Oxenium Ion Research Articles

Aryl Nitrenium and Oxenium Ions with Unusual High-Spin π,π* Ground States: Exploiting (Anti)Aromaticity.

Nitrenium and oxenium ions are important reactive intermediates in synthetic and biological processes, and their ground electronic configurations are of great interest due to having distinct reactivities and properties. In general, the closed-shell singlet state of these intermediates usually react as electrophiles, while reactions of the triplet states of these ions react like typical diradicals (e.g., H atom abstractions). Nonsubstituted phenyl nitrenium ions (Ph-NH+) and phenyl oxenium ions (Ph-O+) have closed-shell singlet ground states with large singlet-triplet gaps resulting from a strong break in the degeneracy of the p orbitals on the formal nitrenium/oxenium center. Remarkably, we find computationally (CBS-QB3 and G4MP2) that azulenyl nitrenium and oxenium ions can have triplet ground states depending upon the attachment position on the azulene core. For instance, CBS-QB3 predicts that 1-azulenyl nitrenium ion and 1-azulenyl oxenium ion are singlet ground-state species with considerable singlet-triplet gaps of -47 and -45 kcal/mol to the lowest-energy triplet state, respectively. In contrast, 6-azulenyl nitrenium ion and 6-azulenyl oxenium ion have triplet ground states with a singlet-triplet gap of +7 and +10 kcal/mol, respectively. Moreover, the triplet states are π,π* states, rather than the typical n,π* states seen for many aryl nitrenium or oxenium ions. This dramatic switch in favored electronic states can be ascribed to changes in ring aromaticity/antiaromaticity, with the switch from ground-state singlet ions to triplet-favored ions resulting from both a destabilized singlet state (Hückel antiaromatic) and a stabilized triplet (Baird aromatic) state. Density functional theory (UB3LYP/6-31+G(d,p)) was used to determine substituent effects on the singlet-triplet energy gap for azulenyl nitrenium and oxenium ions, and we find that the unusual ground triplet states can be further tuned by employing electron-donating or -withdrawing groups on the azulene ring. This work demonstrates that azulenyl nitrenium and oxenium ions can have triplet π,π* ground states and provides a simple recipe for making ionic intermediates with distinct electronic configurations and consequent prediction of unique reactivity and magnetic properties from these species.

Direct Detection of the Open-Shell Singlet Phenyloxenium Ion: An Atom-Centered Diradical Reacts as an Electrophile.

A new photoprecursor to the phenyloxenium ion, 4-methoxyphenoxypyridinium tetrafluoroborate, was investigated using trapping studies, product analysis, computational investigations, and laser flash photolysis experiments ranging from the femtosecond to the millisecond time scale. These experiments allowed us to trace the complete arc of the photophysics and photochemistry of this photoprecursor beginning with the initially populated excited states to its sequential formation of transient intermediates and ultimate formation of stable photoproducts. We find that the excited state of the photoprecursor undergoes heterolysis to generate the phenyloxenium ion in ∼2 ps but surprisingly generates the ion in its open-shell singlet diradical configuration (1A2), permitting an unexpected look at the reactivity of an atom-centered open-shell singlet diradical. The open-shell phenyloxenium ion (1A2) has a much shorter lifetime (τ ∼ 0.2 ns) in acetonitrile than the previously observed closed-shell singlet (1A1) phenyloxenium ion (τ ∼ 5 ns). Remarkably, despite possessing no empty valence orbitals, this open-shell singlet oxenium ion behaves as an even more powerful electrophile than the closed-shell singlet oxenium ion, undergoing solvent trapping by weakly nucleophilic solvents such as water and acetonitrile or externally added nucleophiles (e.g., azide) rather than engaging in typical diradical chemistry, such as H atom abstraction, which we have previously observed for a triplet oxenium ion. In acetonitrile, the open-shell singlet oxenium ion is trapped to generate ortho and para Ritter intermediates, one of which (para) is directly observed as a longer-lived species (τ ∼ 0.1 ms) in time-resolved resonance Raman experiments. The Ritter intermediates are ultimately trapped by either the 4-methoxypyridine leaving group (in the case of para addition) or trapped internally via an essentially barrierless rearrangement (in the case of ortho addition) to generate a cyclized product. The expectation that singlet diradicals react similarly to triplet or uncoupled diradicals needs to be reconsidered, as a recent study by Perrin and Reyes-Rodríguez (J. Am. Chem. Soc. 2014, 136, 15263) suggested the unsettling possibility that singlet p-benzyne could suffer nucleophilic attack to generate a naked phenyl anion. Now, this study provides direct spectroscopic observation of this phenomenon, with an atom-centered open-shell singlet diradical reacting as a powerful electrophile. To the question of whether a nucleophile can attack a singly occupied molecular orbital, the answer is apparently yes, at least if another partially occupied orbital is available to avoid violation of the rules of valence.

