Bartłomiej J. Jankiewicz

Properties and reactivity of gaseous distonic radical ions with aryl radical sites.

The reactivity of carbon-centered distonic radical ions has been of interest for decades. The existence of distonic radical ions was first postulated by Gross and McLafferty in the early 1970’s.1,2 In 1978, Bouma, MacLeod and Radom reported experimental results that supported theoretical predictions of the existence of a stable ring-opened ethylene oxide distonic radical cation.3 Ions with spatially separated charge and radical sites were coined as “distonic ions” by Yates, Bouma, and Radom4 in 1984. They later refined this definition5 to correspond to radical ions generated by ionization of a zwitterion, ylide, or diradical. Eberlin and co-workers later introduced the term “distonoid”, meaning distonic like, to encompass any radical ion that displays distonic “character” (i.e., ions with a high degree of discrete (non-mandatory) charge-spin separation) and is over-looked as a result of the strict distonic ion definition.6 However, the “distonoid” classification is not commonly used by the scientific community. Currently, the term “distonic” is widely accepted and used to denote ions with formally separated charge and radical sites even if they do not fall into the formal definition.7 According to the conventional valence bond description, the charge and radical sites are on adjacent atoms in α-distonic ions while they are separated by one and two atoms in β- and γ-distonic ions, respectively. A vast amount of experimental and theoretical studies were dedicated to distonic ions from the 1980’s to 1990’s, which have been previously reviewed separately by Hammerum and Kenttamaa.8,9,10 The focus of this review is on gaseous ions with one or more aryl radical sites, a subgroup of distonic radical cations. The interest in these distonic ions was initially sparked by the limited knowledge on the reactivity of neutral phenyl radicals and their diradical counterparts in spite of the vast amount of research dedicated to these reactive intermediates.11–70 Many such mono- and diradicals have been investigated as they are thought to play a vital role in numerous fields, including combustion,11–13 polymerization,14–16 atmospheric chemistry,17–19 interstellar chemistry,20 organic synthesis8 and the biological activity of certain drugs.21–33 In the 1990’s, the formation of such aromatic diradicals in naturally occurring anti-tumor antibiotics was associated with their DNA-cleaving ability.21–33 The two radical sites are thought to abstract a hydrogen atom from each strand of double stranded DNA, thus causing irreversible DNA cleavage. Since then, theoretical and experimental research on aryl mono- and diradicals has boomed. An area of special interest has been the mechanistic understanding of hydrogen atom abstraction by these radicals from small organic and biological molecules both in solution34–45 and in the gas phase.46–70 However, the ability to predict the rates of such seemingly simple reactions has proven challenging due to a poor understanding of the nature of the transition states for these reactions. Further, the examination of the chemical properties of neutral radicals is a challenge due to the difficulty to cleanly generate them both in solution and in the gas phase. In order to address the above difficulties, studies were carried out in the early 1990’s on distonic radical cations’ ion-molecule reactions inside mass spectrometers as ions can be easily manipulated in this environment.46–70 Distonic radical cations that have a phenyl radical site spatially separated from a chemically inert charge site were found to almost exclusively undergo radical reactions at the radical site(s) in the gas phase46–70 and lately also in solution.45 Hence, examination of these distonic ions will provide information on the properties of phenyl mono- and diradicals. A special benefit of using mass spectrometry to study above species is that the desired charged radical can be isolated before examining its reactivity. Hence, the precursors to any products formed in these gas-phase experiments are known, which is not always true for solution experiments wherein highly reactive molecules cannot be isolated. The chemical properties of many aryl mono-, di- and triradicals have been successfully examined in mass spectrometers by using this ‘distonic ion approach’.49,50,52 The results obtained in these studies provide valuable information on the relative reactivities of mono- and polyradicals, which would otherwise not be available. This paper reviews the current knowledge of the properties and reactivity of distonic radical ions with aryl radical sites and the mechanisms of these reactions. Distonic phenyl radical ions generated within peptides are not included due to space limitations and also since these radicals are usually generated as precursors to less reactive nonaromatic peptide radicals that are the true interest of the researchers. However, this is an important and exciting new field of distonic ion research that should be reviewed separately.

Gas-phase reactivity of protonated 2-, 3-, and 4-dehydropyridine radicals toward organic reagents.

