignancies. At the molecular level, details on the coordination geometries of the Ho complexes are however elusive. Infrared ion spectroscopy (IRIS) was used to characterize several 165Ho-acetylacetonate complexes derived from non-radioactive microspheres. The coordination geometry of four distinct ionic complexes were fully assigned by comparison of their measured IR spectra with spectra calculated at the density functional theory (DFT) level. The coordination of each acetylacetonate ligand is dependent on the presence of other ligands, revealing an asymmetric chelation motif in some of the complexes. A fifth, previously unknown constituent of the microspheres was identified as a coordination complex containing an acetic acid ligand. These results pave the way for IRIS-based identification of microsphere constituents upon neutron activation of the metal center.

Liquid chromatography-mass spectrometry (LC-MS) is, due to its high sensitivity and selectivity, currently the method of choice in (bio)analytical studies involving the (comprehensive) profiling of metabolites in body fluids. However, as closely related isomers are often hard to distinguish on the basis of LC-MS(MS) and identification is often dependent on the availability of reference standards, the identification of the chemical structures of detected mass spectral features remains the primary limitation. Infrared ion spectroscopy (IRIS) aids identification of MS-detected ions by providing an infrared (IR) spectrum containing structural information for a detected MS-feature. Moreover, IR spectra can be routinely and reliably predicted for many types of molecular structures using quantum-chemical calculations, potentially avoiding the need for reference standards. In this work, we demonstrate a workflow for reference-free metabolite identification that combines experiments based on high-pressure liquid chromatography (HPLC), MS and IRIS with quantum-chemical calculations that efficiently generate IR spectra and give the potential to enable reference-standard free metabolite identification. Additionally, a scoring procedure is employed which shows the potential for automated structure assignment of unknowns. Via a simple, illustrative example where we identify lysine in the plasma of a hyperlysinemia patient, we show that this approach allows the efficient assignment of a database-derived molecular structure to an unknown.

Infrared multiple photon dissociation action spectroscopy was performed on the AlaOrn b(2)(+) and AlaAlaOrn b(3)(+) fragment ions from ornithine-containing tetrapeptides. Infrared spectra were obtained in the fingerprint region (1000 – 2000 cm(−1)) using the infrared free electron lasers at the Centre Laser Infrarouge d’Orsay (CLIO) facility in Orsay, France and the Free Electron Lasers for Infrared eXperiments (FELIX) facility in Nijmegen, the Netherlands. A novel terminal ornithine lactam AO(+) b2(+) structure was synthesized for experimental comparison and spectroscopy confirms that the b2(+) fragment ion from AOAA forms a lactam structure. Comparison of experimental spectra with scaled harmonic frequencies at the B3LYP/6-31+G(d,p) level of theory shows that AO(+) b(2)(+) forms a terminal lactam protonated either on the lactam carbonyl oxygen or the N-terminal nitrogen atom. Several low-lying conformers of these isomers are likely populated following IRMPD dissociation. Similarly, a comparison of the experimental IRMPD spectrum with calculated spectra shows that AAO(+) b(3)(+)-ions also adopt a lactam structure, again with multiple different protonation sites, during fragmentation. This study provides spectroscopic confirmation for the lactam cyclization proposed for the “ornithine effect” and represents an alternative b(n)(+) structure to the oxazolone and diketopiperazine/macrocycle structures most often formed.

Uronic acids are important constituents of polysaccharides found on the cell membranes of different organisms. To prepare uronic-acid-containing oligosaccharides, uronic acid 6,3-lactones can be employed as they display a fixed conformation and a unique reactivity and stereoselectivity. Herein, we report a highly β-selective and efficient mannosyl donor based on C-4 acetyl mannuronic acid 6,3-lactone donors. The mechanism of glycosylation is established using a combination of techniques, including infrared ion spectroscopy combined with quantum-chemical calculations and variable-temperature nuclear magnetic resonance (VT NMR) spectroscopy. The role of these intermediates in glycosylation is assayed by varying the activation protocol and acceptor nucleophilicity. The observed trends are analogous to the well-studied 4,6-benzylidene glycosides and may be used to guide the development of next-generation stereoselective glycosyl donors.

