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Leucine enkephalin (LeuEnk), a biologically active endogenous opioid pentapeptide, has been under intense investigation because it is small enough to allow efficient use of sophisticated computational methods and large enough to provide insights into low-lying minima of its conformational space. Here, we reproduce and interpret experimental infrared (IR) spectra of this model peptide in gas phase using a combination of replica-exchange molecular dynamics simulations, machine learning, and ab initio calculations. In particular, we evaluate the possibility of averaging representative structural contributions to obtain an accurate computed spectrum that accounts for the corresponding canonical ensemble of the real experimental situation. Representative conformers are identified by partitioning the conformational phase space into subensembles of similar conformers. The IR contribution of each representative conformer is calculated from ab initio and weighted according to the population of each cluster. Convergence of the averaged IR signal is rationalized by merging contributions in a hierarchical clustering and the comparison to IR multiple photon dissociation experiments. The improvements achieved by decomposing clusters containing similar conformations into even smaller subensembles is strong evidence that a thorough assessment of the conformational landscape and the associated hydrogen bonding is a prerequisite for deciphering important fingerprints in experimental spectroscopic data.

The amino acid arginine plays a key role in the interaction of proteins with adenosine phosphates, as its protonated guanidinium side group is capable of building multipodal H-bonding interactions with the oxygen atoms of the phosphate, phosphoester and ribose moieties and with the nitrogen atoms of adenine. Protein interactions often take place in competition with other ionic species, typically metal cations, which are prone to build concerted coordination arrangements with the same centers of negative charge as guanidinium. We report on a vibrational spectroscopy and computational investigation of a positively charged ternary complex formed by adenosine monophosphate (AMP) with methyl guanidinium and Na

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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Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) and the hydroxyl radical (•OH) have specific functions in biological processes, while their uncontrolled production and reactivity are known to be determining factors in pathophysiology. Methionine (Met) residues act as endogenous antioxidants, when they are oxidized into methionine sulfoxide (MetSO), thus depleting ROS and protecting the protein. We employed tandem mass spectrometry combined with IR multiple photon dissociation spectroscopy to study the oxidation induced by OH radicals produced by γradiolysis on model cyclic dipeptides c(LMetLMet), c(LMetDMet), and c(GlyMet). Our aim was to characterize the geometries of the oxidized peptides in the gas phase and to understand the relationship between the structure of the 2-center 3-electron (2c-3e) free radical formed in the first step of the oxidation process and the final compound. Density functional theory calculations were performed to characterize the lowest energy structures of the final product of oxidation and to interpret the IR spectra. Collision-induced dissociation tandem mass spectrometry (CID-MS2) experiments of oxidized c(LMetLMet)H+ and c(LMetDMet)H+ led to the loss of one or two oxidized sulfenic acid molecules, indicating that the addition of one or two oxygen atoms occurs on the sulfur atom of both methionine side chains and no sulfone formation was observed. The CID-MS2 fragmentation mass spectrum of oxidized c(GlyMet)H+ showed only the loss of one oxidized sulfenic acid molecule. Thus, the final products of oxidation are the same regardless of the structure of the precursor sulfur-centered free radical.

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.

Sodiated complexes of the aliphatic amino acids, Gly, Ala, Val, Leu, and Ile, were examined with infrared multiple-photon dissociation action spectroscopy utilizing light from a free-electron laser. To identify structures, the experimental spectra were compared to linear spectra calculated at the B3LYP/6-311+G(d,p) level of theory. Relative energetics of all complexes were calculated at B3LYP, B3P86, MP2(full), B3LYP-GD3BJ, and M06-2X levels using a 6-311+G(2d,2p) basis set. Spectral comparison for all complexes indicates that the dominant conformation, [N, CO], binds to the amino nitrogen and carbonyl oxygen. For all complexes except Gly, contributions are observed from [CO2-] structures, where the sodium cation binds to both oxygens of the carboxylate group in the zwitterionic form of the amino acid. The semiquantitative distribution between these two structures appears to be best-predicted by the B3LYP and MP2(full) levels of theory, with predictions from the other three levels inconsistent with the experiment.

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.

