Elusive Radical Research Articles

Independent LUMO Reactivity in Mesoionic N-Heterocyclic Thiones: Synthesis of a Stable Radical Anion.

Mesoionic compounds, with positive and negative charges, are expected to have dual-site highest occupied molecular orbital (HOMO, donor) and lowest unoccupied molecular orbital (LUMO, acceptor) reactivity. Herein, we report a novel class of air-stable mesoionic N-heterocyclic thiones (mNHTs) synthesized from abnormal N-heterocyclic carbenes (aNHCs). DFT studies revealed a highly polarized exocyclic thione moiety and computed Fukui function analysis suggests the dual-site HOMO/LUMO reactivity of mNHTs predicting donor property at the negatively charged 'S' center while acceptor property at the cationic imidazole ring. The independent LUMO reactivity of the mNHT was realized by its chemical reduction to an elusive radical anion, which was characterized by a single crystal X-raydiffraction study. Further, we explore the reactivity of radical anion for the activation of SO2 gas, C-Br bonds of aryl bromide and photocatalytic functionalization of C-X (X = F, Br) bonds. This work unlocks the independent LUMO reactivity of a mesoionic compound.

Independent LUMO Reactivity in Mesoionic N‐Heterocyclic Thiones: Synthesis of a Stable Radical Anion

AbstractMesoionic compounds, with positive and negative charges, are expected to have dual‐site highest occupied molecular orbital (HOMO, donor) and lowest unoccupied molecular orbital (LUMO, acceptor) reactivity. Herein, we report a novel class of air‐stable mesoionic N‐heterocyclic thiones (mNHTs) synthesized from abnormal N‐heterocyclic carbenes (aNHCs). DFT studies revealed a highly polarized exocyclic thione moiety and computed Fukui function analysis suggests the dual‐site HOMO/LUMO reactivity of mNHTs predicting donor property at the negatively charged ‘S’ center while acceptor property at the cationic imidazole ring. The independent LUMO reactivity of the mNHT was realized by its chemical reduction to an elusive radical anion, which was characterized by a single crystal X‐raydiffraction study. Further, we explore the reactivity of radical anion for the activation of SO2 gas, C−Br bonds of aryl bromide and photocatalytic functionalization of C−X (X = F, Br) bonds. This work unlocks the independent LUMO reactivity of a mesoionic compound.

Modular Access to Chiral Amines via Imine Reductase-Based Photoenzymatic Catalysis.

The development of catalysts serves as the cornerstone of innovation in synthesis, as exemplified by the recent discovery of photoenzymes. However, the repertoire of naturally occurring enzymes repurposed by direct light excitation to catalyze new-to-nature photobiotransformations is currently limited to flavoproteins and keto-reductases. Herein, we shed light on imine reductases (IREDs) that catalyze the remote C(sp3)-C(sp3) bond formation, providing a previously elusive radical hydroalkylation of enamides for accessing chiral amines (45 examples with up to 99% enantiomeric excess). Beyond their natural function in catalyzing two-electron reductive amination reactions, upon direct visible-light excitation or in synergy with a synthetic photoredox catalyst, IREDs are repurposed to tune the non-natural photoinduced single-electron radical processes. By conducting wet mechanistic experiments and computational simulations, we unravel how engineered IREDs direct radical intermediates toward the productive and enantioselective pathway. This work represents a promising paradigm for harnessing nature's catalysts for new-to-nature asymmetric transformations that remain challenging through traditional chemocatalytic methods.

Access to γ‐Iodo‐<i>gem</i>‐Diborylated Cyclopentanes and to Bicyclic Cyclopropanes

A formal atom transfer radical [3+2] annulation (ATRAn) reaction between different homoallyl radical precursors and 1,1‐diborylethene was developed. It provides a rapid access to polysubstituted cyclopentanes containing a gem‐diboronic ester moiety. The synthetic utility of theses uniquely functionalized 5‐membered rings is highlighted by their easy conversion to attractive borylated building blocks such as 1‐borylated bicyclo[3.1.0]hexanes. The ATRAn reaction was extended to homopropagylic radicals giving access to unique allylic gem‐diboronic esters that could be used in allylboration of aldehydes. Furthermore, this work highlights that 1,1‐diborylethene represents a synthetic equivalent to ketene, a so far elusive radical trap due to its daunting reactivity.