Electrospray ionization was used to generate species such as [ZnNO3(CH3OH)2]+ from Zn(NO3)2•XH2O dissolved in a mixture of CH3OH and H2O. Collision-induced dissociation of [ZnNO3(CH3OH)2]+ causes elimination of CH3OH to form [ZnNO3(CH3OH)]+. Subsequent collision-induced dissociation of [ZnNO3(CH3OH)]+ causes elimination of 47 mass units (u), consistent with ejection of HNO2. The neutral loss shifts to 48 u for collision-induced dissociation of [ZnNO3(CD3OH)]+, demonstrating the ejection of HNO2 involves intra-complex transfer of H from the methyl group methanol ligand. Subsequent collision-induced dissociation causes the elimination of 30 u (32 u for the complex with CD3OH), suggesting the elimination of formaldehyde (CH2 = O). The product ion is [ZnOH]+. Collision-induced dissociation of a precursor complex created using CH3-18OH shows the isotope label is retained in CH2 = O. Density functional theory calculations suggested that the “rearranged” product, ZnOH with bound HNO2 and formaldehyde is significantly lower in energy than ZnNO3 with bound methanol. We therefore used infrared multiple-photon photodissociation spectroscopy to determine the structures of both [ZnNO3(CH3OH)2]+ and [ZnNO3(CH3OH)]+. The infrared spectra clearly show that both ions contain intact nitrate and methanol ligands, which suggests that rearrangement occurs during collision-induced dissociation of [ZnNO3(CH3OH)]+. Based on the density functional theory calculations, we propose that transfer of H, from the methyl group of the CH3OH ligand to nitrate, occurs in concert with the formation of a Zn–C bond. After dissociation to release HNO2, the product rearranges with the insertion of the remaining O atom into the Zn–C bond. Subsequent C–O bond cleavage, with H transfer, produces an ion–molecule complex composed of [ZnOH]+ and O = CH2.

The gas-phase structures of protonated unsymmetrical 1,1-dimethylhydrazine (UDMH) and the proton-bound dimers of UDMH and hydrazine are examined by infrared multiple photon dissociation (IRMPD) action spectroscopy utilizing light generated by a free electron laser and an optical parametric oscillator laser system. To identify the structures present in the experimental studies, the measured IRMPD spectra are compared to spectra calculated at the B3LYP-GD3BJ/6-311+G(d,p) level of theory. These comparisons show that protonated UDMH binds the proton at the methylated nitrogen atom (α) with two low-lying α conformers probably being populated. For (UDMH)2H+, the proton is shared between the methylated nitrogen atoms with several low-lying α conformers likely to be populated. Higher-lying conformers of (UDMH)2H+ in which the proton is shared between α and β (unmethylated) nitrogen atoms cannot be ruled out on the basis of the IRPMD spectrum. For (N2H4)2H+, there are four low-lying conformers that all reproduce the IRMPD spectrum reasonably well. As hydrazine and UDMH see usage as fuels for rocket engines, such spectra are potentially useful as a means of remotely monitoring rocket launches, especially in cases of unsuccessful launches where environmental hazards need to be assessed.

The identification of disease biomarkers plays a crucial role in developing diagnostic strategies for inborn errors of metabolism and understanding their pathophysiology. A primary metabolite that accumulates in the inborn error phenylketonuria is phenylalanine, however its levels do not always directly correlate with clinical outcomes. Here we combine infrared ion spectroscopy and NMR spectroscopy to identify the Phe-glucose Amadori rearrangement product as a biomarker for phenylketonuria. Additionally, we find analogous amino acid-glucose metabolites formed in the body fluids of patients accumulating methionine, lysine, proline and citrulline. Amadori rearrangement products are well-known intermediates in the formation of advanced glycation end-products and have been associated with the pathophysiology of diabetes mellitus and ageing, but are now shown to also form under conditions of aminoacidemia. They represent a general class of metabolites for inborn errors of amino acid metabolism that show potential as biomarkers and may provide further insight in disease pathophysiology., Rianne van Outersterp et al. combine mass spectrometry, NMR, and infrared ion spectroscopy to identify amino acid-hexose conjugates in the blood plasma from patients with metabolic disorders such as phenylketonuria (PKU). These conjugates, or Amadori rearrangement products, are generally not detectable in blood samples from unaffected individuals, and may therefore represent disease biomarkers.

