Metastable Ion Studies Research Articles

ChemInform Abstract: Mass Spectrometry of Hydroxylamines, Oximes and Hydroxamic Acids

AbstractReview: 192 refs.

Johan Klaas Terlouw, Scientist

It gives me great pleasure to introduce this special issue of the European Journal of Mass Spectrometry, created to celebrate the achievements of Hans Terlouw. It will necessarily be a somewhat personal account, because of my long-standing friendship and productive collaboration with JKT over nearly 40 years of research into the mysteries of gas phase ion chemistry. We have shared countless, intense hours of experimental mass spectrometry that produced a very satisfying number of mini-Eureka moments. We were also extremely fortunate to be able to spend many long discussions (in person and by trans-Atlantic ‘phone call) with the late Fred Lossing whose scientific wisdom, good humour and great technical expertise with his electron monochromator, provided the quantitative energetic foundations for so many of our mass spectral observations. Hans was born in Gouda in 1945 and his University education was completed at the University of Utrecht. After his BSc degree in 1965, which inter alia produced his first publication, he obtained an MSc in 1968, working in analytical chemistry. His PhD research was directed by Professor Geo Dijkstra, culminating in his PhD in 1972 and followed by his appointment as Assistant Professor. The thesis was entitled “A new approach to the quantitative analysis of metals by electron impact ionization mass spectrometry.” Of his first nine publications (up to 1974), five concerned the trace analysis of metals by MS. His first independent research was on the pyrolysis of cannabidol and related metastable ion and isotopic labelling studies of isomeric cannabinoids. At the 1973 International MS meeting at Edinburgh University, Professor Dijkstra asked me if I would accommodate Hans in my Ottawa laboratory for a year’s visiting Fellowship. Hans came to see me shortly thereafter at University College (London) where I was on sabbatical leave and the rest, as they say, is our history. It is difficult to overstate the value of a close, non-competitive collaboration in science and the following 15 or so years were exceptionally happy and productive, each of us spending extended visits in the other’s laboratory and inter alia getting to know each others’ co-workers. I find that we have co-authored some 70 articles in books, reviews and journals. Our first joint venture in 1973/4 involved metastable ions studies, using an AEI MS902S mass spectrometer. We then believed that analysis of metastable peak shapes could provide a useful method for ion structure identification. Fortuitously we began with the C2H4O +• isomers, vinyl alcohol, acetaldehyde and oxirane, each of which is readily identified by the characteristic profiles of their metastable H• loss peaks. Johan Klaas Terlouw, Scientist

Mass spectrometry as test bench for medicinal chemistry studies

This review describes how mass spectrometry can be used as a powerful test bench to obtain information on the biological activity of target compounds. Considering that mass spectrometry is based on the chemical reactivity of the analytes, it is possible to investigate the stability of the active compounds, to predict their behaviour in the environment of interest, and to obtain structure-reactivity relationships for new molecules of pharmacological interest. Electron ionization and metastable ion studies give evidence of the correlation between the mutagenic properties of a series of aryl and heteroaryl triazenes and mass spectrometric data. A linear relationship between the energetics of C(O)-O bond cleavage of some carbamic acid O-aryl esters and their FAAH inhibition activity has been proved by electrospray-ionization ion-trap mass spectrometry. An inverse correlation between the stability and cytotoxic activity of some copper complexes has been clearly established by electrospray-ionization mass spectrometry. Moreover, because of the sensitivity and specificity of mass spectrometry, it has been possible to determine and characterize impurities that in some cases can be the real bioactive compound.

