Are N-heterocyclic carbene radical cations relevant intermediates in radical transformations?

Abstract

N-Heterocyclic carbene (NHC) radical cations have been increasingly hypothesized as key intermediates in NHC-promoted radical reactions, but have eluded direct observation so far. Herein, we report joint experimental and theoretical efforts to assess the issues surrounding the possible existence, generation and observation of these postulated species. We show that they are unlikely to be the relevant intermediates in most NHC-promoted radical reactions.

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Introduction

For the last decades, stable N-Heterocyclic Carbenes (NHCs) 1 have stood out as handleable reagents, efficient ligands and original synthetic building blocks.¹ Recent developments in radical NHC-catalysis have drawn attention to the corresponding NHC radical cations 1˙⁺ as possible key intermediates.² Despite the convenience of these radicals for proposing catalytic cycles, they have eluded spectroscopic observation so far³ and evidence for their genuine involvement remains indirect and tenuous.

Yet, radicals 1˙⁺ should be readily accessible through oxidation of the corresponding NHC.⁴ Indeed, imidazol-2-ylidenes 1a–b perform the stoichiometric reduction of ferricenium⁵ (E = +0.38 V vs. SCE) and trityl (E = +0.27 V vs. SCE) cations (Fig. 1a).^6,7 Cyclic alkylaminocarbene (CAAC) 1c ^3,8 and mesoionic carbene (MIC) 1d ⁹ were used for the one electron-reduction of iminium derivatives and quinones, respectively. Although these reactions involved the formal oxidation of a free NHC 1 and should lead to the generation of corresponding radical cation 1˙⁺, only the formation of azolium salts 1·H⁺ was observed. This suggested that H˙ abstraction from solvent molecules by 1˙⁺ is very fast. However, even the formation of 1·H⁺ does not necessarily imply the formation of 1˙⁺ by single electron transfer (SET). Indeed, Song and Lee revisited the reaction of trityl cation with 1a, which affords 1a·H⁺ and triphenylmethane. Their DFT study unveiled an alternative mechanism involving 1a–trityl cation adduct¹⁰ in place of the initially proposed SET with formation of 1˙⁺ and trityl radicals.⁶ Interestingly, Clyburne et al. reported that the oxidation of 1b with tetracyanoethylene led to the formation of dicationic dimer 2b²⁺, resulting either from direct dimerization of radical cation 1b˙⁺, or (more likely) from its reaction with 1 to produce 2b˙⁺ which was then oxidised to afford 2b²⁺ (Fig. 1b).⁵

Fig. 1 (a) Oxidation of N-heterocyclic carbenes 1, putative formation of the corresponding radical cation 1˙⁺ and subsequent H˙ abstraction to afford azolium 1·H⁺. (b) Formation of dicationic dimer 2b²⁺ upon oxidation of 1b with tetracyanoethylene (TCNE). (c) Oxidized version of the Wanzlick equilibrium as a possible source of NHC radical cations.

Dimers 2²⁺ could constitute a reservoir for transient radicals 1˙⁺ (Fig. 1c), similarly to olefins 2 (the reduced forms of dications 2b²⁺), which have been used as sources of NHC ligands long before the advent of stable NHCs 1.^11–13 The formal relationship between 1 and their dimers 2 is well-known as the Wanzlick equilibrium.^11,14 Note that a genuine equilibrium has been evidenced for benzimidazolylidenes only.¹⁵

In fact, the Wanzlick equilibrium is fully shifted towards the free carbene in the case of electron-rich aromatic heterocycles (typically: imidazol- and triazol-ylidenes).¹⁶ Conversely, the dimerization of saturated and/or more electrophilic NHC (imidazolidinylidenes, thiazolylidenes, CAAC, etc.) is thermodynamically favoured, unless high steric demand around the carbene centre prevents it. Importantly, in the absence of acid catalyst, the formation of the dimer 2 is significantly slowed, to the point that even metastable NHC with smaller substituents can be isolated prior to their dimerization.¹⁷ In contrast with the well-studied Wanzlick equilibrium, the potential of dicationic dimers 2²⁺ as sources of radical 1˙⁺ has never been considered: their reactivity studies have been confined to their redox relation to electron donors 2¹⁸ and their anecdotical conversion to ureas.¹⁹

Herein, we report our experimental and theoretical efforts to assess the issues surrounding the possible existence and generation of elusive NHC radical cations. We examined: (i) whether a tuning of substituents can allow for the stabilization and observation of a NHC radical cation and, conversely, (ii) whether transient NHC radical cations 1˙⁺ could be generated from the homolytic dissociation of dications 2²⁺. In other words, we probe for the possibility of an oxidized equivalent to the Wanzlick equilibrium.