Metallated gas-phase structures consisting of an intact and deprotonated histidine (His) ligand, M(His-H)(His)+, where M = Ca and Ni, were examined using infrared multiple photon dissociation (IRMPD) action spectroscopy utilizing light from a free-electron laser (FEL). In parallel, ab initio quantum-chemical calculations identified several low-energy isomers for each complex. Experimental action spectra were compared to linear absorption spectra calculated at the B3LYP level of theory, using the 6-311+G(d,p) basis set. Single-point energies were calculated at B3LYP, B3LYP-GD3BJ, B3P86, and MP2(full) levels using the 6-311+G(2d,2p) basis set. For Ca(His-H)(His)+, the dominant structure has the metal center coordinating with the π nitrogen of the imidazole ring (Nπ) and both oxygen atoms of the carboxylate group of the deprotonated His ligand while coordinating with the backbone amine (Nα), Nπ, and the carbonyl oxygen of the carboxylic acid of the intact His ligand. The Ni(His-H)(His)+ species coordinates the metal ion through Nα, Nπ, and the carbonyl oxygen for both the deprotonated and intact His ligands, but also shows evidence for a minor secondary structure where the deprotonated His coordinates the metal at Nα, Nπ, and the deprotonated carbonyl oxygen and the intact His ligand is zwitterionic, coordinating the metal with both carboxylate oxygens. Different levels of theory predict different ground structures, highlighting the need for utilizing multiple levels of theory to help identify the gas-phase structure actually observed experimentally.

Uranium trioxide, UO3, has a T-shaped structure with bent uranyl, UO22+, coordinated by an equatorial oxo, O2-. The structure of cation UO3+ is similar but with an equatorial oxyl, O center dot-. Neutral and cationic uranium trioxide coordinated by nitrates were characterized by collision induced dissociation (CID), infrared multiple-photon dissociation (IRMPD) spectroscopy, and density functional theory. CID of uranyl nitrate, [UO2 (NO3)3]- (complex A1), eliminates NO2 to produce nitrate-coordinated UO3+, [UO2 (O. )(NO3)2]-(B1), which ejects NO3 to yield UO3 in [UO2 (O)(NO3)]- (C1). Finally, C1 associates with H2O to afford uranyl hydroxide in [UO2(OH)2 (NO3)]- (D1). IRMPD of B1, C1, and D1 confirms uranyl equatorially coordinated by nitrate(s) along with the following ligands: (B1) radical oxyl O.-; (C1) oxo O2-; and (D1) two hydroxyls, OH- . As the nitrates are bidentate, the equatorial coordination is six in A1, five in B1, four in D1, and three in C1. Ligand congestion in low-coordinate C1 suggests orbital-directed bonding. Hydrolysis of the equatorial oxo in C1 epitomizes the inverse trans influence in UO3, which is uranyl with inert axial oxos and a reactive equatorial oxo. The uranyl v3 IR frequencies indicate the following donor ordering: O2- [best donor] >> O.- > OH-> NO3-.

Cisplatin, (NH3)2PtCl2, has been known as a successful metal-based anticancer drug for more than half a century. Its analogue, Argplatin, arginine-linked cisplatin, (Arg)PtCl2, is being investigated because it exhibits reactivity towards DNA and RNA that differs from that of cisplatin. In order to understand the basis for its altered reactivity, the deprotonated and sodium cationized forms of Argplatin, [(Arg-H)PtCl2]− and [(Arg)PtCl2 + Na]+, are examined by infrared multiple photon dissociation (IRMPD) action spectroscopy in the IR fingerprint and hydrogen-stretching regions. Complementary electronic structure calculations are performed using density functional theory approaches to characterize the stable structures of these complexes and to predict their infrared spectra. Comparison of the theoretical IR spectra predicted for various stable conformations of these Argplatin complexes to their measured IRMPD spectra enables determination of the binding mode(s) of Arg to the Pt metal center to be identified. Arginine is found to bind to Pt in a bidentate fashion to the backbone amino nitrogen and carboxylate oxygen atoms in both the [(Arg-H)PtCl2]− and [(Arg)PtCl2 + Na]+ complexes, the NO− binding mode. The neutral side chain of Arg also interacts with the Pt center to achieve additional stabilization in the [(Arg-H)PtCl2]− complex. In contrast, Na+ binds to both chlorido ligands in the [(Arg)PtCl2 + Na]+ complex and the protonated side chain of Arg is stabilized via hydrogen-bonding interactions with the carboxylate moiety. These findings are consistent with condensed-phase results, indicating that the NO− binding mode of arginine to Pt is preserved in the electrospray ionization process even under variable pH and ionic strength.