E-Selective Radical Difunctionalization of Unactivated Alkynes: Preparation of Functionalized Allyl Alcohols from Aliphatic Alkynes.

Radical difunctionalization of aliphatic alkynes provides direct access to valuable multi-substituted alkenes, but achieving a high level of chemo- and stereo-control remains a formidable challenge. Herein a novel photoredox neutral alkyne di-functionalization is reported through functional group migration followed by a radical-polar crossover and energy transfer-enabled stereoconvergent isomerization of alkenes. In this sequence, a hydroxyalkyl and an aryl group are incorporated concomitantly into an alkyne, leading to diversely functionalized E-allyl alcohols. The scope of alkynes is noteworthy, and the reaction tolerates aliphatic alkynes containing hydrogen donating C─H bonds that are prone to intramolecular hydrogen atom transfer. The protocol features broad functional group compatibility, high product diversity, and exclusive chemo- and stereoselectivity, thus providing a practical strategy for the elusive radical di-functionalization of unactivated alkynes.

Chemically Induced Spin Hyperpolarization: Coherence Formation in Reaction Products

Chemically induced dynamic nuclear polarization (CIDNP) has emerged as a highly informative method to study spin-dependent radical reactions by analyzing enhanced NMR (nuclear magnetic resonance) signals of their diamagnetic reaction products. In this way, one can probe the structure of elusive radical intermediates and determine their magnetic parameters. A careful examination of experimental CIDNP data at variable magnetic fields shows that formation of hyperpolarized molecules in a coherent state is a ubiquitous though rarely discussed phenomenon. The presence of nuclear spin coherences commonly leads to subsequent polarization transfer among coupled spins in the diamagnetic products of radical recombination reaction that must be taken into account when analyzing the results of CIDNP experiments at low magnetic field. Moreover, such coherent polarization transfer can be efficiently exploited to polarize spins, which do not acquire CIDNP directly. Here we explain under what conditions such coherences can be generated, focusing on the key role of level anti-crossings in coherent polarization transfer, and provide experimental approaches to probing nuclear spin coherences and their time evolution. We illustrate the theoretical consideration of the outlined coherent spin phenomena in CIDNP by examples, obtained for the dipeptide tryptophan–tryptophan.

Dioxygen-Derived Nonheme Mononuclear FeIII(OH) Complex and Its Reactivity with Carbon Radicals

A new tetradentate, monoanionic, mixed N/O donor ligand (BNPAPh2O-) with second coordination sphere H-bonding groups has been synthesized for stabilization of a terminal FeIII(OH) complex. The complex FeII(BNPAPh2O)(OTf) (1) reacts with O2 to give a mononuclear terminal FeIII(OH) complex, FeIII(OH)(BNPAPh2O)(OTf) (2), both of which were characterized by X-ray diffraction, electrospray ionization mass spectrometry, UV-vis, 1H and 19F nuclear magnetic resonance, 57Fe Mössbauer, and electron paramagnetic resonance spectroscopies. Treatment of 2 with carbon radicals (Ar3C·) gives Ar3COH and the FeII complex 1, in direct analogy with the elusive radical "rebound" process proposed for nonheme iron enzymes.