Results and discussion

Evaluation of the stabilization of NHC radical cations

Jana et al. observed an EPR signal when monitoring the reaction of CAAC 1c with NO·BF₄.^3b The authors initially attributed the 1 : 1 : 1 triplet to the CAAC radical cation 1c˙⁺, but they later invalidated this interpretation on the basis of MINDO calculations.^3a Interestingly, they found that H˙ abstraction from solvents by radical 1c˙⁺ was highly exothermic, supporting further the high reactivity and elusiveness of this radical. The stability of organic radicals is commonly expressed using isodesmic H-transfer reactions. In particular, the enthalpy of H-abstraction from methane to afford methyl radical is regarded as a standard metric for radical stabilisation energy (RSE) for C-centred radicals.²⁰

We computed the RSE of radicals 1a–e˙⁺ at the B3LYP-GD3(BJ)/def2svp level of theory (see Fig. 2).²¹ We found negative values, indicating stabilities even lower than that of the methyl radical. This was unsurprising, since 1a–e˙⁺ are non-conjugated electron-poor carbon-centred radicals that are destabilized by the -I electronic effect of the amino groups. In line with this reasoning, CAAC-based radical 1c˙⁺ was found less unstable because of the replacement of an amino with an electron-donating alkyl group, resulting in an RSE of −9.4 kcal mol⁻¹, instead of about −20 kcal mol⁻¹ for 1a–b˙⁺ and 1d–e˙⁺. RSE correlates well with the inverses of ionization energy (IE) of NHC 1 and bond dissociation enthalpy of 2²⁺, which could be considered as alternative metrics for the stability of radicals 1˙⁺ (Fig. 2). Importantly, despite their bulky 2,6-di(isopropyl)phenyl (Dipp) or 2,4,6-trimethylphenyl (Mes) groups, enthalpies of dimerization of 1a–e˙⁺ (BDE) remain very high, especially when considering that their reduced forms 1a–e are stable as free NHC and do not dimerize.

Fig. 2 Computed (B3LYP-GD3(BJ)/def2svp) enthalpy of hydrogen atom exchange between methane and 1˙⁺ (RSE), ionization energy of NHC 1 (IE) and enthalpy of homolytic bond dissociation of dimers 2²⁺ (BDE).

When decreasing steric hindrance with small methyl N-substituents (model NHCs 1′a–e) enthalpies of dimerization did not increase significantly and trends in relative stability remained unchanged.

Next, we turned to electron-enriched NHCs 1f ²² and 1g,²³ which feature bis(dimethylamino)ethylene and bis(dimethylamino) oxyallyl patterns, respectively (Scheme 1). The redox-active patterns resulted in positive RSE of 0.3 and 8.3 kcal mol⁻¹ (−5.4 and +9.4 kcal mol⁻¹ for methyl substituted 1′f–g˙⁺), respectively. These values still correspond to highly reactive radicals. As a comparison, at this level of theory, RSE for phenyl (C₆H₅˙), tert-butyl (C₄H₉˙) and allyl (C₃H₅˙) radicals are −7.5, +11.3 and +19.5 kcal mol⁻¹ respectively, whereas radical HC(O)C·(H)NH₂, featuring stabilizing capto-dative substitutions, has a RSE of +32.1 kcal mol⁻¹ (Fig. 3).

Scheme 1 Mesomeric limit forms of NHC radical cations 1f˙⁺ and 1g˙⁺.

Fig. 3 Comparative stabilities of methyl N-substituted NHC radical cations on the RSE scale.

Nevertheless, 1f˙⁺ and 1g˙⁺ are very different in nature from localized radicals 1a–e˙⁺. DFT calculations indicated that the spin density of 1f˙⁺ and 1g˙⁺ is spread over the redox-active pattern, with only 19% and 10% Mulliken spin density on the former carbene centre, respectively (Fig. 4a). Furthermore, in contrast to NHCs 1a–f, the HOMO of the electron-rich NHC 1g is not the lone pair of the carbene (HOMO−1), but a π-orbital of the oxyallyl system (Fig. 4b). In the case of 1f, both molecular orbitals are close in energy. From an experimental point of view, 1,3-bis(dimethylamino)oxyallyl,²⁴ as well as di(amino)ethylene radical cations^4b,25 often display a remarkable stability. In particular, the one-electron oxidation of adducts of NHC 1f and 1g can lead to stable or persistent radical cations.^22,23 Overall, we considered that chances were fair that 1f˙⁺ and 1g˙⁺ could be generated and observed.