Infrared multiple photon dissociation (IRMPD) spectroscopy experiments in the 600-2000 cm-1 region and computational chemistry studies were combined with the aim of elucidating the structures of protonated imidacloprid (pIMI), and its unimolecular decomposition products. The computed IR spectra for the lowest energy structures for pIMI as well as for protonated desnitrosoimidacloprid, corresponding to the loss of NO radical (pIMI-NO), and protonated imidacloprid urea corresponding to the loss of N2O (pIMIU) were found to reproduce the experimental IRMPD spectrum quite well. The complex IRMPD spectrum for protonated desnitroimidaclpride (pDIMI), resulting from the loss of NO2 radical from pIMI, was explained as a contribution from several computed structures, including those involving simple loss of NO2 radical and some isomerization. However, based on a comparison of the computed IR spectrum for the lowest energy structure of pDIMI and the IRMPD spectrum, it was concluded that the lowest energy structure is a minor contributor to the experimental spectrum. This observation is rationalized as being due to the energy requirement for isomerization to the lowest energy structure, being substantially higher than that for simple loss of NO2 radical. Experimental mass spectrometry fragmentation results indicated that the loss of N, O2, H was the result of a loss of NO radical followed by loss of OH radical. A comparison of the experimental IRMPD and computed IR spectra revealed that following NO radical loss, the structure entailing a hydride shift from the methylene bridge to the guanidine moiety followed by OH radical elimination, generated the best match with the experimental IRMPD spectrum. This was consistent with the computed potential energy surfaces showing this structure as having the lowest energy requirement.

With the detection of C60, C70, and in the interstellar medium, fullerenes are currently the largest molecules identified in space. The relatively high proton affinities of C60 and C70 support the hypothesis that protonated fullerenes may also be abundant in the interstellar matter. Here, we present the first experimental vibrational spectrum of C70H+, recorded in the gas phase. The attachment of a proton to C70 causes a drastic symmetry lowering, which results in a rich vibrational spectrum. As compared to C60, where all C-atoms are equivalent due to the icosahedral symmetry, C70 belongs to the D5h point group and has five nonequivalent C-atoms, which are available as protonation sites. Combined analysis of the experimental spectrum and spectra computed at the density functional theory level enables us to evaluate the protonation isomers being formed. We compare the IR spectra of C60H+ and C70H+ to IR emission spectra from planetary nebulae, which suggests that a mixture of these fullerene analogs could contribute to their IR emission.

The digital revolution sets a milestone in the progressive miniaturization of working devices and in the underlying advent of molecular machines. Foldamers involving mechanically entangled components with modular secondary structures are among the most promising designs for molecular switch‐based applications. Characterizing the nature and dynamics of their intramolecular network following the application of a stimulus is the key to their performance. Here, we use non‐dissociative electron transfer as a reductive stimulus in the gas phase and probe the consecutive co‐conformational transitions of a donor‐acceptor oligorotaxane foldamer using electrospray mass spectrometry interfaced with ion mobility and infrared ion spectroscopy. A comparison of collision cross section distributions for analogous closed‐shell and radical molecular ions sheds light on their respective formation energetics, while variations in their respective infrared absorption bands evidence changes in intramolecular organization as the foldamer becomes more compact. These differences are compatible with the advent of radical‐pairing interactions., Gas‐phase non‐dissociative electron transfer is used for charge reduction of a donor‐acceptor oligorotaxane foldamer (green). The consecutive co‐conformational transition is monitored using ion mobility spectrometry and infrared ion spectroscopy. Comparing the collision cross section distributions (blue) and infrared spectra (red) recorded for analogous closed‐shell and radical systems highlights differences that can be attributed to radical‐pairing interactions.

