Low-energy collision-induced fragmentation of negative ions derived from ortho-, meta-, and para-hydroxyphenyl carbaldehydes, ketones, and related compounds

Collision-induced dissociation (CID) mass spectra of anions derived from several hydroxyphenyl carbaldehydes and ketones were recorded and mechanistically rationalized. For example, the spectrum of m/z 121 ion of deprotonated ortho-hydroxybenzaldehyde shows an intense peak at m/z 93 for a loss of carbon monoxide attributable to an ortho-effect mediated by a charge-directed heterolytic fragmentation mechanism. In contrast, the m/z 121 ion derived from meta and para isomers undergoes a charge-remote homolytic cleavage to eliminate an *H and form a distonic anion radical, which eventually loses CO to produce a peak at m/z 92. In fact, for the para isomer, this two-step homolytic mechanism is the most dominant fragmentation pathway. The spectrum of the meta isomer on the other hand, shows two predominant peaks at m/z 92 and 93 representing both homolytic and heterolytic fragmentations, respectively. (18)O-isotope-labeling studies confirmed that the oxygen in the CO molecule that is eliminated from the anion of meta-hydroxybenzaldehyde originates from either the aldehydic or the phenolic group. In contrast, anions of ortho-hydroxybenzaldehyde and 2-hydroxy-1-naphthaldehyde, both of which show two consecutive CO eliminations, specifically lose the carbonyl oxygen first, followed by that of the phenolic group. Anions from 2-hydroxyphenyl alkyl ketones lose a ketene by a hydrogen transfer predominantly from the alpha position. Interestingly, a very significant charge-remote 1,4-elimination of a H(2) molecule was observed from the anion derived from 2,4-dihydroxybenzaldehyde. For this mechanism to operate, a labile hydrogen atom should be available on the hydroxyl group adjacent to the carbaldehyde functionality.     

Fragmentation pathways of deprotonated ortho-hydroxybenzyl alcohol

The ortho, meta, and para isomers of hydroxybenzyl alcohol can be unequivocally distinguished by the collision-induced dissociation mass spectra of their anions. The presence of a prominent peak at m/z 121 for an elimination of a dihydrogen molecule renders the ortho-isomer spectrum markedly different from those of its meta and para congeners. Investigations carried out with deuterium-labeled isotopologues of the ortho isomer verified that the labile hydrogen atom on the hydroxyl group and one of the benzylic hydrogen atoms are specifically removed in the formation of the m/z 121 ion. The ortho-isomer spectrum also showed a prominent peak at m/z 93. Experimental data indicated that the m/z 93 product ion originates either from a two-step H₂and CO elimination mechanism or from a direct loss of a HCHO molecule from the precursor anion. The intensity ratio of the m/z 93 and 94 peaks in the spectrum recorded from the m/z 124 ion generated from a sample of o-hydroxybenzyl alcohol dissolved in D₂O supported the notion that the direct HCHO loss is the more dominant pathway for the generation of the phenolate ion under low activation conditions. In contrast, the two-step mechanism becomes the more dominant pathway under high collisional activation conditions. The spectrum also showed a weak peak at m/z 105 for a water loss. Based on computational data, the m/z 105 ion generated in this way appears to be a composite generated from a common ion-neutral complex intermediate in which a hydroxyl anion is positioned equidistantly between one of the benzylic hydrogens and a nearby hydrogen atom of the benzene ring. Upon activation, the complex dissociates to form either a phenide or a quinone methide anion. The reaction forming a carbon dioxide adduct under ion-mobility conditions was used to support the proposed water-loss mechanism.     