Direct Spectroscopic Detection and EPR Investigation of a Ground State Triplet Phenyl Oxenium Ion.

Oxenium ions are important reactive intermediates in synthetic chemistry and enzymology, but little is known of the reactivity, lifetimes, spectroscopic signatures, and electronic configurations of these unstable species. Recent advances have allowed these short-lived ions to be directly detected in solution from laser flash photolysis of suitable photochemical precursors, but all of the studies to date have focused on aryloxenium ions having closed-shell singlet ground state configurations. To study alternative spin configurations, we synthesized a photoprecursor to the m-dimethylamino phenyloxenium ion, which is predicted by both density functional theory and MRMP2 computations to have a triplet ground state electronic configuration. A combination of femtosecond and nanosecond transient absorption spectroscopy, nanosecond time-resolved Resonance Raman spectroscopy (ns-TR(3)), cryogenic matrix EPR spectroscopy, computational analysis, and photoproduct studies allowed us to trace essentially the complete arc of the photophysics and photochemistry of this photoprecursor and permitted a first look at a triplet oxenium ion. Ultraviolet photoexcitation of this precursor populates higher singlet excited states, which after internal conversion to S1 over 800 fs are followed by bond heterolysis in ∼1 ps, generating a hot closed-shell singlet oxenium ion that undergoes vibrational cooling in ∼50 ps followed by intersystem crossing in ∼300 ps to generate the triplet ground state oxenium ion. In contrast to the rapid trapping of singlet phenyloxenium ions by nucleophiles seen in prior studies, the triplet oxenium ion reacts via sequential H atom abstractions on the microsecond time domain to ultimately yield the reduced m-dimethylaminophenol as the only detectable stable photoproduct. Band assignments were made by comparisons to computed spectra of candidate intermediates and comparisons to related known species. The triplet oxenium ion was also detected in the ns-TR(3) experiments, permitting a more clear assignment and identifying the triplet state as the π,π* triplet configuration. The triplet ground state of this ion was further supported by photolysis of the photoprecursor in an ethanol glass at ∼4 K and observing a triplet species by cryogenic EPR spectroscopy.

Direct spectroscopic observation of closed-shell singlet, open-shell singlet, and triplet p-biphenylyloxenium ion.

The photophysics and photochemistry of p-biphenylyl hydroxylamine hydrochloride was studied using laser flash photolysis ranging from the femtosecond to the microsecond time scale. The singlet excited state of this photoprecursor is formed within 350 fs and partitions into three different transients that are assigned to the p-biphenyloxy radical, the open-shell singlet p-biphenylyloxenium ion, and the triplet p-biphenylyloxenium ion, having lifetimes of 40 μs, 45 ps, and 1.6 ns, respectively, in CH3CN. The open-shell singlet p-biphenylyloxenium ion predominantly undergoes internal conversion to produce the closed-shell singlet p-biphenylyloxenium ion, which has a lifetime of 5-20 ns. The longer-lived radical is unambiguously assigned by nanosecond time-resolved resonance Raman (ns-TR(3)) spectroscopy, and the assignment of the short-lived singlet and triplet oxenium ion transient absorptions are supported by matching time-dependent density functional theory (TD-DFT) predictions of the absorptions of these species, as well as by product studies that implicate the intermediacy of charged electrophilic intermediates. Product studies from photolysis give p-biphenylol as the major product and a chloride adduct as the major product when NaCl is added as a trap. Thermolysis studies give p-biphenylol as a major product, as well as water, ammonium, and chloro adducts. These studies provide a rare direct look at a discrete oxenium ion intermediate and the first detection of open-shell singlet and triplet configurations of an oxenium ion, as well as providing an intriguing example of the importance of excited state dynamics in governing the electronic state population of reactive intermediates.

