Acyclic distonic acylium ions: Dual free radical and acylium ion reactivity in a single molecule

Three gaseous acyclic distonic acylium ions: *CH2-CH2-C+=O, *CH2-CH2-CH2-C+=O, and *CH2=C(CH2)-C+=O, are found to display dual free radical and acylium ion reactivity; with appropriate neutrals, they react selectively either as free radicals with inert charge sites, or (and more pronouncedly) as acylium ions with inert radical sites. The free radical reactivity of the ions is demonstrated via the Kenttamaa reaction: CH3S* abstraction with the spin trap dimethyl disulfide; their ion reactivity by two reactions most characteristic of acylium ions: transacetalization with 2-methyl-1,3-dioxolane and the gas-phase Meerwein reaction, that is, expansion of the three-membered epoxide ring of epichlorohydrin to the five-membered 1,3-dioxolanylium ion ring. In "one-pot" reactions with gaseous mixtures of epichlorohydrin and dimethyl disulfide, the ions react selectively at either site, but more readily at the acylium charge site, to form the two mono-derivatized ions. Further reaction at either the remaining free radical or acylium charge site forms a single bi-derivatized ion as the final product. Becke3LYP/6-31G(d) calculations predict the reactions at the acylium charge sites of the three distonic ions to be highly exothermic, and both the "hot" transacetalization and epoxide ring expansion products of *CH2-CH2-CH2-C+=O to dissociate rapidly by H2C=CH2 loss in overall exothermic processes. The calculations also predict highly spatially separate odd spin and charge sites for the novel cyclic distonic ketal ions formed by the reactions at the acylium charge sites.     

Ketalization of gaseous acylium ions

A novel reaction of gaseous acylium ions: ketalization with diols and analogs, has been systematically studied via pentaquadrupole MS2 and MS3 experiments and ab initio calculations. A variety of alpha,beta-diols and their amino, thiol, ether, and thioether analogs have been tested for reactivity, mechanism evaluation, site selectivity, and for the effects of alpha- and beta-interfunctional separation. As for condensed-phase ketalization of neutral carbonyl compounds followed by hydrolysis, gaseous acylium ions are chemically deactivated in the form of cyclic ionic ketals by ketalization, and are efficiently released via on-line collision-induced dissociation. Ketalization of acylium ions is shown to identify and structurally characterize alpha,beta-diols and their analogs, and to distinguish regioisomers. Diastereomers can also be distinguished, as illustrated for cis and trans 1,2-diaminocyclohexane. The MS2 and MS3 data together with 18O-labeling and ab initio calculations establish for acylium ion ketalization a mechanism of anchimeric assistance with participation of the neighboring acyl group.     

The gas-phase Meerwein reaction

A systematic investigation of a novel epoxide and thioepoxide ring expansion reaction promoted by gaseous acylium and thioacylium ions is reported. As ab initio calculations predict, and 18O-labeling and MS3 pentaquadrupole experiments demonstrate, the reaction proceeds by initial O(S)-acylation of the (thio)epoxides followed by rapid intramolecular nucleophilic attack that results in three-to-five-membered ring expansion, and forms cyclic 1,3-dioxolanylium, 1,3-oxathiolanylium, or 1,3-dithiolanylium ions. This gas-phase reaction is analogous to a condensed-phase reaction long since described by H. Meerwein (Chem. Ber. 1955, 67, 374), and is termed as "the gas-phase Meerwein reaction"; it occurs often to great extents or even exclusively, but in some cases, particularly for the most basic (thio)epoxides and the most acidic (thio)acylium ions, proton transfer (eventually hydride abstraction) competes efficiently, or even dominates. When (thio)epoxides react with (thio)-acylium ions, the reaction promotes O(S)-scrambling; when epoxides react with thioacylium ions and the adducts are dissociated, it promotes S/O replacement. An analogous four-to-six-membered ring expansion also occurs predominantly in reactions of trimethylene oxide with acylium and thioacylium ions.     