Low-energy collision-induced fragmentation of negative ions derived from diesters of aliphatic dicarboxylic acids made with hydroxybenzoic acids

Diesters of ortho-hydroxybenzoic acid (salicylic acid) made with glutaric, adipic, and pimelic acids are the monomers of some potential drug candidates for aspirin patches. Collision-induced dissociation (CID) spectra of negative ion derived from these compounds show a 120-Da 'neutral loss' specific to the ortho isomers. In contrast, the anions derived from diesters of meta- and para-hydroxybenzoic acids show a 138-Da loss for an elimination of elements of hydroxybenzoic acid by a charge-remote mechanism. Deuterium labeling studies confirmed that the hydrogen atom transferred for hydroxybenzoic acid loss originates specifically from the alpha position of the dicarboxylic acid moiety. Although all spectra showed a peak at m/z 137, a charge-mediated process specific for the ortho compounds renders it the most prominent peak in the spectra of ortho compounds. Appropriate deuterium labeling experiments demonstrated that the hydrogen atom transferred for the formation of the m/z 137 ion in ortho compounds is specifically derived from the alpha position of the dicarboxylic acid moiety.     

Ortho effect in electron ionization mass spectrometry of <Emphasis Type="Italic">N</Emphasis>-acylanilines bearing a proximal halo substituent

Electron ionization (EI) mass spectra are not very helpful for characterizing ortho, meta, and para isomers of underivatized haloanilines since their spectra are virtually identical. In contrast, when the amino group of chloro-, bromo-, or iodoanilines is transformed to an N-formyl, N-acetyl, or N-benzoyl derivative, the spectra of the derivatives reveal a highly dramatic loss of a halogen radical, instead of an HX elimination usually expected from an "ortho effect." For example, the spectra of N-formyl, N-acetyl, and N-benzoyl derivatives of ortho isomers of chloro-, bromo-, and iodoanilines show a very prominent peak at m/z 120, 134, and 196, respectively, for the loss of the corresponding halogen atom.     

Substituted 3-phenylpropenoates and related analogs: electron ionization mass spectral fragmentation and density functional theory calculations

Analysis of ethyl 3-(2-chlorophenyl)propenoate by electron ionization mass spectrometry showed the distinct loss of an ortho chlorine. To characterize the structural requisites for the observed mass fragmentation, a series of 30 halogen-substituted 3-phenylpropenoate-related structures were examined. All ester-containing alkene derivatives exhibited loss of the distinctive chlorine from the 2-position of the phenyl ring. Analogous derivatives with the halogen (chlorine or bromine) in the para position did not evidence selective halogen loss. Results demonstrated that substituted 3-phenylpropenoates and their analogs fragment via the formation of a previously reported benzopyrylium intermediate. To understand the correlation between the intramolecular radical substitution and the abundance and selectivity of the chlorine (or other halogen) displacement, density functional theory calculations were performed to determine the charge on the principal cation involved in the chlorine loss (in the ortho, meta, and para positions), the charge for the neutral radical (noncation), the excess alpha-electron density on the relevant atom and the energy to form the cation from the neutral atom (ionization energy). Results showed that the selectivity and extent of halogen displacement correlated highly to the electrophilicity of the radical cation as well as the neutral radical. These data further support the proposed fragmentation mechanism involving intramolecular radical elimination.     

“Meta Elimination,” a Diagnostic Fragmentation in Mass Spectrometry

The diagnostic value of the “ortho effect” for unknown identification by mass spectrometry is well known. Here, we report the existence of a novel “meta effect,” which adds to the repertoire of useful mass spectrometric fragmentation mechanisms. For example, the meta-specific elimination pathway described in this report enables unequivocal identification of meta isomers from ortho and para isomers of carboxyanilides. The reaction follows a specific path to eliminate a molecule of meta-benzyne, from the anion produced after the initial decarboxylation of the precursor. Consequently, in the CID spectra of carboxyanilides, a peak for the (R-CO-NH)^– anion is observed only for the meta isomers. For example, the peaks observed at m/z 58, 86, 120, 128, and 170 from acetamido-, butamido-, benzamido, heptamido-, and decanamido-benzoates, respectively, were specific only to the spectra of meta isomers.     

Unusual luminescence characteristics of aminobiphenyls

Analysis of fluorescence solvatochromic shifts of ortho, meta and para aminobiphenyls reveals that the change in dipolemoment of m-aminobiphenyl on excitation is more when compared to other isomers. This change is due to the resonance interaction of unsubstituted phenyl ring with -NH2 group at meta position in the excited singlet state. The fluorimetric titration curves of three aminobiphenyls are found to be different from each other. The stretched sigmoidal curves obtained for m-aminobiphenyl indicates that the rates of proton transfer in S1 state are comparable to the rates of fluorescence.     