The gas phase Smiles rearrangement of anions PhO(CH2)nO− (n = 2–4). A joint theoretical and experimental approach

A combination of experimental data [using (18)O labelling fragmentation data together with metastable ion studies in a reverse sector mass spectrometer (from a previous study)] and ab initio reaction coordinate studies at the CCSD(T)/6-31++G(d,p)//B3LYP/6-31++G(d,p) level of theory, have provided the following data concerning the formation of PhO(-) in the gas-phase from energized systems PhO(CH(2))(n)O(-) (n = 2-4). All DeltaG values were calculated at 298 K. (1) PhO(CH(2))(2)O(-) effects an ipso Smiles rearrangement (DeltaG(r) = +35 kJ mol(-1); barrier to transition state DeltaG(#) = +40 kJ mol(-1)) equilibrating the two oxygen atoms. The Smiles intermediate reverts to PhO(CH(2))(2)O(-) which then undergoes an S(N)i reaction to form PhO(-) and ethylene oxide (DeltaG(r) = -24 kJ mol(-1); DeltaG(#) = +54 kJ mol(-1)). (2) The formation of PhO(-) from energized PhO(CH(2))(3)O(-) is more complex. Some 85% of the PhO(-) formed originates via a Smiles intermediate (DeltaG(r) = +52 kJ mol(-1); DeltaG(#) = +61 kJ mol(-1)). This species reconverts to PhO(CH(2))(3)O(-) which then fragments to PhO(-) by two competing processes, namely, (a) an S(N)i process yielding PhO(-) and trimethylene oxide (DeltaG(r) = -27 kJ mol(-1); DeltaG(#) = +69 kJ mol(-1)), and (b) a dissociation process giving PhO(-), ethylene and formaldehyde (DeltaG(r) = -65 kJ mol(-1); DeltaG(#) = +69 kJ mol(-1)). The other fifteen percent of PhO(-) is formed prior to formation of the Smiles intermediate, occurring directly by the S(N)i and dissociation processes outlined above. The operation of two fragmentation pathways is supported by the presence of a composite metastable ion peak. (3) Energized PhO(CH(2))(4)O(-) fragments exclusively by an S(N)i process to form PhO(-) and tetrahydrofuran (DeltaG(r) = -101 kJ mol(-1); DeltaG(#) = +53 kJ mol(-1)). The Smiles ipso cyclization (DeltaG(r) = +64 kJ mol(-1); DeltaG(#) = +74 kJ mol(-1)) is not detected in this system.

Fe+-Mediated Interconversion of n- and i-C3H7OH Preceding Their Gas-Phase Dehydrations: Experimental and Computational Evidence for Memory Effects and Inherent Asymmetry of Constitutionally Equivalent Methyl Groups,

The n-propyl/isopropyl isomerization operative in Fe+-mediated dehydrations of n-propyl and isopropyl alcohols has been rigorously analyzed by tandem mass spectrometry and density functional calculations. Metastable ion studies of complexes of atomic Fe+ with a set of selectively deuterated propyl alcohols address structural details of the reversibility of β-hydrogen transfer steps. The labeling distributions in the ionic products reveal that the transiently focused, constitutionally equivalent methyl groups remain distinguishable in the course of n-C3H7 → i-C3H7 isomerizations. This asymmetry causes a memory effect operative in the Fe+-mediated dehydration of n-propyl alcohol. While density functional calculations provide detailed insight into the nature of the reaction intermediates and, inter alia, suggest that the experimentally deduced asymmetry can be attributed to agostic interactions of the iron center with a β-hydrogen atom of the emerging methyl group, a comprehensively consistent, quantitative ...

Fragmentation reactions of protonated peptides containing glutamine or glutamic acid.