Reversible formation of aryloxenium ions from the corresponding quinols under acidic conditions

Quinols, 1, are products of the hydration of O‐aryloxenium ions, 2, and N‐arylnitrenium ions, 3, and they are being investigated for medical uses. Under acidic conditions (pH 1–3) kinetics and products of Br– trapping demonstrate that 1a, 4‐phenyl‐4‐hydroxy‐2,5‐cyclohexadienone, and 1b, 4‐p‐tolyl‐4‐hydroxy‐2,5‐cyclohexadienone, generate the corresponding oxenium ions 2a and 2b, respectively, as steady‐state intermediates. Formation and trapping of the oxenium ions occurs in competition with the acid catalyzed dienone–phenol rearrangement. Because oxenium ion formation is reversible, the ion can only be detected by trapping with a nucleophile. Br– is an efficient trap under acidic conditions because, unlike N3–, it is not protonated under those conditions. Attempts to detect the oxenium ions 2a and 2b at pH 4.6 and 7.1 with N3– were unsuccessful indicating that oxenium ion formation only occurs under acidic conditions. The oxenium ion 2c could not be detected under acidic conditions from the quinol 1c, 4‐(benzothiazol‐2‐yl)‐4‐hydroxy‐2,5‐cyclohexadienone, by Br– trapping methods, even though this ion can be detected during hydrolysis of the corresponding ester, 4c. Although the benzothiazol‐2‐yl group is a resonance electron donor that is capable of stabilizing an O‐aryloxenium ion, it is also a strong inductive electron withdrawing group that hinders the formation of 2c from 1c by decreasing the extent of protonation of 1c to generate 1cH+ and by destabilizing the transition state for ionization of 1cH+. Generation of an oxenium ion from the corresponding quinol is feasible under acidic conditions as long as the 4‐substituent of the quinol is both a resonance and inductive electron donor. Copyright © 2012 John Wiley & Sons, Ltd.

Heteroaryl Oxenium Ions Have Diverse and Unusual Low-Energy Electronic States

The electronic state orderings and energies of heteroaryl oxenium ions were computed using high-level CASPT2//CASSCF computations. We find that these ions have a number of diverse, low-energy configurations. Depending on the nature of the heteroaryl substituent, the lowest-energy configuration may be open-shell singlet, closed-shell singlet, or triplet, with further diversity found among the subtypes of these configurations. The 2- and 3-pyridinyl oxenium ions show small perturbations from the phenyl oxenium ion in electronic state orderings and energies, having closed-shell singlet ground states with significant gaps to an n,π* triplet state. In contrast, the 4-pyridinyl oxenium ion is computed to have a low-energy nitrenium ion-like triplet state. The pyrimidinyl oxenium ion is computed to have a near degeneracy between an open-shell singlet and triplet state, and the pyrizidinyl oxenium ion is computed to have a near-triple degeneracy between a closed-shell singlet state, an open-shell singlet state, and a triplet state. Therefore, the ground state of these latter heteroaryl oxenium ions cannot be predicted with certainty; in principle, reactivity from any of these states may be possible. These systems are of fundamental interest for probing the spin- and configuration-dependent reactivity of unusual electronic states for this important class of reactive intermediate.