In this study, dissociative one-electron transfer dissociation of [CuII (dien)Y(G/A)W]•2+ [dien = diethylenetriamine; Y(G/A)W = tyrosyl (glycyl/alanyl)tryptophan] was used to generate the tripeptide radical cations [Y(G/A)W]•+ ; subsequent loss of the Tyr side chain formed [Gα• (G/A)W]+ . The π-centered species [YGWπ• ]+ generated the α-centered species [Gα• GW]+ through Cα -Cβ bond cleavage, as revealed using infrared multiple photon dissociation (IRMPD) measurements and density functional theory (DFT) calculations. Comparisons of experimental and theoretical IR spectra confirmed that both the charge and spin densities of [Y(G/A)Wπ• ]+ were delocalized initially at the tryptophan indolyl ring; subsequent formation of the final [Gα• (G/A)W]+ structure gave the highest spin density at the α-carbon atom of the N-terminal glycine residue, with a proton solvated by the first amide oxygen atom. The IRMPD mass spectra and action spectra of the [Gα• (G/A)W]+ species were all distinctly different from those of their isomeric [G(G/A)Wπ• ]+ species. The mechanism of formation of the captodative [Gα• (G/A)W]+ species-with the charge site separated from the radical site-from [Y(G/A)Wπ• ]+ has been elucidated. DFT calculations suggested that the Cα -Cβ bond cleavage of the tyrosine residue in the radical cationic [Y(G/A)Wπ• ]+ precursor involves (a) through-space electron transfer between the indolyl and phenolic groups; (b) formation of proton-bound dimers through Cα -Cβ cleavage of the tyrosine residue; and (c) a concerted proton rearrangement from the phenolic OH group to the carboxyl group and formation of the α-carbon-centered product [Gα• (G/A)W]+ through hydrogen bond cleavage. The barriers for the electron transfer (a), the Cα -Cβ cleavage (b), and the protonation rearrangement (c) were 12.8, 26.5, and 10.3 kcal mol-1 , respectively.

We report herein the first detailed study of the mechanism of redox reactions occurring during the gas-phase dissociative electron transfer of prototypical ternary [CuII(dien)M]˙2+ complexes (M, peptide). The two final products are (i) the oxidized non-zwitterionic π-centered [M]˙+ species with both the charge and spin densities delocalized over the indole ring of the tryptophan residue and with a C-terminal COOH group intact, and (ii) the complementary ion [CuI(dien)]+. Infrared multiple photon dissociation (IRMPD) action spectroscopy and low-energy collision-induced dissociation (CID) experiments, in conjunction with density functional theory (DFT) calculations, revealed the structural details of the mass-isolated precursor and product cations. Our experimental and theoretical results indicate that the doubly positively charged precursor [CuII(dien)M]˙2+ features electrostatic coordination through the anionic carboxylate end of the zwitterionic M moiety. An additional interaction exists between the indole ring of the tryptophan residue and one of the primary amino groups of the dien ligand; the DFT calculations provided the structures of the precursor ion, intermediates, and products, and enabled us to keep track of the locations of the charge and unpaired electron. The dissociative one-electron transfer reaction is initiated by a gradual transition of the M tripeptide from the zwitterionic form in [CuII(dien)M]˙2+ to the non-zwitterionic M intermediate, through a cascade of conformational changes and proton transfers. In the next step, the highest energy intermediate is formed; here, the copper center is 5-coordinate with coordination from both the carboxylic acid group and the indole ring. A subsequent switch back to 4-coordination to an intermediate IM1, where attachment to GGW occurs through the indole ring only, creates the structure that ultimately undergoes dissociation.

Infrared multiple photon dissociation (IRMPD) spectroscopy shows the [GPGG + H – H2O]+ ion to have an imidazolone structure. Collision-induced dissociation of this [b4]+ ion results in the loss of HN CH2 from the first residue; the IRMPD spectrum of this MS3 product ion is very similar to that of the [b4]+ ion itself, strongly indicating that the [b4 – HN CH2]+ ion also has an imidazolone structure. Losses of CO and glycine are the dominant dissociation pathways for the [b4 – HN CH2]+ ion. The latter loss requires tautomerism of the keto-form of the imidazolone ring to become the lower-energy enol-form, prior to dissociation. Isotopic labelling showed that loss of CO occurs from the ring of the keto-form. Density functional theory calculations were performed at both the B3LYP/6–311++G (d,p) and M06–2X/6–311++G (d,p) levels and the results are in good agreement.

The molecular structures of six open-shell z3-ions resulting from electron transfer dissociation mass spectrometry (ETD MS) were investigated using infrared ion spectroscopy in the 800–1850 and 3200–3700 cm−1 spectral ranges in combination with density functional theory and molecular mechanics/molecular dynamics calculations. We assess in particular the question of whether the radical remains at the Cα-site of the backbone cleavage, or whether it migrates by H-atom transfer to another, energetically more favorable position. Calculations performed herein as well as by others show that radical migration to an amino acid side chain or to an α-carbon along the peptide backbone can lead to structures that are more stable, by up to 33 kJ mol−1 for the systems investigated here, by virtue of resonance stabilization of the radical in these alternative positions. Nonetheless, for four out of the six z3-ions considered here, our results quite clearly indicate that radical migration does not occur, suggesting that the radical is kinetically trapped at the site of ETD cleavage. For the two remaining systems, a structural assignment is less secure and we suggest that a mixture of migrated and unmigrated structures may be formed.