To explore the effects of the electronic nature of charged phenyl radicals on their reactivity, reactions of the three distonic isomers of n-dehydropyridinium cation (n = 2, 3, or 4) have been investigated in the gas phase by using Fourier-transform ion cyclotron resonance mass spectrometry. All three isomers react with cyclohexane, methanol, ethanol, and 1-pentanol exclusively via hydrogen atom abstraction and with allyl iodide mainly via iodine atom abstraction, with a reaction efficiency ordering of 2 > 3 > 4. The observed reactivity ordering correlates well with the calculated vertical electron affinities of the charged radicals (i.e., the higher the vertical electron affinity, the faster the reaction). Charged radicals 2 and 3 also react with tetrahydrofuran exclusively via hydrogen atom abstraction, but the reaction of 4 with tetrahydrofuran yields products arising from nonradical reactivity. The unusual reactivity of 4 is likely to result from the contribution of an ionized carbene-type resonance structure that facilitates nucleophilic addition to the most electrophilic carbon atom (C-4) in this charged radical. The influence of such a resonance structure on the reactivity of 2 is not obvious, and this may be due to stabilizing hydrogen-bonding interactions in the transition states for this molecule. Charged radicals 2 and 3 abstract a hydrogen atom from the substituent in both phenol and toluene, but 4 abstracts a hydrogen atom from the phenyl ring, a reaction that is unprecedented for phenyl radicals. Charged radical 4 reacts with tert-butyl isocyanide mainly by hydrogen cyanide (HCN) abstraction, whereas CN abstraction is the principal reaction for 2 and 3. The different reactivity observed for 4 (as compared to 2 and 3) is likely to result from different charge and spin distributions of the reaction intermediates for these charged radicals.

On the factors that control the reactivity of meta-benzynes

The reactivities of eleven 3,5-didehydropyridinium and six 2,4-didehydropyridinium cations toward cyclohexane were examined in the gas phase by using Fourier-transform ion cyclotron resonance (FT-ICR) mass spectrometry as well as high-level quantum chemical calculations. The results unequivocally demonstrate that the reactivity of meta-benzyne analogs can be “tuned” from more radical-like to less radical-like by changing the type and position of substituents. For example, σ-acceptor substituents at the 4-position and π-donor substituents at the 2-position in 3,5-didehydropyridinium cations partially decouple the biradical electrons, which results in lower energy transition states, and faster radical reactions. In contrast, σ-acceptors at the 2-position and π-donors at the 4-position in 3,5-didehydropyridinium cations cause stronger coupling between the biradical electrons, which results in lower radical reactivity. Three main factors are found to control the reactivity of these biradicals: (1) the energy required to distort the minimum energy dehydrocarbon atom separation to the separation of the transition state, (2) the S–T splitting at the separation of the transition state, and (3) the electron affinity at the separation of the transition state.

Experimental and Computational Studies on the Formation of Three para‐Benzyne Analogues in the Gas Phase

Experimental and computational studies on the formation of three gaseous, positively-charged para-benzyne analogues in a Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer are reported. The structures of the cations were examined by isolating them and allowing them to react with various neutral reagents whose reactions with aromatic carbon-centered σ-type mono- and biradicals are well understood. Cleavage of two iodine-carbon bonds in N-deuterated 1,4-diiodoisoquinolinium cation by collision-activated dissociation (CAD) produced a long-lived cation that showed nonradical reactivity, which was unexpected for a para-benzyne. However, the reactivity closely resembles that of an isomeric enediyne, N-deuterated 2-ethynylbenzonitrilium cation. A theoretical study on possible rearrangement reactions occurring during CAD revealed that the cation formed upon the first iodine atom loss undergoes ring-opening before the second iodine atom loss to form an enediyne instead of a para-benzyne. Similar results were obtained for the 5,8-didehydroisoquinolinium cation and the 2,5-didehydropyridinium cation. The findings for the 5,8-didehydroisoquinolinium cation are in contradiction with an earlier report on this cation. The cation described in the literature was regenerated by using the literature method and demonstrated to be the isomeric 5,7-didehydro-isoquinolinium cation and not the expected 5,8-isomer.

Reactivity of a σ,σ,σ,σ-Tetraradical: The 2,4,6-Tridehydropyridine Radical Cation

The 2,4,6-tridehydropyridine radical cation, an analogue of the elusive 1,2,3,5-tetradehydrobenzene, was generated in the gas phase and its reactivity examined. Surprisingly, the tetraradical was found not to undergo radical reactions. This behavior is rationalized by resonance structures hindering fast radical reactions. This makes the cation highly electrophilic, and it rapidly reacts with many nucleophiles by quenching the N-C ortho-benzyne moiety, thereby generating a relatively unreactive meta-benzyne analogue.