Characterization of the 4-(Benzothiazol-2-yl)phenylnitrenium Ion from a Putative Metabolite of a Model Antitumor Drug

The 4-(benzothiazol-2-yl)phenylnitrenium ion 11 is generated from hydrolysis or photolysis of O-acetoxy-N-(4-(benzothiazol-2-yl)phenyl)hydroxylamine 8, a model metabolite of 2-(4-aminophenyl)benzothiazole 1 and its ring-substituted derivatives that are being developed for a variety of medicinal applications, including antitumor, antibacterial, antifungal, and imaging agents. Previously, we showed that 11 had an aqueous solution lifetime of 530 ns, similar to the 560 ns lifetime of the 4-biphenylylnitrenium ion 12 derived from the well-known chemical carcinogen 4-aminobiphenyl. We now show that the analogy between these two cations extends well beyond their lifetimes. The initial product of hydration of 11 is the quinolimine 16, which can be detected as a long-lived reactive intermediate that hydrolyzes in a pH-dependent manner into the final hydrolysis product, the quinol 15. This hydrolysis behavior is equivalent to that previously described for a large number of ester metabolites of carcinogenic arylamines, including 4-aminobiphenyl. The major azide trapping product (90% of azide products) of 11, 20, is generated by substitution on the carbons ortho to the nitrenium ion center of 11. This product is a direct analogue of the major azide adducts, such as 22, generated from trapping of the nitrenium ions of carcinogenic arylamines. The azide/solvent selectivity for 11, k(az)/k(s), is also nearly equivalent to that of 12. A minor product of the reaction of 11 with N(3)(-), 21, contains no azide functionality but may be generated by a process in which N(3)(-) attacks 11 at the nitrenium ion center with loss of N(2) to generate a diazene 25 that subsequently decomposes into 21 with loss of another N(2). The adduct derived from attack of 2'-deoxyguanosine (d-G) on 11, 28, is a familiar C-8 adduct of the type generated from the reaction of d-G with a wide variety of arylnitrenium ions derived from carcinogenic arylamines. The rate constant for reaction of d-G with 11, k(d-G), is very similar to that observed for the reaction of d-G with 12. The similar lifetimes and chemical reactivities of 11 and 12 can be rationalized by B3LYP/6-31G(d) calculations on the two ions that show that they are of nearly equivalent stability relative to their respective hydration products. The calculations also help to rationalize the different regiochemistry observed for the reaction of N(3)(-) with 11 and its oxenium ion analogue, 13. Since 8 is the likely active metabolite of 1 and a significant number of derivatives of 1 are being developed as pharmaceutical agents, the similarity of the chemistry of 11 to that of carcinogenic arylnitrenium ions is of considerable importance. Consideration should be given to this chemistry in continued development of pharmaceuticals containing the 2-(4-aminophenyl)benzothiazole moiety.

Multiple Decomposition Pathways for the Oxenium Ion Precursor O-(4-(4′-Methylphenyl)phenyl)-N-methanesulfonylhydroxylamine

Although O-arylhydroxylamine derivatives have been claimed to be sources of oxenium ions in a large number of studies, it is not clear that the products of these reactions are due to oxenium ions. Previously, we had shown through azide trapping studies that the quinol ester 2a and the title compound 3a generate the oxenium ion 1a. The ester 2a exclusively generates 1a in water and is also a photoprecursor of 1a in water. This is not true of 3a. The oxenium ion pathway accounts for a significant fraction of the reaction of 3a under neutral and acidic pH conditions, but there are three other pathways that account for hydrolysis of 3a. Both 3a and its conjugate base 3a(-) are present in aqueous solution under mild pH conditions. In addition to the oxenium ion product 4a, two other significant products are generated: the phenol 6a and the rearrangement product 8a. Both 4a and 8a are generated exclusively from 3a, whereas 6a is generated from both 3a and 3a(-). Azide trapping studies show that 6a and 8a are not generated from the oxenium ion. The phenol 6a is generated by two paths, one involving an apparent radical intermediate 7a and the other through a stepwise alpha-elimination pathway through 3a(-). The rearrangement product 8a is generated either through a concerted rearrangement or via an ion-pair rearrangement. Photolysis of 3a does not generate 1a. The only products of photolysis of 3a in water are 6a (major) and 8a (minor). The weak O-N bond of 3a is susceptible to homolysis under photolysis conditions, and the radical 7a is observed after laser flash photolysis of 3a. The cation 1a that is observed during laser flash photolysis experiments on 2a cannot be detected during similar experiments on 3a. These results suggest that the previous attribution of oxenium ions as the source of the decomposition products of other O-arylhydroxylamine derivatives in aromatic solvents via thermolysis or acid-catalyzed decomposition may not be correct.