The biological activity of the macrocycle nonactin is intimately related to its ionophore properties and ability to act as a selective cation carrier. While the focus of most investigations on nonactin has been on the binding of metal cations and small molecular ions, this study pursues the characterization of its inclusion complexes with primary amines with bulky structured side groups of different polarity. To this end, the complexes of nonactin with aniline and with the amino acid L-serine, both in protonated form, are considered as case studies and their relevant coordination arrangements are assessed by means of infrared action spectroscopy, quantum chemical density functional theory and Born-Oppenheimer molecular dynamics. The study suggests that the oxygen atoms from the oxolane (tetrahydrofuran) groups of nonactin constitute the preferential docking sites of the ammonium moiety of the guest cation, although conformational constraints promote interactions with the ester carbonyl backbone groups. In the aniline complex, the benzyl side ring is oriented outwards from the cavity, whereas in the case of L-serine, the side carboxylic acid and alcohol groups participate actively in the coordination process. Interestingly, the accommodation of L-serine is favoured when nonactin adopts an enantiomeric-selective folding, that promotes the tripodal coordination of the protonated amine group with oxolane rings from three nonactinic acid blocks with enantiomeric sequence (+)-(-)-(+), which allows for a facile coordination of the serine side groups. This is recognized as a general feature associated with the alternation of chiral domains in globally achiral natural nonactin, yielding mirror-symmetric complexes with the enantiomers of chiral amines.

The gas-phase structures of cationized glycine (Gly), including complexes with Li+, Na+, K+, Rb+, and Cs+, are examined using infrared multiple-photon dissociation (IRMPD) spectroscopy utilizing light generated by a free electron laser, in conjunction with ab initio calculations. To identify the structures present in the experimental studies, measured IRMPD spectra are compared to spectra calculated at B3LYP/6-311+G(d,p) for the Li+, Na+, and K+ complexes and at B3LYP/def2TZVP for the Rb+ and Cs+ complexes. Single-point energy calculations were carried out at the B3LYP, B3P86, and MP2(full) levels using the 6-311+G(2d,2p) basis set for Li+, Na+, K+ and the def2TZVPP basis set for Rb+ and Cs+. The Li+ and Na+ complexes are identified as metal cation coordination to the amino nitrogen and carbonyl oxygen, [N,CO]-tt, although Na+(Gly) may have contributions from additional structures. The heavier metal cations coordinate to either the carbonyl oxygen, [CO]-cc, or the carbonyl oxygen and hydroxy oxygen, [CO,OH]-cc, with the former apparently preferred for Rb+ and Cs+ and the latter for K+. These two structures reside in a double-well potential and different levels of theory predict very different relative stabilities. Some experimental evidence is provided that MP2(full) theory provides the most accurate relative energies.

The infrared multiple-photon dissociation (IRMPD) spectrum of the hexa-coordinated complex of hexacyclen (18-azacrown-6) with Ni2+ shows that the complex has a meridional – and not facial – chelation geometry in the gas phase.

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.

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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.

A large variety of 1,2,3-thiadiazoles and 1,2,3-triazoles are used extensively in modern pure and applied organic chemistry as important structural blocks of numerous valuable products. Creation of new methods of synthesis of these isomeric compounds requires the development of reliable analytical tools to reveal the structural characteristics of these novel compounds, which are able to distinguish between isomers. Mass spectrometry (MS) is a clear choice for this task due to its selectivity, sensitivity, informational capacity, and reliability. Here, the application of electrospray ionization (ESI) with ion detection in positive and negative modes was demonstrated to be useful in structural studies. Additionally, interconversion of isomeric 4,5-functionalized 1,2,3-triazoles and 1,2,3-thiadiazoles was demonstrated. Application of accurate mass measurements and tandem mass spectrometry in MS2 and MS3 modes indicated the occurrence of gas-phase rearrangement of 1,2,3-triazoles into 1,2,3-thiadiazoles under (+)ESI-MS/MS conditions, independent of the nature of substituents, in line with the reaction in the condensed phase. Infrared multiple photon dissociation (IRMPD) spectroscopy enabled the establishment of structures of some of the most crucial common fragment ions, including [M+H-N2]+ and [M+H-N2-RSO2]+ species. The (−)ESI-MS/MS experiments were significantly more informative for the sulfonyl alkyl derivatives compared to the sulfonyl aryl ones. However, there was insufficient evidence to confirm the solution-phase transformation of 1,2,3-thiadiazoles into the corresponding 1,2,3-triazoles.

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.

Gas-phase conformations of the sodium-cationized forms of the 2′-deoxycytidine and cytidine mononucleotides, [pdCyd+Na]+ and [pCyd+Na]+, are examined by infrared multiple photon dissociation action spectroscopy. Complimentary electronic structure calculations at the B3LYP/6-311+G(2d,2p)//B3LYP/6-311+G(d,p) level of theory provide candidate conformations and their respective predicted IR spectra for comparison across the IR fingerprint and hydrogen-stretching regions. Comparisons of the predicted IR spectra and the measured infrared multiple photon dissociation action spectra provide insight into the impact of sodium cationization on intrinsic mononucleotide structure. Further, comparison of present results with those reported for the sodium-cationized cytidine nucleoside analogues elucidates the impact of the phosphate moiety on gas-phase structure. Across the neutral, protonated, and sodium-cationized cytidine mononucleotides, a preference for stabilization of the phosphate moiety and nucleobase orientation is observed, although the details of this stabilization differ with the state of cationization. Several low-energy conformations of [pdCyd+Na]+ and [pCyd+Na]+ involving several different orientations of the phosphate moiety and sugar puckering modes are observed experimentally.