Optimized production of the acylium diagnostic ions in the chemical ionization NO+ mass spectra of long-chain monoolefins

A recent reinvestigation of the reactivity of NO⁺ towards straight-chain monoolefinic compounds revealed that the characteristic acylium ions, previously reported for alkenyl acetates and related compounds, could also be obtained from alkenes and alkenoic acids (or esters). In this study, the influence of the sample pressure and that of NO on the production of the acylium ions was investigated, leading to disappearance graphs indicative of a strong dependence on these experimental factors. This gives a further explanation for previous apparent discrepancies in the literature and the optimum conditions of use for double-bond location in a variety of substituted or unsubstituted monoolefins.     

Experiments on the formation of acylium ions from alkenic compounds following chemical ionization with no +

Alkenic compounds when subjected to chemical ionization with NO⁺ yield two acylium ions by oxidative cleavage of the double bond. Studies on the mechanism of formation of these ions are reported.     

N-terminal derivatization and fragmentation of neutral peptides via ion--molecule reactions with acylium ions: toward gas-phase Edman degradation?

The gas-phase ion-molecule reactions of neutral alanylglycine have been examined with various mass-selected acylium ions RCO(+) (R= CH(3), CD(3), C(6)H(5), C(6)F(5) and (CH(3))( 2)N), as well as the transacylation reagent O-benzoylbenzophenone in a Fourier transform ion cyclotron resonance mass spectrometer. Reactions of the gaseous dipeptide with acylium ions trapped in the ICR cell result in the formation of energized [M + RCO](+) adduct ions that fragment to yield N-terminal b-type and C-terminal y-type product ions, including a modified b(1) ion which is typically not observed in the fragmentation of protonated peptides. Judicious choice of the acylium ion employed allows some control over the product ion types that are observed (i.e., b versus y ions). The product ion distributions from these ion--molecule reactions are similar to those obtained by collision-activated dissociation in a triple quadrupole mass spectrometer of the authentic N-acylated alanylglycine derivatives. These data indicate that derivatization of the peptide in the gas-phase occurs at the N-terminal amine. Ab initio molecular orbital calculations, performed to estimate the thermochemistry of the steps associated with adduct formation as well as product ion formation, indicate that (i) the initially formed adduct is energized and hence likely to rapidly undergo fragmentation, and (ii) the likelihood for the formation of modified b(1) ions in preference to y(1) ions is dependent on the R substituent of the acylium ion. The reaction of the tetrapeptide valine--alanine--alanine--phenylalanine with the benzoyl cation was also found to yield a number of product ions, including a modified b(1) ion. This result suggests that the new experimental approach described here may provide a tool to address one of the major limitations associated with traditional mass spectrometric peptide sequencing approaches, that is, determination of the identity and order of the two N-terminal amino acids. Analogies are made between the reactions observed here and the derivatization and N-terminal cleavage reactions employed in the condensed-phase Edman degradation method.     

Gas-phase oxirane addition to acylium ions on reaction with 1,3-dioxolanes elucidated by tandem and triple stage mass spectrometric experiments

Acylium ions containing a variety of substituents all undergo an unprecedented reaction with 1,3-dioxolanes which gives rise to a cyclic, resonance-stabilized oxonium ion, formally the product of oxirane (C₂H₄O) addition to the reagent ion. The structure for the ion–molecule product is supported by multiple-stage mass spectrometric experiments, performed in a pentaquadrupole mass spectrometer, which show the expected fragmentation by C₂H₄O loss to yield the original reactant acylium ions. The oxonium ions are formed in relatively high abundance in many cases and are observed even when proton-transfer reactions would be expected to occur competitively owing to the acidity of some of the acylium ions studied. This ion–molecule reaction is proposed to serve as a general method for identification and/or trapping of ions of the whole acylium ion class and also for the gas-phase generation of the oxonium ions. The reaction with 1,3-dioxolane is also useful in distinguishing the most stable C₂H₃O⁺ ion, the acetyl cation, from its two stable isomers, O-protonated ketene and the oxiranyl cation. The thioacetyl cation, the only sulfur analog investigated, also reacts with dioxolane to form the corresponding oxirane addition product, indicating that the C₂H₄O addition reaction occurs and that it may be useful for identification of the thioacylium class and for the gas-phase generation of sulfur analogs of oxonium ions.     