Fig. 4 (a) Representation of Mulliken spin density of NHC radical cations 1˙⁺, 1f˙⁺ and 1g˙⁺. (b) Representation of HOMO and HOMO−1 of the corresponding NHCs.

Attempts to observe stabilized NHC radical cations

We synthesized NHC 1f in an electrochemical cell by adding 1.1 equivalent of potassium bis(trimethylsilyl)amide to a THF solution of 1f·H⁺ and 0.1 M [Bu₄N]PF₆. The corresponding cyclic voltammograms featured an irreversible oxidation wave at about +0.8 V versus SCE (Fig. 5). A second reversible oxidation was observed at about +1.3 V, which corresponded to the one-electron oxidation of precursor 1f·H⁺ to radical 1f·H˙²⁺. Therefore, we concluded that the oxidation of 1f afforded a transient radical 1f˙⁺, which underwent a fast H˙ abstraction to yield imidazolium 1f·H⁺, similarly to non-stabilized NHC radical cations 1a–e˙⁺.

Fig. 5 Cyclic voltammograms of 1f (black) and 1f·H⁺ (orange) in THF + 0.1M [Bu₄N]PF₆, scan rate: 10 mV s⁻¹.

In contrast, the cyclic voltammogram of 1g in a 0.1M [Bu₄N]PF₆ THF solution featured a pseudo-reversible oxidation wave at about −0.5 V versus SCE (Fig. 6a). We performed the electrolysis of the solution at −0.3 V. UV-vis monitoring indicated the formation of an intermediate featuring an absorption in the typical region for oxyallyl radical cations, at 495 nm (Fig. 6b). X-band EPR of an aliquot confirmed the formation of a radical, which could be observed for a few minutes at room temperature (Fig. 6c). However, the EPR spectrum couldn't correspond to radical 1g˙⁺. Indeed, the hyperfine structure displayed an even number of bands and, therefore, corresponded to an odd number of coupled atomic spins of ½ (protons). Accordingly, the experimental spectrum could be simulated by considering a 12.0 MHz coupling with an isolated proton, in addition to 6 equivalent protons (14.0 MHz) and 2 nitrogen atoms (6.5 MHz).²⁶

Fig. 6 (a) Cyclic voltammograms of 1g in THF + 0.1M [Bu₄N]PF₆, scan rate: 100 mV s⁻¹. (b) UV monitoring of electrolysis at E = −0.3 V vs. SCE. (c) Resulting experimental X-band isotropic EPR spectrum and corresponding simulated spectrum with Lorentzian line-broadening parameter L_w = 0.3, a(¹⁴N) = 6.5 MHz (2 nuclei), a(¹H) = 12.0 MHz (1 nucleus) and 14.0 MHz (6 nuclei). (d) EPR of a solution of 1g in THF upon addition of Cp₂FePF₆, corresponding simulated spectrum with L_w = 0.2, a(¹⁴N) = 6.7 MHz (2 nuclei), a(¹H) = 11.7 MHz (1 nucleus) and 14.0 MHz (6 nuclei). (e) Proposed formation of oxyallyl radical 3˙⁺ and representation of computed Mulliken spin density.

Considering the tendency of electron-poor N-heterocyclic carbene centres to undergo intramolecular C–H insertion,²⁷ we hypothesized that the oxidation of 1g triggered a C–H insertion into a methyl group of a mesityl N-substituent to afford oxyallyl radical cation 3˙⁺ (Fig. 6e). Our assumption was further supported by DFT calculations (B3LYP-GD3(BJ)/def2svp), which indicated that the isomerization of 1˙⁺ into 3˙⁺ was highly exergonic (ΔG = −33 kcal mol⁻¹). Importantly, the conjugation of one (dimethyl)amino group with the oxyallyl system of 3˙⁺ is prevented by steric constraints from the polycyclic structure. As a consequence, the spin density of 3˙⁺ is concentrated on one side of the 6-membered heterocycle and significant hyperfine couplings (B3LYP/EPR-III) are limited to a few atoms: the proton at the former carbene centre (a_DFT = 15 MHz), two nitrogen atoms (a_DFT = 9 and 8.6 MHz) and six protons of a dimethyl amino group (a_DFT = 11 MHz). These values fit well with experimental data, in contrast with computed hyperfine couplings for 1g˙⁺ (a_DFT = 9 MHz with two ¹⁴N and 13 MHz with 12 protons).

