Distonic Radical Cations in Visible‐Light‐Driven Cycloadditions

Recently, electron has been recognized as the simplest catalyst in the field of synthetic organic chemistry. Addition or removal of electron can activate small molecules for further chemical transformations, which is referred to as redox catalysis. Reductive and/or oxidative single electron transfer (SET) can be induced by means of electro- and photochemistry, where an electron can play a role of catalysts. Radical ions are primarily generated via SET, offering unique reactive intermediates.Distonic radical ions are transient species with formally separated radical and charge cites. They potentially exhibit radical and ion reactivities independently, which may differ from usual radical ions. However, distonic radical ions are not commonly used as reactive intermediates in the field of synthetic organic chemistry, probably because of lack of their simple generation methods.We have been developing oxidative SET-triggered cycloadditions in a lithium perchlorate/nitromethane solution. Radical cations are involved in the reactions as distinctive reactive intermediates, facilitating intermolecular carbon-carbon bond formations. We questioned whether the distonic radical cation can also be generated by oxidative SET, leading to novel chemical transformations. In this presentation, oxidative SET-catalyzed vinylcyclopopane rearrangements will be described. Figure 1

In the field of synthetic organic chemistry, photochemical and electrochemical methods are often considered to be competing techniques that induce single electron transfer (SET). Recently, metal complexes and organic dyes have been extensively used as molecular sensitizers that can induce homogeneous bidirectional SET. On the other hand, heterogeneous monodirectional SET can be induced by electrodes, which differs from the photochemical methods. In this context, semiconductors are unique alternatives, since they can induce heterogeneous but bidirectional SET, potentially enjoying advantages of both photochemical and electrochemical methods. Such semiconductor "photoelectrochemical" methods may trigger the reactions that are otherwise difficult to achieve.We have been developing electrochemical SET-triggered cycloadditions in lithium perchlorate (LiClO4)/nitromethane (CH3NO2) solution, which facilitates the generation of radical cations from electron-rich alkenes and styrenes. Recently, we also have been focusing on TiO2 photoelectrochemical SET-triggered cycloadditions, expanding a scope of the electrochemical versions. During the course of our study to develop new TiO2 photoelectrochemical SET-triggered cycloadditions, we unexpectedly found that vinylcyclopropane rearrangements was also possible in LiClO4/CH3NO2 solution. The reactions are initiated by oxidative SET by hole, which is followed by immediate ringopening of the cyclopropanes to generate distonic radical cations. It is expected that reductive SET by excited electron is also involved to realize effective net redox-neutral transformations. Experimental details, including preliminary mechanistic studies, will be presented in this talk.

Explosive growth in the use of open shell reactivity, including neutral radicals and radical ions, in the field of synthetic organic chemistry has been observed in the past decade, particularly since the advent of ruthenium complexes in 2008. These complexes generally induce single-electron transfer (SET) processes via visible-light absorption. Additionally, recent significant advancements in organic electrochemistry involving SET processes to provide open shell reactivity offer a complementary method to traditional polarity-driven reactions described by two-electron transfer processes. In this Review, we highlight the importance of intramolecular SET processes in the field of synthetic organic chemistry, which seem to be more elusive than the intermolecular versions, since they are net redox-neutral and thus cannot simply be regarded as oxidations or reductions. Such intramolecular SET processes can rationally be understood in combination with concomitant bond formations and/or cleavages, and are regulated by a structural motif that we call a "redox tag." In order to describe modern radical-driven reactions involving SET processes, we focus on a classical formalism in which electrons are treated as particles rather than waves, which offers a practical yet powerful approach to explain and/or predict synthetic outcomes.

Although radical ion chain pathways have long been recognized in the field of synthetic organic chemistry and are expected to be operative in various reactions, it is somewhat complicated to verify their involvement, since counting the number of electrons is not straightforward. Herein, a series of bis‐styrenes is designed and synthesized to investigate electron transfer events by using radical cation [4+2] cycloadditions as probes. It is demonstrated that the intramolecular single electron transfer seems to be ineffective, while the intermolecular variants are highly effective. Therefore, a truly catalytic amount of electricity is enough for full conversions, confirming that chain pathways were definitely involved.

In the field of synthetic organic chemistry, photochemical and electrochemical approaches are often considered to be competing technologies that induce single electron transfer (SET). Recently, their fusion, i. e., the "photoelectrochemical" approach, has become the focus of attention. In this approach, both solar and electrical energy are used in creative combinations. Historically, the term "photoelectrochemistry" has been used in more inorganic fields, where a photovoltaic effect exhibited by semiconducting materials is employed. Semiconductors have also been studied intensively as photocatalysts; however, they recently have taken a back seat to molecular photocatalysts. In this account, we would like to revisit semiconductor photocatalysts in the field of synthetic organic chemistry to demonstrate that semiconductor "photoelectrochemical" approaches are more than mere alternatives to molecular photochemical and/or electrochemical approaches.