The molecular family of nucleotide triphosphates (NTPs), with adenosine 5′-triphosphate (ATP) as its best-known member, is of high biochemical importance as their phosphodiester bonds form Nature's main means to store and transport energy. Here, gas-phase IR spectroscopic studies and supporting theoretical studies have been performed on adenosine 5′-triphosphate, cytosine 5′-triphosphate and guanosine 5′-triphosphate to elucidate the intrinsic structural properties of NTPs, focusing on the influence of the nucleobase and the extent of deprotonation. Mass spectrometric studies involving collision induced dissociation showed similar fragmentation channels for the three studied NTPs within a selected charge state. The doubly charged anions exhibit fragmentation similar to the energy-releasing hydrolysis reaction in nature, while the singly charged anions show different dominant fragmentation channels, suggesting that the charge state plays a significant role in the favorability of the hydrolysis reaction. A combination of infrared ion spectroscopy and quantum-chemical computations indicates that the singly charged anions of all NTPs are preferentially deprotonated at their β-phosphates, while the doubly-charged anions are dominantly αβ-deprotonated. The assigned three-dimensional structure differs for ATP and CTP on the one hand and GTP on the other, in the sense that ATP and CTP show no interaction between nucleobase and phosphate tail, while in GTP they are hydrogen bonded. This can be rationalized by considering the structure and geometry of the NTPs where the final three dimensional structure depends on a subtle balance between hydrogen bond strength, flexibility and steric hindrance.

Synthesis and spectra of isocytosino-8-trifluoromethylquinolone (1), as well as the gas phase InfraRed Multiple Photon Dissociation (IRMPD) spectra in the fingerprint region of the corresponding deprotonated anion (3), its d3 analogue, the monodeprotonated homodimer (2), and its d7 analogue are reported here. The anions represent nucleobase analogues having the hydrogen bonding pattern ADAAD (where A stands for acceptor and D stands for donor), in which the site of negative charge is unambiguous (as opposed to guanine, which has more than one acidic nitrogen). The match between experimental vibrational spectra and calculation is good, except for the out-of-plane HNH bends of the undeuterated and deuterated monomer anions between 400 and 600 cm−1. The anionic homodimers form in a parallel orientation.

The role of specific amino acid side-chains in the fragmentation chemistry of gaseous protonated peptides resulting from collisional activation remains incompletely understood. For small peptides containing asparagine and glutamine, a dominant fragmentation channel induced by collisional activations is, in addition to deamidation, the loss of neutral water. Identifying the product ion structures from H2O-loss from four protonated dipeptides containing Asn or Gln using infrared ion spectroscopy, mechanistic details of the dissociation reactions are revealed. Several sequential dissociation reactions have also been investigated and provide additional insights into the fragmentation chemistry. While water loss can in principle occur from the C-terminus, the side chain or the amide bond carbonyl oxygen, in most cases the C-terminus was found to detach H2O, leading to a b2-sequence ion with an oxazolone structure for AlaGln, and bifurcating mechanisms leading to both oxazolone and diketopiperazine species for AlaAsn and AsnAla. In contrast, GlnAla expels water from the amide side chain leading to an imino-substituted prolinyl structure.

Complexes of divalent metal ions (Cu2+ and Ni2+) with histidine tripeptide complexes (HAA, AHA and AAH) are interesting gas-phase models for some of the most widely observed patterns of metal ion binding to peptides and proteins. Gas-phase structures were characterized using infrared multiple photon dissociation (IRMPD) spectroscopy in ion-trapping mass spectrometers, along with density functional theory (DFT) computations. Ground states are square-planar with two deprotonated amide nitrogens bound to the metal ion via a double iminol rearrangement (IM binding mode), but contrary to expectations based on solution behavior, the histidine imidazole group is not bound to the metal, but instead is hydrogen bonded remote from the metal ion. The alternative “charge-solvated” (CS) binding mode (amide carbonyl oxygens binding the metal ion) lies higher in energy, but in many cases was observed to be present as conformationally unrelaxed ions with an abundance (relative to the IM conformation) that was dependent on instrument configuration and source and trap conditions. Taking advantage of the ability to form and trap both IM and CS conformations for a few of the complexes, the infrared spectroscopy of both conformations was explored in the fingerprint (1000–1800 cm−1) and hydrogen-stretching (3200–3800 cm−1) regions. For the fingerprint region, agreement is very good between the observed IRMPD spectra and the spectra predicted by DFT calculations at the B3LYP/6–311 + +g(d,p) level. Agreement in the H-stretching region is not perfect, but the characteristic IM and CS spectral patterns are evident.