(Invited) Synthesis of the Elusive Dimetallofullerenes

The metal-metal (M-M) bonding in dimetallofullerenes presents the peculiar electronic structures as well as the chemical and physical properties.[1-2] For Y and medium-size lanthanides, computations by Shinohara et al. showed that M2@C80 has one unpaired electron occupying the M–M bonding molecular orbitals, and the other electron is delocalized over the carbon cage.[3] Such molecules are elusive radicals. Recently, we have succeeded in the capture of the elusive M2@C80 (M=Y, Gd, Tb, Dy, Ho, and Er) as benzyl derivatives.[4] In this contribution, the synthesis and structural characterizations of these M2@C80–CH2Ph will be discussed. [1] A. A. Popov, S. Yang, L. Dunsch, Chem. Rev. 2013, 113, 5989-6113. [2] A. A. Popov, S. M. Avdoshenko, A. M. Pendas, L. Dunsch, Chem. Commun. 2012, 48, 8031-8050. [3] Z. Wang, R. Kitaura, H. Shinohara, J. Phys. Chem. C 2014, 118, 13953-13958. [4] F. Liu, D. S. Krylov, L. Spree, S. M. Avdoshenko, N. A. Samoylova, M. Rosenkranz, A. Kostanyan, T. Greber, A. U. B. Wolter, B. Büchner, A. A. Popov, Nat. Commun. 2017, 8, 16098.

Efficient Docking–Migration Strategy for Selective Radical Difluoromethylation of Alkenes

AbstractRadical‐mediated difunctionalization of alkenes is a powerful tactic for olefin utilization. However, the transformation of unactivated alkenes still remains a formidable challenge. Now a conceptually new docking–migration strategy is presented for the difunctionalization of alkenes with photoredox catalysis. Both activated and unactivated alkenes are suitable substrates. A vast array of functional groups are compatible with the mild reaction conditions. Heteroaryl and difluoromethyl are concomitantly incorporated into alkenes, leading to synthetically valuable products that are readily converted into a variety of fluorine‐containing molecules. The protocol provides a kinetic control of stereoselectivity for cycloalkenes to generate the unusual cis‐products, and offers an efficient approach for the late‐stage functionalization of complex natural products and drug molecules. A portfolio of dual‐function reagents are prepared for the elusive radical difunctionalization of alkenes.

Easy access to elusive radical reactions.

Two mild approaches generate radical intermediates from masked aldehydes

Discovery of the elusive radical NCO and confirmation of H2NCO+ in space.

The isocyanate radical (NCO) is the simplest molecule containing the backbone of the peptide bond, C(=O)-N. This bond has a prebiotic interest since is the one linking two amino acids to form large chains of proteins. It is also present in some organic molecules observed in space such as HNCO, NH2CHO and CH3NCO. In this letter we report the first detection in space of NCO towards the dense core L483. We also report the identification of the ion H2NCO+, definitively confirming its presence in space, and observations of HNCO, HOCN, and HCNO in the same source. For NCO, we derive a column density of 2.2×1012 cm-2, which means that it is only ~5 times less abundant than HNCO. We find that H2NCO+, HOCN and HCNO have abundances relative to HNCO of 1/400, 1/80, and 1/160, respectively. Both NCO and H2NCO+ are involved in the production of HNCO and several of its isomers. We have updated our previous chemical models involving NCO and the production of the CHNO isomers. Taking into account the uncertainties in the model, the observed abundances are reproduced relatively well. Indeed, the detection of NCO and H2NCO+ in L483 supports the chemical pathways to the formation of the detected CHNO isomers. Sensitive observations of NCO in sources where other molecules containing the C(=O)-N subunit have been detected could help in elucidating its role in prebiotic chemistry in space.

What Happens after Activation of Ascaridole? Reactive Compounds and Their Implications for Skin Sensitization.