Heterocyclic compounds are an important class of compounds in the field of pharmaceutical and synthetic organic chemistry. The Schiff bases contain azomethine linkages which are obtained by the condensation of aldehyde/ketone with amines. Among the various types of Schiff bases, the chalcone-based Schiff bases play a vital role in the treatment of various ailments and various applications, which can be synthesized by using different types of chalcones as the starting materials. These types of compounds were synthesized by using various techniques like conventional means of synthesis, microwave-assisted reaction, heterocyclic catalyst-mediated synthesis and also by means of trituration. The chalcone or bis-chalcone-based Schiff bases and their derivatives contain -C=N linkage which exhibits various activities including antimicrobial, anticancer, antioxidant, antidiabetic and immunosuppressant activities. Beyond these activities, these types of Schiff bases are also used in various chemical industries and fluorescent sensors, which also play a major role in the field of synthetic organic chemistry and coordination chemistry as intermediates. This review discusses the numerous synthetic strategies along with their applications in the field of medicine. Thus, this review will be helpful in developing more effective drug-like scaffolds for use in future drug design. Keywords: Schiff bases, Chalcone-based Schiff bases, Antimicrobial, Anticancer, Antioxidant, Biological Applications

In addition to electrochemical and photochemical approaches, the photoelectrochemical method using semiconductors as photoelectrodes is a third type of approach in the field of synthetic organic chemistry that enables precise control of single electron transfer (SET) reactions. Herein, we report mechanistic studies on TiO2 photoelectrochemical redox neutral reactions, where both reductive and oxidative SET are involved, using radical cation [2 + 2] cycloadditions as models. In the presence of platinum nanoparticles or molecular oxygen as electron sink or electron acceptor, respectively, the mechanistic details for the photoelectrochemical reactions can be investigated because the excited electron at the conduction band of TiO2 is removed.

In this work, we regiospecifically generate and compare the gas-phase properties of two isomeric forms of tryptophan radical cations-a distonic indolyl N-radical (H3N(+) - TrpN(•)) and a canonical aromatic π (Trp(•+)) radical cation. The distonic radical cation was generated by nitrosylating the indole nitrogen of tryptophan in solution followed by collision-induced dissociation (CID) of the resulting protonated N-nitroso tryptophan. The π-radical cation was produced via CID of the ternary [Cu(II)(terpy)(Trp)](•2+) complex. CID spectra of the two isomeric species were found to be very different, suggesting no interconversion between the isomers. In gas-phase ion-molecule reactions, the distonic radical cation was unreactive towards n-propylsulfide, whereas the π radical cation reacted by hydrogen atom abstraction. DFT calculations revealed that the distonic indolyl radical cation is about 82 kJ/mol higher in energy than the π radical cation of tryptophan. The low reactivity of the distonic nitrogen radical cation was explained by spin delocalization of the radical over the aromatic ring and the remote, localized charge (at the amino nitrogen). The lack of interconversion between the isomers under both trapping and CID conditions was explained by the high rearrangement barrier of ca.137 kJ/mol. Finally, the two isomers were characterized by infrared multiple-photon dissociation (IRMPD) spectroscopy in the ~1000-1800 cm(-1) region. It was found that some of the main experimental IR features overlap between the two species, making their distinction by IRMPD spectroscopy in this region problematic. In addition, DFT theoretical calculations showed that the IR spectra are strongly conformation-dependent.

Review: 329 refs.

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.