Electron capture dissociation of b (2+) peptide fragments reveals the presence of the acylium ion structure

Electron capture dissociation (ECD) of peptides and their fragments has now been extended to b ( n) ( 2+) ions, where it also produced far more structural information than collisional activation. Interestingly, b ( n) ( 2+) ions revealed abundant loss of CO from radical monocations and the presence of c ((n - 1)) ( +.) fragments. The CO loss from peptide radical cations is unusual and was attributed to neutralization of the -C identical with O(+) group in the acylium ion structure, supported by the observation of c ( (n - 1)) ( +.) ions that can only be formed from an open-chain ion. These characteristic features were most prominent for b ( 12)( 2+) ions of renin substrate and least prominent for b ( n) ( 2+) ions of substance P (n = 9,10). Totally, out of seven b ( n) ( 2+) ions studied, CO loss above 3% level was present in all spectra as well as c ( (n - 1))( +.) fragments of three species, suggesting that the acylium ion structure plays a significant role for at least some b ( 2+) ions. This is an unexpected result in view of the literature data for small, singly charged b ions, for which the protonated oxazolone structure is favoured in ab initio calculations. Apparently, more studies are required before extrapolating the small molecule results to large species. The CO loss in ECD can be used for distinguishing between b and y ions in the MS/MS spectrum of larger molecules.     

Fragmentation of acylium ions from methyl levulinate. Isomerization processes involving carbon and oxygen atoms of both carbonyl groups

The fragmentations of the acylium ions O?C⁺? CH₂? CH₂? CO₂CH₃ and O?C⁺? CH₂? CH₂? COCH₃ generated from methyl levulinate are governed extensively by the interaction of the two carbonyl groups. Both species eliminate a molecule of CO unimolecularly and under CID conditions. The results derived from measurements of ¹³C and ¹⁸O labelled precursors, together with kinetic energy release values, have been used to study the mechanisms. In the first of these acylium ions, both carbonyl groups are equivalent; this phenomenon can be the result of a 1,4 methoxy shift. In the second acylium ion, only the oxygen atoms change their positions; this isomerization occurs via the [M? H]⁺ of γ-valerolactone. Some other fragmentation processes also discussed in relation to ²H labelling are the formation of the [M ? COOCH₃] ⁺ ion and the loss of HCOOCH₃ in the collision-induced dissociation mass spectra of the first acylium ion, and the formation of the [CH₃CO]⁺ ion and the loss of H₂O for the second one.     

The atmospheric pressure Meerwein reaction

We have already shown that the in-vacuum gas-phase Meerwein reaction of (thio)acylium ions is general in nature and useful for class-selective screening of cyclic (thio)epoxides. Herein we report that this gas-phase reaction can also be performed efficiently at atmospheric pressure under both electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) conditions. This alternative expands the range of molecules that can be reacted by gas-phase Meerwein reaction. Phenyl epoxide, thiirane, 3-methoxy-2,2-dimethyloxirane, propylene oxide, 2,2'-bioxirane, trans-1,3-diphenyl-2,3-epoxypropan-1-one, epichloridrine and propylene oxide are shown to react efficiently in both ESI and APCI conditions. Tetramethylurea (TMU) and (thio)TMU were both used as dopants, being co-injected with either toluene, acetonitrile or methanol solutions of the (thio)epoxides, with similar results. In both ESI and APCI, (thio)TMU is protonated preferentially, and these labile species dissociate promptly to yield (CH3)2N-C+=O and (CH3)2NCS+, which are the least acidic and most reactive (thio)acylium ions so far tested in the gas-phase Meerwein reaction. Under the low-energy ESI conditions set to favor both the formation of the (thio)acylium ion and ion/molecule reactions, (CH3)2NCO(S)+ react competitively with (thio)TMU to form acylated (thio)TMU and with the (thio)epoxide to form the characteristic Meerwein products. Enhanced selectivity in structural characterization or for the screening of (thio)epoxides is achieved by performing on-line collision-induced dissociation of Meerwein products, particularly for the more structurally complex (thio)epoxides.     