Noncatalytic kinetic study on site-selective H/D exchange reaction of phenol in sub- and supercritical water

The site-selective H/D exchange reaction of phenol in sub- and supercritical water is studied without added catalysts. In subcritical water in equilibrium with steam at 210-240 degrees C, the H/D exchange proceeds both at the ortho and para sites in the phenyl ring, with no exchange observed at the meta site. The pseudo-first-order rate constants are of the order of 10(-4) s(-1); 50% larger for the ortho than for the para site. In supercritical water, the exchange is observed also at the meta site with the rate constant in the range of 10(-6)-10(-4) s(-1). As the bulk density decreases, the exchange slows down and the site selectivity toward the ortho is enhanced. The enhancement is due to the phenol-water interaction preference at the atomic resolution. The site selectivity toward the ortho is further enhanced when the reaction is carried out in benzene/water solution. Using such selectivity control and the reversible nature of the hydrothermal deuteration/protonation process, it is feasible to synthesize phenyl compounds that are deuterated at any topological combination of ortho, meta, and para sites.     

Collision‐induced dissociation processes of protonated benzoic acid and related compounds: competitive generation of protonated carbon dioxide or protonated benzene

Upon activation in the gas phase, protonated benzoic acid (m/z 123) undergoes fragmentation by several mechanisms. In addition to the predictable water loss followed by a CO loss, the m/z 123 ion more intriguingly eliminates a molecule of benzene to generate protonated carbon dioxide (H ‐ O⁺ ═ C ≡ O , m/z 45), or a molecule of carbon dioxide to yield protonated benzene (m/z 79). Experimental evidence shows that the incipient proton ambulates during the fragmentation processes. For the CO₂ or benzene loss, protonated benzoic acid transfers the charge‐imparting proton initially to the ortho position and then to the ipso position to generate a transient species which dissociates to form an ion‐neutral complex between benzene and protonated CO₂. The formation of the m/z 45 ion is not a phenomenon unique to benzoic acid: spectra from protonated isophthalic acid, terephthalic acid, trans‐cinnamic acid and some aliphatic acids also displayed a peak for m/z 45. However, the m/z 45 peak is structurally diagnostic only for certain benzene polycarboxylic acids because the spectra of compounds with two carboxyl groups on adjacent ring carbons do not produce a peak at m/z 45. For the m/z 79 ion to be formed, an intramolecular reaction should take place in which protonated CO₂ within the ion‐neutral complex acts as the attacking electrophile to transfer a proton to benzene. Copyright © 2017 John Wiley & Sons, Ltd.     

Regioselective Synthesis of Para‐Bromo Aromatic Compounds

Reaction of substituted benzene rings with N‐bromophthalimide, under neutral conditions, gave the corresponding bromo derivatives with a preference for the formation of the para bromo isomer over the ortho isomer. The simple work‐up procedure minimizes loss of product and the yields are good.     

Acid generation in the thermal decomposition of diaryliodonium salts

Diphenyliodonium tetrafluoroborate and diphenyliodonium hexafluorophosphate have been found to generate up to two equivalents of hydrogen fluoride per equivalent of the iodonium salt by pyrolysis at 239°C in the neat state and at 150°C in the presence of anisole or nitrobenzene. The formation of hydrogen fluoride is presumed to arise by dissociation of hydrogen tetrafluoroborate or hydrogen hexafluorophosphate initially formed, due to the high temperatures, thus giving rise also to the Lewis acids boron trifluoride and phosphorus pentafluoride, respectively. A detailed analysis of the volatile organic products of the decomposition of the diphenyliodonium salts was also carried out. Many products were identified in all of the cases studied. For example, the neat decomposition of diphenyliodonium tetrafluoroborate afforded benzene, fluorobenzene, iodobenzene, the three isomeric iodobiphenyls, biphenyl, three isomeric terphenyls, and one or more of the diiodobiphenyls, iodoterphenyls, and polyaromatics. Among the iodobiphenyls, the ortho and para isomers were found to predominate over the meta isomer. The terphenyl isomers did not exhibit this ortho, para selectivity. It was significant that decomposition of the diaryliodonium salts in anisole suspension did not afford methoxybiphenyls or iodomethoxybiphenyls. An interpretation of these results is presented. © 1996 John Wiley & Sons, Inc.     