Chemical synthesis by electrocatalysis and photocatalysis has been developed as a new energy conversion system and it can realize sustainable production processes for various products. Electron transfer is driven by electrical energy and solar energy under ambient temperature and pressure. In the case of electrocatalysis, voltage and current are tunable, and it can realize easy control of reaction conditions. In photocatalysis with semiconductor nanoparticles, one particle can work as both oxidant and reductant, and it would be beneficial toward redox neutral reactions. To understand mechanistic details of both electrocatalysis and photocatalysis is important to develop new processes with high efficiency. We reported oxidative single electron transfer (SET) triggered radical cation cycloaddition reactions in lithium perchlorate (LiClO4)/nitromethane (CH3NO2) by electrolysis and TiO2 semiconductor photocatalysis. These reactions start by substrate activation to form radical cation species, which is derived from anodic oxidation (in electrolysis) or hole oxidation (in photocatalysis). In this research, the [2+2] cycloaddition reactions in LiClO4/CH3NO2 solution were used as model reactions to study mechanistic details of three different SET catalysis, including electrocatalysis TiO2 photocatalysis with and without Pt loading. TiO2 and Pt loaded TiO2 (Pt-TiO2) were selected as photocatalyst in this work. Commercially available TiO2 nanoparticles (P25, 20–40 nm) were used. Pt-TiO2 was synthesized from the TiO2 (P25) and H2PtCl6 as a Pt precursor. H2PtCl6 was reduced by NaBH4 in the presence of TiO2 in H2O to give Pt-TiO2. From TEM observations and EDS measurement, Pt nanoparticles were located on the surface of TiO2 with 3.8 wt% of loading ratio and the size was 2.9 nm. Two types of model [2+2] cycloaddition reactions were used in this research. One is reaction between enol ether and olefin, the other is reaction between enyloxy benzene and olefin. All reactions were carried out in 1 mol/L LiClO4/CH3NO2 solution. For electrocatalysis, constant potential (1.2 V, 1.0 F/mol) was used with carbon felt electrodes as both anode and cathode. For photocatalysis, TiO2 or Pt-TiO2 nanoparticles were dispersed in the solution with 10 mg/mL and the solution was irradiated by 15 W UV lamp. From cyclic voltammetry (CV) of substrate, it was indicated these reactions were driven by SET of enol ether or enyloxy benzene. In the case of enol ether model reaction under air, yield of cyclobutane product was similar to electrocatalysis (78%) and TiO2 photocatalysis (79%), however, Pt-TiO2 photocatalysis showed relatively low yield (46%). Previously, it was proposed that Pt can function as an electron trap to alter the mechanism of reductive SET. It could be explained that the reductive SET from Pt was not involved in the reaction, decreasing the yield of the product. In the case of enyloxy benzene model reaction under air, electrocatalysis realized high yield of cyclobutane product (81%), however, TiO2 and Pt-TiO2 photocatalysis showed low yields (53% and 17%, receptively). We found that O2 bubbling to solution improved the yield of the product when TiO2 photocatalysis (80%) was used, in contrast, it was not the case for the reaction using Pt-TiO2 photocatalysis (trace). It was indicated that O2 can work as a mediator or an oxidant and this role is important for the [2+2] cycloaddition between enyloxy benzene and olefin when TiO2 photocatalysis was used, however, it was not observed under Pt-TiO2 condition. One possibility is that, O2 functions as a reductive redox mediator. Specifically, O2 was reduced by excited electron in TiO2 conduction band via single electron reduction and superoxide species were generated. Since these species have high reducing ability, they can reduce cyclobutane intermediate radical cation to form cyclobutane product. In the case of Pt-TiO2, excited electron could be trapped by Pt, which altered the reductive SET from one-electron mechanism to two- or four-electron pathways that produced H2O2 or H2O from O2. Since these species cannot reduce the radical cation, cyclobutane product was not formed. In addition, H2O2 can change to OH radical species that have high oxidative potential and they potentially decomposed substrate and/or product. In conclusion, we demonstrated the mechanistic differences among electrocatalysis and TiO2 in the presence or absence of Pt by using SET triggered [2+2] cycloaddition reactions as models. Pt-TiO2 might decrease the reduction ability of TiO2. O2 bubbling can increase yield of product in enyloxy benzene reaction because superoxide species might be generated by excited electron in TiO2 and they function as a redox mediator to reduce radical cation intermediate. This O2 mediated system cannot be realized when Pt-TiO2 was used, probably because Pt can reduce O2 into H2O2 or H2O. Figure 1