A variety of protonated dipeptides and tripeptides containing glutamic acid or glutamine were prepared by electrospray ionization or by fast atom bombardment ionization and their fragmentation pathways elucidated using metastable ion studies, energy-resolved mass spectrometry and triple-stage mass spectrometry (MS(3)) experiments. Additional mechanistic information was obtained by exchanging the labile hydrogens for deuterium. Protonated H-Gln-Gly-OH fragments by loss of NH(3) and loss of H(2)O in metastable ion fragmentation; under collision-induced dissociation (CID) conditions loss of H-Gly-OH + CO from the [MH - NH(3)](+) ion forms the base peak C(4)H(6)NO(+) (m/z 84). Protonated dipeptides with an alpha-linkage, H-Glu-Xxx-OH, are characterized by elimination of H(2)O and by elimination of H-Xxx-OH plus CO to form the glutamic acid immonium ion of m/z 102. By contrast, protonated dipeptides with a gamma-linkage, H-Glu(Xxx-OH)-OH, do not show elimination of H(2)O or formation of m/z 102 but rather show elimination of NH(3), particularly in metastable ion fragmentation, and elimination of H-Xxx-OH to form m/z 130. Both the alpha- and gamma-dipeptides show formation of [H-Xxx-OH]H(+), with this reaction channel increasing in importance as the proton affinity (PA) of H-Xxx-OH increases. The characteristic loss of H(2)O and formation of m/z 102 are observed for the protonated alpha-tripeptide H-Glu-Gly-Phe-OH whereas the protonated gamma-tripeptide H-Glu(Gly-Gly-OH)-OH shows loss of NH(3) and formation of m/z 130 as observed for dipeptides with the gamma-linkage. Both tripeptides show abundant formation of the y(2)'' ion under CID conditions, presumably because a stable anhydride neutral structure can be formed. Under metastable ion conditions protonated dipeptides of structure H-Xxx-Glu-OH show abundant elimination of H(2)O whereas those of structure H-Xxx-Gln-OH show abundant elimination of NH(3). The importance of these reaction channels is much reduced under CID conditions, the major fragmentation mode being cleavage of the amide bond to form either the a(1) ion or the y(1)'' ion. Particularly when Xxx = Gly, under CID conditions the initial loss of NH(3) from the glutamine containing dipeptide is followed by elimination of a second NH(3) while the initial loss of H(2)O from the glutamic acid dipeptide is followed by elimination of NH(3). Isotopic labelling shows that predominantly labile hydrogens are lost in both steps. Although both [H-Gly-Glu-Gly-OH]H(+) and [H-Gly-Gln-Gly-OH]H(+) fragment mainly to form b(2) and a(2) ions, the latter also shows elimination of NH(3) plus a glycine residue and formation of protonated glycinamide. Isotopic labelling shows extensive mixing of labile and carbon-bonded hydrogens in the formation of protonated glycinamide.

Dissociative photoionisation of hexafluorobenzene

Abstract Breakdown of the ions created by photoionisation of C 6 F 6 at 73.6, 58.4 and 30.4 nm has been examined by two separate photoelectron–photoion coincidence techniques and has been interpreted using density functional theory calculations. A full breakdown diagram, amplifying earlier metastable ion studies, is determined. The rate of the main dissociative rearrangement reaction forming C 5 F 3 + , measured as a function of the internal energy of the ion, has been fitted by RRKM calculations and a large kinetic shift is found. The structure of the C 5 F 3 + ion and its 0 K threshold have been obtained from the experiments and also from theoretical calculations. Calculations of all the vibrational frequencies of the ground state hexafluorobenzene cation agree with existing experimental data.

Fragmentation reactions of protonated peptides containing phenylalanine: a linear free energy correlation in the fragmentation of H–Gly–Xxx–Phe–OH

The fragmentation reactions of a variety of protonated tri- and tetra-peptides containing phenylalanine have been examined using metastable ion studies and energy-resolved collision-induced dissociation studies. For peptides with the sequence H–Gly–Xxx–Phe–OH (Xxx=Gly,Ala,Val,Leu,Phe) the major primary fragmentation of MH + involves cleavage of the C-terminus amide bond to form either the b 2 ion or the y 1″ ion. For metastable ion fragmentation it is found that log([b 2]/[ y 1″]) increases linearly with the increase in the gas phase basicity of H–Xxx–OH. This linear free energy correlation is in contrast to the lack of such a correlation in the fragmentation of protonated H–Gly–Xxx–Gly–OH [J. Mass Spectrom. 30 (1995) 290]. When Phe is the central residue in tripeptides, the major primary fragmentation reaction involves formation of the b 2 ion which fragments further to the a 2 ion; at higher internal energies the a 2 ion fragments to give the phenylalanine immonium ion which becomes the dominant fragment. When Phe is in the N-terminus position, as in Phe–Gly–Gly–OH, the phenylalanine immonium ion is the dominant fragment and is formed, in part, directly by fragmentation of MH +. The fragmentation of the tetrapeptides H–Gly–Gly–Phe–Leu–OH, H–Phe–Gly–Gly–Phe–OH and H–Val–Ala–Ala–Phe–OH are more complex but show a substantial directional effect of the phenylalanine residue(s).