Cation-modified silikalit-2 as a selective adsorbent for gas chromatography columns

A selective adsorbent was proposed on the basis of synthetic zeolite silikalit-2 modified with cadmium, tallium, and silver cations. It is intended for the gas chromatographic separation of some isomeric benzene derivatives. The adsorbent possesses pronounced retention properties to para isomers of aromatic compounds, which is due to the molecular sieve properties of the zeolite and the ability of benzene derivatives to form unstable complexes with cations entering the composition of the zeolite. Low selectivity to ortho and meta isomers is due to only the complexation effect.     

Chlorination of 2-phenoxypropanoic acid with NCP in aqueous acetic acid: using a novel ortho-para relationship and the para/meta ratio of substituent effects for mechanism elucidation

Rate constants were measured for the oxidative chlorodehydrogenation of (R,S)-2-phenoxypropanoic acid and nine ortho-, ten para- and five meta-substituted derivatives using (R,S)-1-chloro-3-methyl-2,6-diphenylpiperidin-4-one (NCP) as chlorinating agent. The kinetics was run in 50% (v/v) aqueous acetic acid acidified with perchloric acid under pseudo-first-order conditions with respect to NCP at temperature intervals of 5 K between 298 and 318 K, except at the highest temperature for the meta derivatives. The dependence of rate constants on temperature was analyzed in terms of the isokinetic relationship (IKR). For the 20 reactions studied at five different temperatures, the isokinetic temperature was estimated to be 382 K, which suggests the preferential involvement of water molecules in the rate-determining step. The dependence of rate constants on meta and para substitution was analyzed using the tetralinear extension of the Hammett equation. The parameter lambda for the para/meta ratio of polar substituent effects was estimated to be 0.926, and its electrostatic modeling suggests the formation of an activated complex bearing an electric charge near the oxygen atom belonging to the phenoxy group. A new approach is introduced for examining the effect of ortho substituents on reaction rates. Using IKR-determined values of activation enthalpies for a set of nine pairs of substrates with a given substituent, a linear correlation is found between activation enthalpies of ortho and para derivatives. The correlation is interpreted in terms of the selectivity of the reactant toward para- or ortho-monosubstituted substrates, the slope of which being related to the ortho effect. This slope is thought to be approximated by the ratio of polar substituent effects from ortho and para positions in benzene derivatives. Using the electrostatic theory of through-space interactions and a dipole length of 0.153 nm, this ratio was calculated at various positions of a charged reaction center along the benzene C1-C4 axis, being about 2.5 near the ring and decreasing steeply with increasing distance until reaching a minimum value of -0.565 at 1.3 nm beyond the aromatic ring. Activation enthalpies and entropies were estimated for substrates bearing the isoselective substituent in either ortho and para positions, being demonstrated that they are much different from the values for the parent substrate. The electrophilic attack on the phenolic oxygen atom by the protonated chlorinating agent is proposed as the rate-determining step, this step being followed by the fast rearrangement of the intermediate thus formed, leading to products containing chlorine in the aromatic ring.     

Generation and characterization of distonic dehydrophenoxide radical anions under electrospray and atmospheric pressure chemical ionizations

We have explored the possibilities of generating radical anions under electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) conditions. By using different sets of ortho-, meta-, and para-isomers of nitrobenzoic acids, methylphenols, and nitrophenols, and m-, and p-isomers of hydroxybenzaldehydes and hydroxyacetophenones as the precursor molecules, we have successfully generated the isomeric distonic dehydrophenoxide radical anions (m/z 92) using the ESI process by applying relatively high capillary voltages, the in-source dissociation (ISD) condition. Under the same conditions, the o-hydroxybenzaldehyde and the o-hydroxyacetophenone yielded the even-electron dehydrophenoxide anion (m/z 93) due to the well-known ortho-effect. The distonic phenoxide radical anions at m/z 92 were also generated under APCI-ISD conditions by using m- and p-isomers of nitrobenzaldehydes and nitroacetophenones. While the o-nitrobenzaldehyde and the o-nitroacetophenone mainly yielded the phenoxide anion at m/z 93, due to the ortho-effect. The collision-induced dissociation (CID) experiments of all the anionic precursor molecules formed from either ESI or APCI produced comparable mass spectra as those observed in the ESI-ISD or the APCI-ISD experiments. The radical anions at m/z 92 reacted with CO₂ and O₂ to form the CO₂ adduct and the oxygen atom abstraction product, respectively, revealing the dual-character of the distonic radical anions, the phenide ion and the phenyl radical. Computational studies support the results of the ion-molecule reactions.     