Hydrolysis and Photolysis of 4-Acetoxy-4-(benzothiazol-2-yl)-2,5-cyclohexadien-1-one, a Model Anti-Tumor Quinol Ester

4-Acetoxy-4-(benzothiazol-2-yl)-2,5-cyclohexadien-1-one, 1, a quinol derivative that exhibits significant anti-tumor activity against human breast, colon, and renal cancer cell lines, undergoes hydrolysis in aqueous solution to generate an oxenium ion intermediate, 3, that is selectively trapped by N(3)(-) in an aqueous environment. The 4-(benzothiazol-2-yl) substituent slows the rate of ionization of 1 compared to analogues with 4-phenyl or 4-(p-tolyl) substituents, 4a or 4b. However, once generated, 3 is somewhat more selective than the 4-phenyl-substituted cation 5a. Calculations performed at the B3LYP/6-31G(d) level agree that the 4-(benzothiazol-2-yl) substituent does significantly stabilize 3. The structure of the major isolated azide adduct, 4-(6-azidobenzothiazol-2-yl)phenol, 9, confirms that the positive charge is highly delocalized in 3. The results of hydrolysis of 1 show that the 4-(benzothiazol-2-yl) substituent has a significant inductive electron-withdrawing effect as well as a significant resonance effect that is electron-donating. Photolysis of 1 in aqueous solution generates the quinol 2 as one of several photolysis products. The presence of the quinol suggests that photolysis also leads, in part, to generation of 3, but photoionization of 1 is significantly less efficient than is the case for the esters 4a and 4b. This study proves that 3 is generated by ionization of 1 in an aqueous environment. A significant number of other 2-benzothiazole derivatives that are not quinols, including ring-substituted derivatives of 2-(4-aminophenyl)benzothiazole 15, are under development as anti-tumor agents as well. The possible generation of the reactive intermediate 17 by hydrolysis of the putative metabolite 16 is under investigation.

Chemistry of 4-Alkylaryloxenium Ion “Precursors”: Sound and Fury Signifying Something?

Quinol esters 2b, 2c, and 3b and sulfonamide 4c were investigated as possible precursors to 4-alkylaryloxenium ions, reactive intermediates that have not been previously detected. These compounds exhibit a variety of interesting reactions, but with one possible exception, they do not generate oxenium ions. The 4-isopropyl ester 2b predominantly undergoes ordinary acid- and base-catalyzed ester hydrolysis. The 4-tert-butyl ester 2c decomposes under both acidic and neutral conditions to generate tert-butanol and 1-acetyl-1,4-hydroquinone, 8, apparently by an SN1 mechanism. This is also a minor decomposition pathway for 2b, but the mechanism in that case is not likely to be SN1. Decomposition of 2c in the presence of N3- leads to formation of the explosive 2,3,5,6-tetraazido-1,4-benzoquinone, 14, produced by N3--induced hydrolysis of 8, followed by a series of oxidations and nucleophilic additions by N3-. No products suggestive of N3--trapping of an oxenium ion were detected. The 4-isopropyl dichloroacetic acid ester 3b reacts with N3- to generate the two adducts 2-azido-4-isopropylphenol, 5b, and 3-azido-4-isopropylphenol, 11b. Although 5b is the expected product of N3- trapping of the oxenium ion, kinetic analysis shows that it is produced by a kinetically bimolecular reaction of N3- with 3b. No oxenium ion is involved. The sulfonamide 4c predominantly undergoes a rearrangement reaction under acidic and neutral conditions, but a minor component of the reaction yields 4-tert-butylcresol, 17, and 2-azido-4-tert-butylphenol, 5c, in the presence of N3-. These products may indicate that 4c generates the oxenium ion 1c, but they are generated in very low yields (ca. 10%) so it is not possible to definitively conclude that 1c has been produced. If 1c has been generated, the N3--trapping data indicate that it is a very short-lived and reactive species in H2O. Comparisons with similarly reactive nitrenium ions indicate that the lifetime of 1c is ca. 20-200 ps if it is generated, so it must react by a preassociation process. Density functional theory calculations at the B3LYP/6-31G*//HF/6-31G* level coupled with kinetic correlations also indicate that the aqueous solution lifetimes of 1a-c are in the picosecond range.