To replace animal testing and improve the prediction of skin sensitization, significant attention has been directed to the use of alternative methods. The direct peptide reactivity assay (DPRA), the regulatory agencies' approved alternative in chemico method, has been applied for understanding the sensitization capacity of activated ascaridole. Ascaridole, the oxidative metabolite of α-terpinene, is considered to be one of the components responsible for the contact allergy associated with essential oils derived from Chenopodium and Melaleuca species. The recently developed high-throughput screening based on the dansyl cysteamine (HTS-DCYA) method was applied to understand the reported enhanced reactivity of activated ascaridole and possibly to identify the resulting elusive radical or other reactive species. For the first time, a substituted cyclohexenone was identified as a potential electrophilic intermediate resulting in higher depletion of nucleophilic DCYA, along with several nonreactive byproducts of ascaridole via a radical degradation mechanism. Formation of electrophilic species via radical degradation is one of the possible pathways should be considered for the peptide reactivity of in aged tea tree oil or oils rich in terpinenes along with commonly believed reactants, allylic-epoxides and allylic-peroxides.

Level crossing analysis of chemically induced dynamic nuclear polarization: Towards a common description of liquid-state and solid-state cases.

Chemically Induced Dynamic Nuclear Polarization (CIDNP) is an efficient method of creating non-equilibrium polarization of nuclear spins by using chemical reactions, which have radical pairs as intermediates. The CIDNP effect originates from (i) electron spin-selective recombination of radical pairs and (ii) the dependence of the inter-system crossing rate in radical pairs on the state of magnetic nuclei. The CIDNP effect can be investigated by using Nuclear Magnetic Resonance (NMR) methods. The gain from CIDNP is then two-fold: it allows one to obtain considerable amplification of NMR signals; in addition, it provides a very useful tool for investigating elusive radicals and radical pairs. While the mechanisms of the CIDNP effect in liquids are well established and understood, detailed analysis of solid-state CIDNP mechanisms still remains challenging; likewise a common theoretical frame for the description of CIDNP in both solids and liquids is missing. Difficulties in understanding the spin dynamics that lead to the CIDNP effect in the solid-state case are caused by the anisotropy of spin interactions, which increase the complexity of spin evolution. In this work, we propose to analyze CIDNP in terms of level crossing phenomena, namely, to attribute features in the CIDNP magnetic field dependence to Level Crossings (LCs) and Level Anti-Crossings (LACs) in a radical pair. This approach allows one to describe liquid-state CIDNP; the same holds for the solid-state case where anisotropic interactions play a significant role in CIDNP formation. In solids, features arise predominantly from LACs, since in most cases anisotropic couplings result in perturbations, which turn LCs into LACs. We have interpreted the CIDNP mechanisms in terms of the LC/LAC concept. This consideration allows one to find analytical expressions for a wide magnetic field range, where several different mechanisms are operative; furthermore, the LAC description gives a way to determine CIDNP sign rules. Thus, LCs/LACs provide a consistent description of CIDNP in both liquids and solids with the prospect of exploiting it for the analysis of short-lived radicals and for optimizing the polarization level.

Time-resolved CIDNP: an NMR way to determine the EPR parameters of elusive radicals

Chemically Induced Dynamic Nuclear Polarization (CIDNP) of the diamagnetic products of radical reactions is exploited for the purpose of determination of the hyperfine coupling constants (HFCCs) of the radical intermediates. A simple proportionality relation between geminate CIDNP of a nucleus and its HFCC at the radical stage is established. The applicability range of this relation is determined: the relation is fulfilled in the case of a large difference in g-factor between the radicals involved and for the situation where the number of magnetic nuclei in the system is sufficiently large. The validity of the relation was confirmed by CIDNP experiments on radical pairs with precisely known HFCCs. Using the proportionality relation we were able to measure the HFCCs in various short-lived radicals of the amino acids histidine and tryptophan and of the S-N-centered cyclic radical of methionine derived from the methionine-glycine dipeptide in aqueous solution.

Confirmation of the classic tris(2,2′-bipyridyl)ruthenium(ii) and oxalate electrochemiluminescence mechanism using EPR spectroscopy

A chemically initiated adaptation of the classic [Ru(bipy)(3)](2+)/oxalate electrochemiluminescence coreactant system has revealed the elusive radical intermediates of the light-producing pathway. Oxalyl (HC(2)O(4)˙) and hydroxyformyl (HCO(2)˙) radicals have been captured on a quartz surface and characterised using EPR spectroscopy.