Metastable ion study of organosilicon compounds. Part XIV-trimethylsilylacetic acid, (CH(3))(3)SiCH(2)COOH, and its methyl ester, (CH(3))(3)SiCH(2)COOCH(3).

The unimolecular metastable decompositions of trimethylsilylacetic acid, (CH(3))(3)SiCH(2)COOH (1), and its methyl ester, (CH(3))(3)SiCH(2)COOCH(3) (2), were investigated by mass-analyzed ion kinetic energy (MIKE) spectrometry in conjunction with thermochemical data. The abundance of the molecular ions of both compounds, generated by electron ionization, is extremely low. However, the abundance of the ions generated by the loss of (.)CH(3) and observed at m/z 117 and 131 is moderate. These fragment ions further decompose to form the most abundant m/z 75 and 89 ions, respectively, by the loss of CH(2)CO through a (CH(3))(2)Si group migration. The loss of CH(2)CO is also observed to occur from 2(+.) and its fragment ion at m/z 115 generated by the loss of (.)OCH(3). The former reaction is proposed to occur via an ion-radical complex.

Dissociation behavior of ionized valeramide: Part I. Experimental studies

The unimolecular dissociation of ionized valeramide ( n-C 4H 9CONH 2) is examined by mass spectrometric techniques. Photoionization (PI) experiments yield an ionization energy of 9.40±0.03 eV. Besides the formation of the molecular ion, dissociation is observed close to the onset of PI. In addition to the PI experiments, the unimolecular dissociations of metastable valeramide ions generated by electron ionization (EI) are examined by means of tandem mass spectrometry, including extensive deuterium labeling studies. The major dissociation processes correspond to competing losses of (i) neutral propene formed via the McLafferty rearrangement and (ii) an ethyl radical to presumably afford protonated acrylamide; losses of methyl radical as well as ethene occur as side reactions. The labeling studies reveal that the McLafferty reaction occurs with high specificity, whereas loss of an ethyl radical is associated with a pronounced, yet by no means complete hydrogen equilibration of the alkyl backbone. While most results of the dissociative PI experiments and the metastable ion (MI) studies agree quite well, significant variations of the ratios of C 3H 6 and C 2H 5 losses in the various experiments do not find an immediate explanation and require further considerations.

Evidence for an Alkene Metathesis Reaction during the Unimolecular Dissociation of (CH3)3COCHCH2•+

The unimolecular reaction of the metastable tert-butyl vinyl ether radical cation leads mainly to elimination of ethylene. From metastable ion studies as well as Fourier transform ion cyclotron resonance measurements and by using isotopic labeling, it is proposed that the fragmentation begins with the cleavage of the O–C(butyl) bond. This behavior, which contrasts with that of ionized alkylethers, is the consequence of the presence of a vinyl group that allows the formation of a neutral allylic radical. The key intermediate of the fragmentation is likely to be a [CH2CHOH, (CH3)2CCH2]•+ complex in which a cycloaddition–cycloreversion reaction occurs. This intermediate is the same as that produced by a McLafferty rearrangement in appropriate aldehyde radical cations.