Phototransposition reactions of arylboronate esters in acetonitrile and 2,2,2-trifluoroethanol

The phototransposition (para, meta, ortho) reactions of the arylboronate esters 4-, 3-, and 2-(4',4',5',5'-tetramethyl-1',3',2'-dioxaborolanyl)toluenes (1, 2, and 3, respectively) in both acetonitrile and 2,2,2-trifluoroethanol (TFE) using 254 nm irradiation have been examined. The irradiations resulted in steady-state compositions of para (5%), meta (19%), and ortho (76%) isomers in acetonitrile starting from the ortho isomer and para (12%), meta (54%), and ortho (35%) isomers in TFE starting from the para isomer. Analysis of the (13)C NMR spectrum of the product mixture obtained from the photochemistry of the para isomer selectively deuterated at C3 and C5 (1d(2)()) revealed that the boron-substituted carbon is the active one in the phototransposition reactions in both acetonitrile and TFE. Similar results were observed for irradiations of 1 in cyclohexane. Fluorescence spectra, singlet-state lifetimes, and Stern-Volmer quenching of fluorescence with 2,3-dimethyl-1,3-butadiene indicated that the excited singlet states of these three isomers were spectroscopic minima and that the excited singlet state was the reactive one for 3 in acetonitrile.     

Investigations in the benzazole and naphthazole series

1-[1'-Benzylbenzimidazolyl]-5-halogenophenyl-3-methylformazans with the halogen (chlorine or bromine) in the para or ortho positions have been synthesized. In a comparative study of the reactions of the ortho and para halogen-containing isomers, steric hindrance due to a halogen in the ortho position of the phenyl radical has been observed in the formation of tetrazolium salts and nickel and copper complexes, and in the capacity of phototropic transformations.For part XXV, see [1].     

Effect of hydrogen bonding on the polymerization of N-(o-,m-, and p-methoxyphenyl)- and N-(o-,m-, and p-ethoxyphenyl)-methacrylamides

Summary Study of the rates of polymerization of N-(o-, m-, and p-methoxyphenyl)- and N-(o-, m-, and p-ethoxy-phenyl)methacrylamides showed that the ortho isomers of these compounds, in which there is no association between the molecules, polymerize much more rapidly than their meta and para isomers, the molecules of which are associated through hydrogen bonds.     

An unprecedented rearrangement in collision-induced mass spectrometric fragmentation of protonated benzylamines

The collision-induced dissociation (CID) mass spectra of several protonated benzylamines are described and mechanistically rationalized. Under collision-induced decomposition conditions, protonated dibenzylamine, for example, loses ammonia, thereby forming an ion of m/z 181. Deuterium labeling experiments confirmed that the additional proton transferred to the nitrogen atom during this loss of ammonia comes from the ortho positions of the phenyl rings and not from the benzylic methylene groups. A mechanism based on an initial elongation of a C--N bond at the charge center that eventually cleaves the C--N bond to form an ion/neutral complex of benzyl cation and benzylamine is proposed to rationalize the results. The complex then proceeds to dissociate in several different ways: (1) a direct dissociation to yield a benzyl cation observed at m/z 91; (2) an electrophilic attack by the benzyl cation within the complex on the phenyl ring of the benzylamine to remove a pair of electrons from the aromatic sextet to form an arenium ion, which either donates a ring proton (or deuteron when present) to the amino group forming a protonated amine, which undergoes a charge-driven heterolytic cleavage to eliminate ammonia (or benzylamine) forming a benzylbenzyl cation observed at m/z 181, or undergoes a charge-driven heterolytic cleavage to eliminate diphenylmethane and an immonium ion; and (3) a hydride abstraction from a methylene group of the neutral benzylamine to the benzylic cation to eliminate toluene and form a substituted immonium ion. Corresponding benzylamine and dibenzylamine losses observed in the spectra of protonated tribenzylamine and tetrabenzyl ammonium ion, respectively, indicate that the postulated mechanism can be widely applied. The postulated mechanisms enabled proper prediction of mass spectral fragments expected from protonated butenafine, an antifungal drug.     