Direct Detection of a Transient Oxenium Ion in Water Generated by Laser Flash Photolysis

Laser flash photolysis of the quinol ester 2b in O2-saturated aqueous phosphate buffer at pH 7.1 with excitation at 266 nm generates a transient intermediate with lambda(max) 460 nm that decays in a first-order manner with an aqueous solution lifetime of (170 +/- 10) ns at 22 degrees C. This intermediate is not affected by O2, but reacts rapidly with N3- with an apparently diffusion-limited rate constant of (6.6 +/- 0.2) x 10(9) M-1 s-1. Steady state photolysis of 2b yields the quinol 3b as a major reaction product with a yield of ca. 30-35% after correction for photolytic decomposition of 3b. This is the same product that is quantitatively produced by hydrolysis of 2b in the dark. Photolysis of 2b in the presence of 40 mM N3- completely suppresses the yield of 3b The photolytic intermediate is identified as the aryloxenium ion 1b, that was previously indirectly detected by N3--trapping during the hydrolysis of 2b, based on the chemical behavior of the transient and the quantitative agreement of the N3-/solvent selectivity ratio, kaz/ks, measured directly during the flash photolysis experiment, and indirectly by the azide clock procedure during the hydrolysis reaction. Other, as of yet unidentified, transients are produced during the photolysis reaction. A strong transient absorbance band observed at 360 nm decays in a biphasic manner with two first-order rate constants, neither of which are affected by O2 or N3-. The lifetimes of the two intermediates of ca. 12 and 75 mus are considerably longer than that of 1b. Another very short-lived species can be detected at early reaction times (<or=20 ns) in Ar-saturated buffer. This species is suppressed, but not completely eliminated, in O2-saturated buffer.

Ab‐initio‐Studien anN‐ Acyliminium‐Ionen

Ab initioStudies onN‐Acyliminium IonsThe geometric and electronic structure and reactivity of theN‐formylmethyleneiminium ion are calculated in different conformations byab initiomethods and compared to those ofN‐methylformamide and the methyleneiminium ion. The known preferred attack of the C(5) of 3‐acyl‐2,3‐dihydro‐1,3‐oxazoles by electrophiles is explained by the lower (calculated) energy of the corresponding acyliminium ion relative to that of the oxenium ion. The stereoselectivity of additions to these acyliminium ions can not be explained by our calculations.Ab initiocalculations of the subsystems acyliminium and oxenium ion show that the reactivity can be predicted from investigation of these much simpler systems and make us suppose that a nitro instead of an acyl group will reverse the regioselectivity of the addition to 2,3‐dihydro‐1,3‐oxazoles.

The acid-catalyzed oxido-reduction of spiroketals. Evidence for stereoelectronic control in hydride transfer to cyclic oxenium ions

Tricyclic spiroketal 1 undergoes an acid-catalyzed oxidation–reduction reaction which yields equatorial bicyclic ether aldehyde 5 specifically. Similarly, spiroketals 2, 3, and 4 give equatorial bicyclic ether ketone 12. These results are interpreted by invoking an internal hydride transfer from an alcohol function to a cyclic oxenium ion which takes place with stereoelectronic control. The reduction of tricyclic ketals 1 and 22 with sodium cyanoborohydride under acidic conditions is also reported.