TR-CIDNP as tool for quantitative analysis of hyperfine couplings in elusive radicals

For many years Chemically Induced DynamicNuclear Polarization (CIDNP) has been successfullyused for investigating the kinetics of fast reactions ofradicals [1]. The origin of CIDNP is the nuclear spinselective recombination of radical pairs. This case isgiven when the electronic singlettriplet conversion isthe bottleneck for the radical pair recombination. As aconsequence, radical pairs have different reactivity indifferent nuclear spin states, with the result that thediamagnetic reaction products have nonthermal populations of their nuclear spin energy levels. CIDNPmanifests itself in anomalous phase and intensity ofthe NMR spectra of the diamagnetic molecules. Thetimeresolved (TR) version of the CIDNP techniquehas a particularly high content of information abouttransient radicals [2] as it can differentiate primary andsecondary reaction steps. First, CIDNP spectrarecorded right after recombination of the geminateradical pairs (geminate CIDNP) are a fingerprint ofthe transient radicals. Second, CIDNP effects can bedetected in liquids at ambient conditions, whereasconventional EPR spectroscopy often allows one toinvestigate the elusive radical species only in frozenmatrix at cryogenic temperatures. Third, the CIDNPtime dependence (kinetics) gives information aboutthe rates of radical termination, intramolecular electron migration and nuclear spin relaxation in transientradicals.In the present work, we will investigate theoretically and experimentally the possibility of extractinghyperfine coupling constants (HFCCs) in radicalsfrom the geminate CIDNP spectrum recorded at high

EPR studies on carboxylic esters. Part 16. Indirect�generation of the elusive radical anions of alkyl �anthracene-9-carboxylates

Electroreduction of dioxygen in aprotic media yields superoxide anions O2.−. These highly reactive radical anions easily attack sensitive arenes. It is, therefore, not possible to generate the radical anions of anthracene-9-carboxylic esters (1) by direct in situ electroreduction. Because derivatives substituted in the 10-position are stable against these radicals, indirect generation of the radical anion 1.− was realized in order to be able to measure its EPR spectrum. In a series of EPR experiments we were able to study the influence of various substituents on both the stability of the anthracene derivatives against superoxide and the spin density distribution. Copyright © 2000 John Wiley & Sons, Ltd.

Direct Observation of Hydrogen Atom Adducts to Nitromethane and Methyl Nitrite. A Variable-Time Neutralization−Reionization Mass Spectrometric and ab Initio/RRKM Study

Variable-time neutralization−reionization mass spectrometry was used to generate elusive radicals CH3NO2H• (1), CH3O(H)−NO• (2) CH3O−N(H)−O• (3), and CH3O−N−OH• (4) that represent hydrogen atom adducts to nitromethane and methyl nitrite, respectively. Radicals 1, 3, and 4 were stable species on the 3.7 μs time scale of the experiment. Radical 2 dissociated completely to CH3OH and NO. The major unimolecular dissociations of 1 formed CH3NO + OH• and CH3• + NO2H, whereas loss of H• to form CH3NO2 was insignificant. Gaussian 2(MP2) and density functional theory calculations provided the structures and bond dissociation energies of 1−4. The relevant parts of the potential-energy surface were used for RRKM and transition-state theory calculations of unimolecular dissociation kinetics. The calculated branching ratios for 1 were in accord with experiment. The unimolecular chemistry of radicals 1−4 formed by femtosecond collisional electron transfer can be accounted for by the properties of the ground electronic s...

Photocatalytic reactions of acetic acid on platinum-loaded TiO2: ESR evidence of radical intermediates in the photo-Kolbe reaction

Two elusive radical intermediates; a methyl radical (·CH3) and a carboxymethyl radical (·CH2CO2H), have been confirmed for the first time by direct observation of their ESR absorptions at room temperature on the photocatalytic reactions of acetic acid and metal (platinum)-loaded titanium dioxide (Pt/TiO2) in aqueous solution.