L-Thymidine (L-dThd) is the enantiomer of D-thymidine (dThd), a naturally-occurring pyrimidine nucleoside found within DNA nucleic acids. L-dThd, also known as Telbivudine, does not occur naturally, but in the last decade has found successful application as an antiviral medication for hepatitis B virus infection. In this work, the gas-phase conformers of the protonated and sodium cationized forms of L-dThd, [L-dThd+H]+ and [L-dThd + Na]+, are investigated using infrared multiple photon dissociation (IRMPD) action spectroscopy complemented by electronic structure calculations performed at the B3LYP/6-311+G(2d,2p)//B3LYP/6-311+G(d,p) level of theory. Comparisons between the experimental IRMPD spectra and theoretical linear IR spectra elucidate the stable low-energy conformations adopted by these L-dThd complexes generated by electrospray ionization. Minor 2,4-dihydroxy tautomers (T) and O2 protonated conformers contribute to the experimental [L-dThd+H]+ population, whereas conformers involving tridentate binding of Na+ to the O2, O4′, and O5′ atoms primarily contribute to the experimental [L-dThd + Na]+ population. Theory predicts a tautomer as the protonated ground conformer of [L-dThd+H]+ with thymine in an anti orientation and a tridentate (O2O4′O5′) sodium cationized ground conformer with a syn thymine orientation, consistent with theoretical predictions for [dThd+H]+ and [dThd + Na]+, respectively. Both protonated and sodium cationized L-dThd and dThd illustrate highly parallel IRMPD spectral features as expected. Survival yield analyses of data from energy-resolved collision-induced dissociation experiments elucidate the relative stabilities of [L-dThd+H]+ and [L-dThd + Na]+ as compared to the corresponding enantiomeric systems. Identical results are exhibited in the survival yield analyses as anticipated for enantiomeric complexes to simple cations. This work employs the same robust methodology that has provided structural characterization and energetic insight for similar systems preceding it to validate the parallel theoretical and experimental behaviors expected for enantiomers.

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.

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 proton bond is a paradigmatic quantum molecular interaction and a major driving force of supramolecular chemistry. The ring cavities of crown ethers provide an intriguing environment, promoting competitive proton sharing with multiple coordination anchors. This study shows that protons confined in crown ether cavities form dynamic bonds that migrate to varying pairs of coordinating atoms when allowed by the flexibility of the macrocycle backbone. Prototypic native crown ethers (12-crown-4, 15-crown-5 and 18-crown-6) and aza-crown ethers (cyclen, 1-aza-18-crown-6 and hexacyclen) are investigated. For each system, Infrared action spectroscopy experiments and ab initio Molecular Dynamics computations are employed to elucidate the structural effects associated with proton diffusion and its entanglement with the conformational and vibrational dynamics of the protonated host.

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.

We present the gas-phase infrared spectra of the phenyl cation, phenylium, in its perprotio C$_6$H$_5^+$ and perdeutero C$_6$D$_5^+$ forms, in the 260-1925 cm$^{-1}$ (5.2-38 $\mu$m) spectral range, and investigate the observed photofragmentation. The spectral and fragmentation data were obtained using Infrared Multiple Photon Dissociation (IRMPD) spectroscopy within a Fourier Transform Ion Cyclotron Resonance Mass Spectrometer (FTICR MS) located inside the cavity of the free electron laser FELICE (Free Electron Laser for Intra-Cavity Experiments). The $^1$A$_1$ singlet nature of the phenylium ion is ascertained by comparison of the observed IR spectrum with DFT calculations, using both harmonic and anharmonic frequency calculations. To investigate the observed loss of predominantly [2C,nH] (n=2-4) fragments, we explored the potential energy surface (PES) to unravel possible isomerization and fragmentation reaction pathways. The lowest energy pathways toward fragmentation include direct H elimination, and a combination of facile ring-opening mechanisms ($\leq2.4$ eV), followed by elimination of H or CCH$_2$. Energetically, all H-loss channels found are more easily accessible than CCH$_2$-loss. Calculations of the vibrational density of states for the various intermediates show that at high internal energies, ring opening is the thermodynamically the most advantageous, eliminating direct H-loss as a competing process. The observed loss of primarily [2C,2H] can be explained through entropy calculations that show favored loss of [2C,2H] at higher internal energies., Comment: 10 pages, 6 figures and 1 table. Accepted for publication on PCCP on 04 Feb 2021; supplementary Material available on PCCP website