Double transacetalization of diacylium ions

A novel gas-phase reaction of diacylium ions of the O=C=X(+)=C=O type (X = N, CH) is reported: double transacetalization with cyclic acetals or ketals. The reaction is exothermic and highly efficient, and forms members of a new class of highly charged-delocalized ions: cyclic ionic diketals. Pentaquadrupole double- and triple-stage mass spectrometric (MS(2) and MS(3)) experiments reveal the high double transacetalization reactivity of O=C=N(+)=C=O and O=C=CH(+)=C=O, whereas the synthesis of differently substituted cyclic ionic diketals is performed in MS(3) experiments via sequential mono- and double transacetalization of O=C=N(+)=C=O and O=C=CH(+)=C=O with different acetals. With cyclic acetals, the acylium-thioacylium ion O=C=N(+)=C=S reacts promptly and selectively by mono-transacetalization at its acylium site, but the free thiacylium site of its cyclic ionic ketal is nearly unreactive by double transacetalization. Therefore, only the acylium site of O=C=N(+)=C=S can be efficiently protected by transacetalization. Low-energy MS(3) collision-induced dissociation of the cyclic ionic diketals of O=C=N(+)=C=O and O=C=CH(+)=C=O sequentially frees each of the protected acylium site to form the mono-derivatized ion, and then the fully deprotected diacylium ion.     

Mono and double polar [4 + 2(+)] Diels-Alder cycloaddition of acylium ions with O-heterodienes

Gas-phase reactions of acylium ions with alpha,beta-unsaturated carbonyl compounds were investigated using pentaquadrupole multiple-stage mass spectrometry. With acrolein and metacrolein, CH(3)-C(+)(double bond)O, CH(2)(double bond)CH-C(+)(double bond)O, C(6)H(5)-C(+)(double bond)O, and (CH(3))(2)N-C(+)(double bond)O react to variable extents by mono and double polar [4 + 2(+)] Diels-Alder cycloaddition. With ethyl vinyl ketone, CH(3)-C(+)(double bond)O reacts exclusively by proton transfer and C(6)H(5)-C(+)(double bond)O forms only the mono cycloadduct whereas CH(2)(double bond)CH-C(+)(double bond)O and (CH(3))(2)N-C(+)(double bond)O reacts to great extents by mono and double cycloaddition. The positively charged acylium ions are activated O-heterodienophiles, and mono cycloaddition occurs readily across their C(+)(double bond)O bonds to form resonance-stabilized 1,3-dioxinylium ions which, upon collisional activation, dissociate predominantly by retro-addition. The mono cycloadducts are also dienophiles activated by resonance-stabilized and chemically inert 1,3-dioxonium ion groups, hence they undergo a second cycloaddition across their polarized C(double bond)C ring double bonds. (18)O labeling and characteristic dissociations displayed by the double cycloadducts indicate the site and regioselectivity of double cycloaddition, which are corroborated by Becke3LYP/6-311++G(d,p) calculations. Most double cycloadducts dissociate by the loss of a RCO(2)COR(1) molecule and by a pathway that reforms the acylium ion directly. The double cycloadduct of the thioacylium ion (CH(3))(2)N-C(+)(double bond)S with acrolein dissociates to (CH(3))(2)N-C(+)(double bond)O in a sulfur-by-oxygen replacement process intermediated by the cyclic monoadduct. The double cycloaddition can be viewed as a charge-remote type of polar [4 + 2(+)] Diels-Alder cycloaddition reaction.     