Generation of regiospecific carbanions under electrospray ionisation conditions and their selectivity in ion-molecule reactions with CO2

Regiospecific formation of carbanions from a set of geometrical (cis and trans isomers) and five different sets of positional isomers (ortho, meta and para isomers) of aromatic carboxylic acids is reported under negative electrospray ionisation conditions by decarboxylation of the carboxylate anions. The structures of decarboxylated anions, [(M-H)-CO(2)](-), are studied by ion-molecule reactions with carbon dioxide in the collision cell of a triple quadrupole mass spectrometer. The [(M-H)-CO(2)](-) ions generated from the trans and meta/para isomers react with CO(2) to produce product ions corresponding to the addition of one CO(2), which confirms the survival of the [(M-H)-CO(2)](-) ions as carbanions. On the other hand, the [(M-H)-CO(2)](-) ions generated from cis and ortho isomers failed to react with CO(2) due to rapid isomerisation of the initially generated carbanion to a aromatic carboxylate/oxide anion, which is unreactive with CO(2), through a facile intramolecular proton transfer from the proton-containing substituent to the carbanion site. When the experiments were performed at high desolvation temperatures (300 degrees C), instead of 100 degrees C, the relative abundance of [(M-H)-CO(2)](-) ions and the corresponding CO(2) adduct in ion-molecule reaction experiments increased significantly due to minimisation of proton exchange. Quantum chemical calculations on some of the generated isomeric carbanions and their isomerised products due to proton transfer support the selective stability of carbanions.     

Gas-phase reactions of aryl radicals with 2-butyne: experimental and theoretical investigation employing the N-methyl-pyridinium-4-yl radical cation

Aromatic radicals form in a variety of reacting gas-phase systems, where their molecular weight growth reactions with unsaturated hydrocarbons are of considerable importance. We have investigated the ion-molecule reaction of the aromatic distonic N-methyl-pyridinium-4-yl (NMP) radical cation with 2-butyne (CH(3)C≡CCH(3)) using ion trap mass spectrometry. Comparison is made to high-level ab initio energy surfaces for the reaction of NMP and for the neutral phenyl radical system. The NMP radical cation reacts rapidly with 2-butyne at ambient temperature, due to the apparent absence of any barrier. The activated vinyl radical adduct predominantly dissociates via loss of a H atom, with lesser amounts of CH(3) loss. High-resolution Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry allows us to identify small quantities of the collisionally deactivated reaction adduct. Statistical reaction rate theory calculations (master equation/RRKM theory) on the NMP+2-butyne system support our experimental findings, and indicate a mechanism that predominantly involves an allylic resonance-stabilized radical formed via H atom shuttling between the aromatic ring and the C(4) side-chain, followed by cyclization and/or low-energy H atom β-scission reactions. A similar mechanism is demonstrated for the neutral phenyl radical (Ph˙)+2-butyne reaction, forming products that include 3-methylindene. The collisionally deactivated reaction adduct is predicted to be quenched in the form of a resonance-stabilized methylphenylallyl radical. Experiments using a 2,5-dichloro substituted methyl-pyridiniumyl radical cation revealed that in this case CH(3) loss from the 2-butyne adduct is favoured over H atom loss, verifying the key role of ortho H atoms, and the shuttling mechanism, in the reactions of aromatic radicals with alkynes. As well as being useful phenyl radical analogues, pyridiniumyl radical cations may form in the ionosphere of Titan, where they could undergo rapid molecular weight growth reactions to yield polycyclic aromatic nitrogen hydrocarbons (PANHs).