The identification of molecular biomarkers is critical for diagnosing and treating patients and for establishing a fundamental understanding of the pathophysiology and underlying biochemistry of inborn errors of metabolism. Currently, liquid chromatography/high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy are the principle methods used for biomarker research and for structural elucidation of small molecules in patient body fluids. While both are powerful techniques, several limitations exist that often make the identification of unknown compounds challenging. Here, we describe how infrared ion spectroscopy has the potential to be a valuable orthogonal technique that provides highly-specific molecular structure information while maintaining ultra-high sensitivity. Here, we characterize and distinguish two well-known biomarkers of inborn errors of metabolism, glutaric acid for glutaric aciduria and ethylmalonic acid for short-chain acyl-CoA dehydrogenase deficiency, using infrared ion spectroscopy. In contrast to tandem mass spectra, in which ion fragments can hardly be predicted, we show that the prediction of an IR spectrum allows reference-free identification in the case that standard compounds are either commercially or synthetically unavailable. Finally, we illustrate how functional group information can be obtained from an IR spectrum for an unknown and how this is valuable information to, for example, narrow down a list of candidate structures resulting from a database query. Early diagnosis in inborn errors of metabolism is crucial for enabling treatment and depends on the identification of biomarkers specific for the disorder. Infrared ion spectroscopy has the potential to play a pivotal role in the identification of challenging biomarkers.

International audience; Dissociation chemistry of the diproline anion [Pro2-H]− is studied using chemical dynamics simulations coupled with quantum-chemical calculations and RRKM analysis. Pro2– is chosen due to its reduced size and the small number of sites where deprotonation can take place. The mechanisms leading to the two dominant collision-induced dissociation (CID) product ions are elucidated. Trajectories from a variety of isomers of [Pro2-H]− were followed in order to sample a larger range of possible reactivity. While different mechanisms yielding y1– product ions are proposed, there is only one mechanism yielding the b2– ion. This mechanism leads to formation of a b2– fragment with a diketopiperazine structure. The sole formation of a diketopiperazine b2 sequence ion is experimentally confirmed by infrared ion spectroscopy of the fragment anion. Furthermore, collisional and internal energy activation simulations are used in parallel to identify the different dynamical aspects of the observed reactivity.

The following gas-phase uranyl/12-crown-4 (12C4) complexes were synthesized by electrospray ionization: [UO2(12C4)2]2+ and [UO2(12C4)2(OH)]+. Collision-induced dissociation (CID) of the dication resulted in [UO2(12C4-H)]+ (12C4-H is a 12C4 that has lost one H), which spontaneously adds water to yield [UO2(12C4-H)(H2O)]+. The latter has the same composition as complex [UO2(12C4)(OH)]+ produced by CID of [UO2(12C4)2(OH)]+ but exhibits different reactivity with water. The postulated structures as isomeric [UO2(12C4-H)(H2O)]+ and [UO2(12C4)(OH)]+ were confirmed by comparison of infrared multiphoton dissociation (IRMPD) spectra with computed spectra. The structure of [UO2(12C4-H)]+ corresponds to cleavage of a C–O bond in the 12C4 ring, with formation of a discrete U–Oeq bond and equatorial coordination by three intact ether moieties. Comparison of IRMPD and computed IR spectra furthermore enabled assignment of the structures of the other complexes. Theoretical studies of the chemical bonding features of the complexes provide an understanding of their stabilities and reactivities. The results reveal bonding and structures of the uranyl/12C4 complexes and demonstrate the synthesis and identification of two different isomers of gas-phase uranyl coordination complexes.