Solvation of acylium fragment ions in electrospray ionization quadrupole ion trap and Fourier transform ion cyclotron resonance mass spectrometry

In electrospray ionization (ESI) quadrupole ion trap and Fourier transform ion cyclotron resonance mass spectrometry, certain fragment ions (e.g. acylium ions) generated either during the ion transportation process (in the source interface region) or in the ion trap are found to undergo ion--molecule reactions with ESI solvent molecules (water, acetonitrile and aliphatic alcohols) to form adduct species. These unexpected solvated fragment ions severely complicate the interpretation of mass spectrometic data. High-resolution accurate mass measurements are important in establishing the elemental compositions of these adduct species and preventing erroneous data interpretation.     

Friedel-crafts reactions—XXVII : The mechanism for benzoylation of dichlorobenzenes

A search for mechanisms for benzoylation of dichlorobenzenes which are consistent not only with the nature and relative proportions of the eight products but also with the pattern of the non-additivity of substituent effects on the reaction rates, produced just one candidate. It involves chloronium ion migration and secondary protodechlorination in addition to the usual displacement of protons by acylium ions.     

Cycloacylation of chloro-substituted hydroquinone dimethyl ethers with dichloromaleic anhydride

Under the drastic conditions of Zahn—Ochwat cycloacylation of 2-chloroand 2,3-dichlorohydroquinones with dichloromaleic anhydride (a melt of anhydrous AlCl₃ and NaCl, 185—195 °C), the substrates undergo various degrees of disproportionation, which reduces the yields of the target triand tetrachloronaphthazarins. Quantum chemical calculations showed that the cycloacylation in question proceeds as a double aromatic electrophilic substitution of the vicinal protons with the corresponding oxocarbenium ions (acylium cations).     

Analyses of anandamide and endocannabinoid-like compounds using collision-induced dissociation in fast atom bombardment ionization-mass spectrometry and gas chromatography/chemical ionization-mass spectrometry.

The utility of the collision-induced dissociation (CID) of two different forms of precursor cations generated by the fast atom bombardment (FAB) ionization of N-arachidonylethanolamine (anandamide) and a series of endocannabinoid-like compounds, such as N-oleoylethanolamine, N-palmitoylethanolamine, N-stearoylethanolamine, N-linoleoylethanolamine, N-oleoylpropanolamine, and N-palmitoylpropanolamine, as a method of providing general information on their characterizations was examined. The CID spectra of lithium-adduct [M+Li]+ ions of the amines with unsaturated hydrocarbon chains were rich in structurally informative charge-site-remote (CSR) fragmentation patterns that provide information on the locations of double bonds in hydrocarbon chains. On the other hand, the CID reactions of [M+H]+ ions produced acylium ions that are derived from the cleavage of amide bonds, thus providing information on the size of the hydrocarbon chains, although CSR fragmentations were not observed. These compounds without derivatization were analyzed using gas chromatography/chemical ionization-mass spectrometry (GC/CI-MS) with a polyethylene glycol phased column with fused silica capillary pre-tubing. Identifiable molecular-related [M+H]+ ions were observed.     

Isolation, X-ray structures, and electronic spectra of reactive intermediates in Friedel-Crafts acylations

[reaction: see text] Reactive intermediates in the Friedel-Crafts acylation of aromatic donors are scrutinized upon their successful isolation and X-ray crystallography at very low temperatures. Detailed analyses of the X-ray parameters for the [1:1] complexes of different aliphatic and aromatic-acid chlorides with the Lewis acids antimony pentafluoride and pentachloride, gallium trichloride, titanium and zirconium tetrachlorides provide unexpected insight into the activation mechanism for the formation of the critical acylium carbocations. Likewise, the X-ray-structure examinations of aliphatic and aromatic acylium electrophiles also isolated as crystalline salts point to the origins of their electrophilic reactivity. Although the Wheland intermediates (as acylium adducts to arene donors) could not be isolated in crystalline form owing to their exceedingly short lifetimes, transient (UV-vis) spectra of benzenium adducts of acylium carbocations with hexamethylbenzene can be measured and directly related to Wheland intermediates with other cationic electrophiles that have been structurally established via X-ray studies.     