Reactivity of the 4,5-didehydroisoquinolinium cation.

The chemical properties of a 1,8-didehydronaphthalene derivative, the 4,5-didehydroisoquinolinium cation, were examined in the gas phase in a dual-cell Fourier-transform ion cyclotron resonance (FT-ICR) mass spectrometer. This is an interesting biradical because it has two radical sites in close proximity, yet their coupling is very weak. In fact, the biradical is calculated to have approximately degenerate singlet and triplet states. This biradical was found to exclusively undergo radical reactions, as opposed to other related biradicals with nearby radical sites. The first bond formation occurs at the radical site in the 4-position, followed by that in the 5-position. The proximity of the radical sites leads to reactions that have not been observed for related mono- or biradicals. Interestingly, some ortho-benzynes have been found to yield similar products. Since ortho-benzynes do not react via radical mechanisms, these products must be especially favorable thermodynamically.

Effects of a hydroxyl substituent on the reactivity of the 2,4,6-tridehydropyridinium cation, an aromatic σ,σ,σ-triradical.

The reactivity of 3-hydroxy-2,4,6-tridehydropyridinium cation was found to be drastically different from the reactivity of 2,4,6-tridehydropyridinium cation. While the latter triradical reacts with tetrahydrofuran, dimethyl disulfide and ally iodide via three consecutive atom or group abstractions, the former triradical exhibits this behavior only with tetrahydrofuran. Only a single atom or group abstraction was observed for the 3-hydroxy-2,4,6-tridehydropyridinium cation upon interaction with dimethyl disulfide and allyl iodide. This change in reactivity is caused by the hydroxyl group that strengthens the interactions between the two radical sites adjacent to it, thus reducing their reactivity. This explanation is supported by the observation of similar behavior for related biradicals.

Substituent effects on the nonradical reactivity of 4-dehydropyridinium cation.

Recent studies have shown that the reactivity of the 4-dehydropyridinium cation significantly differs from the reactivities of its isomers toward tetrahydrofuran. While only hydrogen atom abstraction was observed for the 2- and 3-dehydropyridinium cations, nonradical reactions were observed for the 4-isomer. In order to learn more about these reactions, the gas-phase reactivities of the 4-dehydropyridinium cation and several of its derivatives toward tetrahydrofuran were investigated in a Fourier transform ion electron resonance mass spectrometer. Both radical and nonradical reactions were observed for most of these positively charged radicals. The major parameter determining whether nonradical reactions occur was found to be the electron affinity of the radicals--only those with relatively high electron affinities underwent nonradical reactions. The reactivities of the monoradicals are also affected by hydrogen bonding and steric effects.

Reactivity Controlling Factors for an Aromatic Carbon-Centered σ,σ,σ-Triradical: The 4,5,8-Tridehydroisoquinolinium Ion.

The chemical properties of the 4,5,8-tridehydroisoquinolinium ion (doublet ground state) and related mono- and biradicals were examined in the gas phase in a dual-cell Fourier-transform ion cyclotron resonance (FT-ICR) mass spectrometer. The triradical abstracted three hydrogen atoms in a consecutive manner from tetrahydrofuran (THF) and cyclohexane molecules; this demonstrates the presence of three reactive radical sites in this molecule. The high (calculated) electron affinity (EA=6.06 eV) at the radical sites makes the triradical more reactive than two related monoradicals, the 5- and 8-dehydroisoquinolinium ions (EA=4.87 and 5.06 eV, respectively), the reactivity of which is controlled predominantly by polar effects. Calculated triradical stabilization energies predict that the most reactive radical site in the triradical is not position C4, as expected based on the high EA of this radical site, but instead position C5. The latter radical site actually destabilizes the 4,8-biradical moiety, which is singlet coupled. Indeed, experimental reactivity studies show that the radical site at C5 reacts first. This explains why the triradical is not more reactive than the 4-dehydroisoquinolinium ion because the C5 site is the intrinsically least reactive of the three radical sites due to its low EA. Although both EA and spin-spin coupling play major roles in controlling the overall reactivity of the triradical, spin-spin coupling determines the relative reactivity of the three radical sites.