Infrared multiple photon dissociation spectroscopy was performed on protonated and cationized canavanine (Cav), a non-protein amino acid oxy-analog of arginine. Infrared spectra in the XH stretching region (3000–4000 cm−1) were obtained at the Centre Laser Infrarouge d’Orsay (CLIO) facility. Comparison of the experimental infrared spectra with scaled harmonic frequencies at the B3LYP/6-31+G(d,p) level of theory indicates that canavanine is in a canonical neutral form in CavH+, CavLi+, and CavNa+; therefore, these cations are charge-solvated structures. The infrared spectrum of CavK+ is consistent with a mixture of Cav in canonical and zwitterionic forms leading to both charge-solvated and salt-bridged cationic structures. The Cav moiety in CavCs+ is shown to be zwitterionic, forming a salt-bridged structure for the cation. Infrared spectra in the fingerprint region (1000–2000 cm−1) obtained at the FELIX Laboratory in Nijmegen, Netherlands support these assignments. These results show that a single oxygen atom substitution in the side chain reduces the stability of the zwitterion compared to that of the protein amino acid arginine (Arg), which has been shown previously to adopt a zwitterionic structure in ArgNa+ and ArgK+. This difference can be explained in part due to the decreased basicity of Cav (PA = 1001 kJ/mol) as compared to arginine (PA = 1051 kJ/mol), but not entirely, as lysine, which has nearly the same proton affinity as Cav, (∼993 kJ/mol) forms only canonical structures with Na+, K +, and Cs+. A major difference between the zwitterionic forms of ArgM+ and CavM+ is that the protonation site is on the side chain for Arg and on the N-terminus for Cav. This results in systematically weaker salt bridges in the Cav zwitterions. In addition, the presence of another hydrogen-bonding acceptor atom in the side chain contributes to the stability of the canonical structures for the smaller alkali cations.

Electron attachment dissociation (electron capture dissociation (ECD) and electron transfer dissociation (ETD)) applied to gaseous multiply protonated peptides leads predominantly to backbone N–Cα bond cleavages and the formation of c- and z-type fragment ions. The mechanisms involved in the formation of these ions have been the subject of much discussion. Here, we determine the molecular structures of an extensive set of c-type ions produced by ETD using infrared ion spectroscopy. Nine c3- and c4-ions are investigated to establish their C-terminal structure as either enol-imine or amide isomers by comparison of the experimental infrared spectra with quantum-chemically predicted spectra for both structural variants. The spectra suggest that all c-ions investigated possess an amide structure; the absence of the NH bending mode at approximately 1000–1200 cm–1 serves as an important diagnostic feature.

Infrared multiple photon dissociation (IRMPD) spectroscopy has been used to probe the structures of the three protonated base-pair mismatches containing 9-ethylguanine (9eG) in the gas phase. Computational chemistry has been used to determine the relative energies and compute the infrared spectra of these complexes. By comparing the IRMPD spectra with the computed spectra, in all cases, it was possible to deduce that what was observed experimentally were the lowest energy computed structures. The protonated complex between 9eG and 1-methylthymine (1mT) is protonated at N7 of 9eG—the most basic site of all three bases in this study—and bound in a Hoogsteen type structure with two hydrogen bonds. The experimental IRMPD spectrum for the protonated complex between 9eG and 9-methyladenine (9mA) is described as arising from a combination of the two lowest energy structures, both which are protonated at N1 of adenine and each containing two hydrogen bonds with 9eG being the acceptor of both. The protonated dimer of 9eG is protonated at N7 with an N7–H+–N7 ionic hydrogen bond. It also contains an interaction between a C–H of protonated guanine and the O6 carbonyl of neutral guanine which is manifested in a slight red shift of that carbonyl stretch. The protonated 9eG/9mA structures have been previously identified by X-ray crystallography in RNA and are contained within the protein database.

Long-range electron transfer in proteins can be rationalized as a sequential short-distance electron-hopping processes via amino acid residues having low ionization energy as relay stations. Tyrosine residues can serve as such redox-active intermediates through one-electron oxidation to form a π-radical cation at its phenol side chain. An electron transfer from a vicinal functional group to this π-electron hole completes an elementary step of charge migration. However, transient oxidized/reduced intermediates formed at those relay stations during electron transfer processes have not been observed. In this study, formation of analog reactive intermediates via electron donor–acceptor coupling is observed by using IRMPD action spectroscopy. An elementary charge migration at the molecular level in model tyrosine-containing peptide radical cations [M]˙+ in the gas phase is revealed with its unusual Cα–Cβ bond cleavage at the side chain of the N-terminal residue. This reaction is induced by the radical character of the N-terminal amino group (–NH2˙+) resulting from an n → π+ interaction between the nonbonding electron pair of NH2 (n) and the π-electron hole at the Tyr side chain (π+). The formation of –NH2˙+ is supported by the IRMPD spectrum showing a characteristic NH2 scissor vibration coupled with Tyr side-chain stretches at 1577 cm−1. This n → π+ interaction facilitates a dissociative electron transfer with NH2 as the relay station. The occurrence of this side-chain cleavage may be an indicator of the formation of reactive conformers featuring the n → π+ interaction.