Why Are B ions stable species in peptide spectra?

Protonated amino acids and derivatives RCH(NH₂)C(+O)X · H⁺ (X = OH, NH₂, OCH₃) do not form stable acylium ions on loss of HX, but rather the acylium ion eliminates CO to form the immonium ion RCH = NH ₂ ⁺ . By contrast, protonated dipeptide derivatives H₂NCH(R)C(+O)NHCH(R′)C(+O)X · H⁺ [X = OH, OCH₃, NH₂, NHCH(R″)COOH] form stable B₂ ions by elimination of HX. These B₂ ions fragment on the metastable ion time scale by elimination of CO with substantial kinetic energy release (T _1/2 = 0.3–0.5 eV). Similarly, protonated N-acetyl amino acid derivatives CH₃C(+O)NHCH(R′)C(+O)X · H⁺ [X = OH, OCH₃, NH₂, NHCH(R″)COOH] form stable B ions by loss of HX. These B ions also fragment unimolecularly by loss of CO with T _1/2 values of ～ 0.5 eV. These large kinetic energy releases indicate that a stable configuration of the B ions fragments by way of activation to a reacting configuration that is higher in energy than the products, and some of the fragmentation exothermicity of the final step is partitioned into kinetic energy of the separating fragments. We conclude that the stable configuration is a protonated oxazolone, which is formed by interaction of the developing charge (as HX is lost) with the N-terminus carbonyl group and that the reacting configuration is the acyclic acylium ion. This conclusion is supported by the similar fragmentation behavior of protonated 2-phenyl-5-oxazolone and the B ion derived by loss of H-Gly-OH from protonated C₆H₅C(+O)-Gly-Gly-OH. In addition, ab initio calculations on the simplest B ion, nominally HC(+O)NHCH₂CO⁺, show that the lowest energy structure is the protonated oxazolone. The acyclic acylium isomer is 1.49 eV higher in energy than the protonated oxazolone and 0.88 eV higher in energy than the fragmentation products, HC(+O)N⁺H = CH₂ + CO, which is consistent with the kinetic energy releases measured.     

The search for stable gas phase b(1) ions derived from aliphatic amino acids: a combined experimental and ab initio study

Several previous studies have shown that b(1) ions (formally acylium ions, H(2)NCHRCO(+)) derived from protonated aliphatic amino acids are unstable in the gas phase, fragmenting via decarbonylation to form a(1) ions (iminium ions, H(2)N = CHR(+)). Herein we examine the fragmentation reactions of ten potential b(1) ion precursors to determine whether stable aliphatic b(1) ions can be formed in the gas phase. Of all the systems studied, only the aziridine b(1) ion and the dehydroalanine b(1) ion were found to be stable. These experimental results are entirely consistent with ab initio calculations (at the MP2(full)/6-311G** level) which indicate that while the loss of CO from the b(1) ion of glycine is barrierless and exoethermic, the related losses from the b(1) ions of aziridine and dehydroalanine have significant barriers (29.5 and 16.2 kcal mol(-1), respectively) and are endothermic overall.     

Studies of cyclic acetals. XXIII—low resolution,electron impact mass spectra of some 6,8-dioxa-3-thiabicyclo[3.2.1]octanes and related 2-acetoxy, 3-oxo and 3,3-dioxo derivatives

Low resolution, electron impact mass spectra of 6,8-dioxa-3-thiabicyclo[3.2.1]octane and eight C-methyl or -phenyl derivatives are, in the main, similar to those of the corresponding 3,6,8-trioxa homologs. Oxygenation on C-2 or on the sulfur atom decreases the number of prominent fragments in the scheme of decomposition and apparently affords greater opportunity for formation of small, stable, acylium ions, but the added oxygen atoms generally do not direct major new modes of fragmentation.