A metastable ion and collision-induced dissociation study of the (M–C 2H 4) •+ ion from 3-phenyl-1-bromopropane

The molecular ion of 3-phenyl-1-bromopropane is known to eliminate ethylene containing the methylene groups of positions 1 and 2 following an exchange between the hydrogen atoms from position 1 and the ortho positions of the phenyl ring. During this reaction migration of the bromine atom to some position in the molecular ion must take place. The eventual position to which the bromine atom has migrated has been probed by studying the metastable behaviour and collision-induced dissociation reactions of the (M–C 2H 4) •+ ion. From comparison with appropriate reference ions it is found that the (M–C 2H 4) •+ ion has the structure of ionized benzyl bromide. The mechanistic implication of this finding is briefly discussed.

Electron impact mass spectrometry of some neuroleptic amino alkyl thieno[β]cycloalkanones

The mass spectrometric behaviour of seven neuroleptic amino alkyl thieno[β]cycloalkanones has been studied under electron ionization conditions and with the aid of metastable ion studies, low energy collisional experiments and accurate mass measurements. The most relevant fragmentation pathways are discussed and the power of the different methodologies for the characterization of structural isomers has been tested. © 1998 John Wiley & Sons, Ltd.

Ion chemistry of protonated aspartic acid derivatives

The fragmentation reactions of the protonated α-monomethyl and β-monomethyl esters of aspartic acid have been elucidated using low-energy collision-induced dissociation (CID) and metastable ion studies. It is shown that, following loss of H2O from protonated H–Asp–OMe, there is a methoxy group migration which is followed by loss of CO from the α-carboxyl position. This migration also is observed for the [MH+-NH3]+ ion derived from H–Asn–OMe. The fragmentation reactions of a variety of protonated α- and β-dipeptides, H–Asp–Xxx–OR and H–Asp(Xxx)–OH, also have been elucidated. For both types of linkage facile formation of the y1″ ion is observed, in line with earlier observations that protonated peptides undergo preferential cleavage at the C-terminus side of acidic residues. A characteristic reaction of protonated dipeptides with the β-linkage is elimination of H2O+CO from the α-carboxyl group of the aspartic acid residue. This is followed by elimination of the C-terminus amino acid to give a characteristic fragment ion at m/z 70, H2N+=CH−CH=C=O. Protonated dipeptides with the α-linkage show loss of H2O from the aspartic acid β-carboxyl group. This water loss is followed by elimination of ketene or ammonia. These fragment ions, which are most abundant at low collision energies, serve to identify dipeptides with the α-linkage. © 1998 John Wiley & Sons, Ltd.

An electron impact and chemical ionization study of some diethyl dicarboxylates

The electron ionization and Brønsted acid chemical ionization mass spectra of the diethyl esters of succinic acid, methylmalonic acid, glutaric acid, ethylmalonic acid and dimethylmalonic acid have been determined. The major primary fragmentation reaction of the molecular ion in the electron ionization mass spectra is by loss of OC 2H 5 while the MH + ions fragment by loss of C 2H 5OH to form the same fragment ion. Using isotopic labelling (diethyl-d 5 esters) and metastable ion studies, it is shown that the [MOC 2H 5] + ions formed from diethyl succinate and diethyl glutarate have ethyl-cationated cyclic anhydride structures which fragment further by elimination of C 2H 4 to form the protonated anhydride. For the remaining esters the [MOC 2H 5] + ions have an acylium ion structure and fragment primarily by elimination of CO to form, initially, substituted α-carboethoxy carbenium ions although there is significant rearrangement to protonated ethyl esters of olefinic acids prior to further fragmentation.

Mass spectrometric investigation of some α-trifluoromethyl-α-amino acids

The fast atom bombardment-induced mass spectrometric behaviour of four fluorinated α-amino acids was studied in detail with the aid of metastable ion studies and accurate mass measurements. Comparison with the behaviour of unfluorinated analogues suggests that the presence of fluorine makes the carbonylic oxygen the most prone to protonation. This hypothesis was confirmed by AM1 semiempirical calculations which indicate that the carbonylic oxygen of the carboxyl group exhibits, in the case of fluorinated compounds only, the highest proton affinity. © 1997 John Wiley & Sons, Ltd.