Trifluoromethyl (CF3) and difluoromethyl (CF2H) groups are versatile structural motifs, especially in the fields of pharmaceuticals and agrochemicals. Thus, the development of new protocols for tri- and difluoromethylation of various skeletons has become a vital subject to be studied in the field of synthetic organic chemistry. For the past decades, a variety of fluoromethylating reagents have been developed. In particular, bench-stable and easy-to-use electrophilic fluoromethylating reagents such as the Umemoto, Yagupolskii-Umemoto, Togni, and Hu reagents serve as excellent fluoromethyl sources for ionic and carbenoid reactions. Importantly, the action of catalysis has become a promising strategy for developing new fluoromethylations. For the past several years, photoredox catalysis has emerged as a useful tool for radical reactions through visible-light-induced single-electron-transfer (SET) processes. Commonly used photocatalysts such as [Ru(bpy)3](2+) and fac-[Ir(ppy)3] (bpy = 2,2'-bipyridine; ppy = 2-pyridylphenyl) have potential as one-electron reductants strong enough to reduce those fluoromethylating reagents, resulting in facile generation of the corresponding fluoromethyl radicals. Therefore, if we can design proper reaction systems, efficient and selective radical fluoromethylation would proceed without any sacrificial redox agents, i.e., via a redox-neutral process under mild reaction conditions: irradiation with visible light, including sunlight, below room temperature. It should be noted that examples of catalytic fluoromethylation of compounds with carbon-carbon multiple bonds have been limited until recent years. In this Account, we will focus on our recent research on photoredox-catalyzed fluoromethylation of carbon-carbon multiple bonds. First, choices of the photocatalyst and the fluoromethylating reagent and the basic concept involving a redox-neutral oxidative quenching cycle are explained. Then photocatalytic trifluoromethylation of olefins is discussed mainly. Trifluoromethylative difunctionalization reactions, i.e., simultaneous introduction of the CF3 group and a different functional group across carbon-carbon double bonds, are in the middle of the discussion. Oxy-, amino-, and ketotrifluoromethylation allow us to synthesize various organofluorine compounds bearing C(sp(3))-CF3 bonds. In addition, the synthesis of valuable trifluoromethylated alkenes is also viable when the olefins have an appropriate leaving group or undergo deprotonation. The present reaction system features high functional group compatibility and high regioselectivity. Furthermore, future prospects, especially trifluoromethylative difunctionalization of alkynes and difluoromethylation of alkenes, are also discussed.

The sulphur centered radicals, produced from various organic compounds, in high efficiency by single-electron-transfer (SET) oxidation. These radicals are highly reactive intermediates having various applications in the construction of organosulphur compounds in the field of synthetic organic chemistry. These S-centred radical-mediated organic transformations have been achieved using photoredox catalysts, including organic dyes and transition metal catalysts, as well as in the absence of any catalyst. Compared with previous methods, photoredox catalysis is inexpensive and features the advantages of being environmentally benign, highly efficient and easy to use. This review focuses on recent developments in the photocatalyzed carbon–sulphur bond formation.

Matrix EPR studies and quantum chemical calculations have been used to characterize the consecutive H-atom shifts undergone by the nitrogen-centered parent radical cations of propargylamine (1b*+) and allylamine (5*+) on thermal or photoinduced activation. The radical cation rearrangements of these unsaturated parent amines occur initially by a 1,2 H-atom shift from C1 to C2 with pi-bond formation at the positively charged nitrogen; this is followed by a consecutive reaction involving a second H-atom shift from C2 to C3. Thus, exposure to red light (lambda > 650 nm) converts 1b*+ to the vinyl-type distonic radical cation 2*+ which in turn is transformed on further photolysis with blue-green light (lambda approximately 400-600 nm) to the allene-type heteroallylic radical cation 3*+. Calculations show that the energy ordering is 1b*+ > 2*+ > 3*+, so that the consecutive H-atom shifts are driven by the formation of more stable isomers. Similarly, the parent radical cation of allylamine 5*+ undergoes a spontaneous 1,2-hydrogen atom shift from C1 to C2 at 77 K with a t1/2 of approximately 1 h to yield the distonic alkyl-type iminopropyl radical cation 6*+; this thermal reaction is attributed largely to quantum tunneling, and the rate is enhanced on concomitant photobleaching with visible light. Subsequent exposure to UV light (lambda approximately 350-400 nm) converts 6*+ by a 2,3 H-shift to the 1-aminopropene radical cation 7*+, which is confirmed to be the lowest-energy isomer derived from the ionization of either allylamine or cyclopropylamine. Although the parent radical cations of N, N-dimethylallylamine (9*+) and N-methylallylamine (11*+) are both stabilized by the electron-donating character of the methyl group(s), the photobleaching of 9*+ leads to the remarkable formation of the cyclic 1-methylpyrrolidine radical cation 10*+. The first step of this transformation now involves the migration of a hydrogen atom to C2 of the allyl group from one of the methyl groups (rather than from C1); the reaction is then completed by the cyclization of the generated MeN + (=CH2) CH2CH2CH2* distonic radical cation, possibly in a concerted overall process. In contrast to the ubiquitous H-atom transfer from carbon to nitrogen that occurs in the parent radical cations of saturated amines, the alternate rearrangements of either 1b*+ or 5*+ to an ammonium-type radical cation by a hypothetical H-atom shift from C1 to the ionized NH2 group are not observed. This is in line with calculations showing that the thermal barrier for this transformation is much higher (approximately 120 kJ mol-1) than those for the conversion of 1b*+ --> 2*+ and 5*+--> 6*+ (approximately 40-60 kJ mol-1).

Abstract