Sulfa drugs are an important class of pharmaceuticals in the treatment of bacterial infections. The amido/imido tautomerism of these molecules in their neutral form has been widely discussed in the literature. Here, we study the protonation preferences of sulfa drugs upon electrospray ionization (ESI) using IR action spectroscopy of the ionized gas-phase molecules in a mass spectrometer. Our set of molecules includes sulfanilamide (SA), the progenitor of the family of sulfa drugs, and the actual, sulfonamide nitrogen substituted, sulfa drugs sulfamethoxazole (SMX), sulfisoxazole (SIX), sulfamethizole (SMZ), sulfathiazole (STZ), sulfapyridine (SP) and sulfaguanidine (SG). IR multiple photon dissociation (IRMPD) spectra were recorded for the protonated sulfa drugs using a Fourier transform ion cyclotron resonance mass spectrometer (FT-ICR-MS) and an optical parametric oscillator/amplifier (OPO/OPA) as well as the FELIX free electron laser (FEL) as IR sources. The OPO provides tunable IR radiation in the NH stretch region (3100–3700 cm$$^{-1}$$ - 1 ), while the FEL covers the fingerprint region (520–1750 cm$$^{-1}$$ - 1 ). Comparison of experimental IR spectra with spectra predicted using density functional theory allowed us to determine the gas-phase protonation site. For SA, the sulfonamide NH$$_2$$ 2 group was identified as the protonation site, which contrasts the situation in solution, where the anilinic NH$$_2$$ 2 group is protonated. For the derivative sulfa drugs, the favored protonation site is the nitrogen atom included in the heterocycle, except for SG, where protonation occurs at the sulfonamide nitrogen atom. The theoretical investigations show that the identified protonation isomers correspond to the lowest-energy gas-phase structures.

Radical cations of an aliphatic tripeptide prolyl-glycyl-glycine (PGG•+) and its sequence ions [a3 + H]•+ and [b2 - H]•+ have been generated by collision-induced dissociation of the [Cu(Phen)(PGG)]•2+ complex, where Phen = 1,10-phenanthroline. Infrared multiple photon dissociation spectroscopy, ion-molecule reaction experiments, and theoretical calculations have been used to investigate the structures of these ions. The unpaired electron in these three radical cations is located at different α-carbons. The PGG•+ radical cation has a captodative structure with the radical at the α-carbon of the proline residue and the proton on the oxygen of the first amide group. This structure is at the global minimum on the potential energy surface (PES). By contrast, the [a3 + H]•+ and [b2 - H]•+ ions are not the lowest-energy structures on their respective PESs, and their radicals are formally located at the C-terminal and second α-carbons, respectively. Density functional theory calculations on the structures of the ternary copper(II) complex ion suggest that the charge-solvated isomer of the metal complex is the precursor ion that dissociates to give the PGG•+ radical cation. The isomer of the complex in which PGG is bound as a zwitterion dissociates to give the [a3 + H]•+ and [b2 - H]•+ ions.

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.

A key decay pathway by which organic sunscreen molecules dissipate harmful UV energy involves excited-state hydrogen atom transfer between proximal enol and keto functional groups. Structural modifications of this molecular architecture have the potential to block ultrafast decay processes, and hence promote direct excited-state molecular dissociation, profoundly affecting the efficiency of an organic sunscreen. Herein, we investigate the binding of alkali metal cations to a prototype organic sunscreen molecule, oxybenzone, using IR characterization. Mass-selective IR action spectroscopy was conducted at the free electron laser for infrared experiments, FELIX (600-1800 cm-1), on complexes of Na+, K+ and Rb+ bound to oxybenzone. The IR spectra reveal that K+ and Rb+ adopt binding positions away from the key OH intermolecular hydrogen bond, while the smaller Na+ cation binds directly between the keto and enol oxygens, thus breaking the intramolecular hydrogen bond. UV laser photodissociation spectroscopy was also performed on the series of complexes, with the Na+ complex displaying a distinctive electronic spectrum compared to those of K+ and Rb+, in line with the IR spectroscopy results. TD-DFT calculations reveal that the origin of the changes in the electronic spectra can be linked to rupture of the intramolecular bond in the sodium cationized complex. The implications of our results for the performance of sunscreens in mixtures and environments with high concentrations of metal cations are discussed.

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.