Pathways to Immonium Ions in the Fragmentation of Protonated Peptides

The pathways leading to the formation of immonium (An) ions in the fragmentation of protonated peptides were investigated using metastable ion studies, including kinetic energy release measurements, and low-energy collision-induced dissociation studies. In addition to the established pathway Bn→An+CO, it is shown that B2 ions, in suitable circumstances, fragment directly to A1 ions. In addition, metastable ion studies show that A1 ions can be formed directly from protonated di- and tripeptides most likely by concerted elimination of CO and an amino acid or smaller peptide. A2 ions can be formed directly from protonated dipeptides in part through the sequential loss of H2O+CO, although kinetic energy release measurements suggest direct elimination of HCOOH also may be occurring. Internal immonium ions are shown to originate by further fragmentation of An ions and by further fragmentation of Yn″ ions. © 1997 by John Wiley & Sons, Ltd.

Metastable ion study of organosilicon compounds. Part X. o-CH 3C 6H 4COOSi(CH 3) 3 and o-CF 3C 6H 4COOSi(CH 3) 3

The unimolecular metastable ion dissociations of o-trimethylsilyl toluate, o-CH 3C 6H 4COOSi(CH 3) 3 (1) and its fluorine analogue, o-trimethylsilyl α, α, α-trifluorotoluate, o-CF 3C 6H 4COOSi(CH 3) 3 ( 2), upon electron impact, have been investigated by means of B/E linked scan and high resolution data. The fragmentation processes of these compounds were elucidated with the aid of those of the corresponding acids, o-toluic acid, o-CH 3C 6H 4COOH ( 3) and o- α, α, α-trifluorotoluic acid, o-CF 3C 6H 4COOH ( 4), respectively. No molecular ion is observed for 2, but a fairly abundant molecular ion is observed for 1. The fragmentation of 1 +· is different from that of 2 +·, except for the loss of −CH 3 from the respective molecular ions. In the case of 1, (CH 3) 3SiOH is eliminated from 1 +· with the migration of the hydrogen from the methyl group attached to the benzene ring to the ether oxygen, giving rise to the peak at m/ z 118. The corresponding loss was not observed in the fragmentation of 2 +·. This was attributable to a greater electronegativity of the fluorine atom than that of a hydrogen atom. In the fragmentations of the compounds studied here, the so-called ortho-effect is operative. During the fragmentation of 2 +· and 4 +·, interesting F atom rearrangements were observed.

Metastable ion study of organosilicon compounds. Part IX. CH 3COOSi(CH 3) 3 and CF 3COOSi(CH 3) 3

The unimolecular metastable dissociation of trimethylsilyl acetate, CH 3COOSi(CH 3) 3 ( 1), and its fluorine analogue, trimethylsilyl trifluoroacetate, CF 3COOSi(CH 3) 3 ( 2), upon electron impact have been investigated by means of a B/E linked scan, high resolution data, and D-labeling. The results are compared with those of the carbon analogue, tert-butyl acetate, CH 3COOC(CH 3) 3 ( 3). No molecular ion of any of these compounds can be observed, but loss of CH 3 occurs exclusively from the trimethylsilyl or tert-butyl groups. The fragmentation of 1 + is slightly different from that of 3 +, and quite different from that of 2 +, In the case of 3 +, (CH 3) 2CO is eliminated from [3-CH 3] +, giving rise to the peak at m z 43 , but the loss of (CH 3) 2SiO does not occur from [ 1-CH 3] +. In the case of 2 +·, an interesting fluorine atom (F) migration is observed.

A Mass Spectrometric Investigation of a Series of [ReOX(PY)2] Complexes Containing Bidentate Phosphinophenolate and Phosphinoamine Ligands

The mass spectrometric characterization of a series of [ReOX(PY)2] complexes containing bidentate phosphinoenolate and phosphinoamine ligands has been achieved by electron impact mass spectrometry and metastable ion studies. The data obtained showed a higher stability of the complexes bearing the phosphinoenolate ligand with respect to the phosphinoamine ligand. An increase in the stability of the complexes by decreasing the atomic radius of the halogen was also observed.