We also performed the chemical oxidation of 1g with ferrocenium hexafluorophosphate in THF at low temperature. The resulting EPR spectrum was more detailed and better resolved, but could be simulated with a very similar set of hyperfine coupling constants, thus indicating the formation of the same radical (Fig. 6d). Monitoring of the oxidation at low temperature showed that 3˙⁺ is already the only radical in solution below −70 °C and we couldn't observe the intermediary formation of 1g˙⁺.

More on the high reactivity of NHC radical cations

A closer look at DFT data suggested a possible alternative fate of non-stabilized radicals 1˙⁺, besides direct H-abstraction from solvent molecules to afford 1˙H⁺. The optimized geometry of 1˙⁺ features two CH₃ groups of the 2,6-di(isopropyl)phenyl (Dipp) N-substituents in close vicinity to the carbene radical centre (Fig. 7a). The short H_CH3–C_carbene distances (about 230 pm) indicated a possible interaction. This assumption was confirmed by an NBO second-order perturbation energy analysis, which indicated hyper-conjugations of the anti-bonding MO with the singly-occupied carbene “lone pair” (1.7 kcal mol⁻¹), as well as of the σ_C–H bonding MO with a vacant C-centred p-orbital (1.9 kcal mol⁻¹). Although most of the spin density is located on the C_carbene atom, the two methyl groups bear 3% residual spin density each. Accordingly, 1˙⁺ is predicted to evolve straight away to distonic alkyl radical 4˙⁺, through an almost barrierless H-migration from the methyl to the carbene centre (Fig. 7e).

Fig. 7 (a) Optimized geometry of 1˙⁺ at the B3LYP-GD3(BJ)/def2svp level of theory. (b) Representation of spin density. (c) Representation of natural molecular orbitals: C-centred sp² SOMO and vacant (1.7 kcal mol⁻¹ second order interaction), and (d) C-centred vacant p orbital and occupied σ_CH (1.9 kcal mol⁻¹). (e) Computed rearrangement of 1˙⁺ into 4˙⁺ (free enthalpies in kcal mol⁻¹).

Although a similar C–H interaction couldn't be found in the optimized structure of NHC radical cations 1b–e˙⁺, H-migrations to the carbene radical cation centre from CH₃ and/or CH groups of isopropyl substituents, were found again nearly barrierless (ΔG^‡ < +5.3 kcal mol⁻¹) and exergonic (Fig. 8). In all instances, the π-delocalized benzylic radicals 5˙⁺ are the most stable isomer. Importantly, in the case of Dipp N-substituents, alkyl radicals 4˙⁺ are found to be more stable than NHC radical cation isomers 1˙⁺. This is in line with the computed RSE values, which already indicated a lower stability of 1a–e˙⁺ compared to the highly reactive methyl radical.

Fig. 8 Computed rearrangement of NHCs 1˙⁺ into distonic alkyl radicals 4˙⁺ and benzylic radicals 5˙⁺ (free enthalpies in kcal mol⁻¹).

Despite its stabilizing scaffold, the evolution of NHC radical cation 1f˙⁺ into isomers 4f˙⁺ and 5f˙⁺ remain thermodynamically favoured (ΔG = −3.6 and −17.5 kcal mol⁻¹, respectively). The most stabilized oxyallyl-based radical cation 1g˙⁺ is more reluctant toward H-migration, with a nearly athermic formation of 5g˙⁺. This rearrangement is likely the first step to the formation of 3˙⁺.

It corresponds to a rather significant computed activation barrier (above 20 kcal mol⁻¹), which suggests that 1g˙⁺ may perhaps be detectable in cryogenic conditions or in the gas phase.

Dicationic dimers as sources of radicals

Overall, our results showed that NHC radical cations 1˙⁺ must be extremely short-lived intermediates in solution. They are very unlikely to be involved as radical catalysts, unless they could be generated from resting state species, such as their dimer 2²⁺. BDE values also indicated that bulkiness does not significantly favour the homolytic dissociation of dicationic dimers 2²⁺. In addition, we considered that efficient intermolecular trapping had better chances with NHC radical cations 1˙⁺ with minimal steric hindrance. Thus, we synthesized dicationic dimers 2a′²⁺, 2e²⁺ and 2h′²⁺ (based on N-methyl substituted imidazolium, N-methyl substituted benzimidazolium patterns and a thiazolium respectively), whose bis(hexafluorophosphate) salts are readily accessible by oxidation of the corresponding NHC dimer 2.^16c,28

We found dications 2a′²⁺ and 2h′²⁺ to be thermally stable. We couldn't evidence any decay after heating an acetonitrile solution under reflux overnight. EPR-monitoring did not indicate the formation of radical traces even when setting the spectrometer temperature up to 70 °C. We also heated acetonitrile solutions in presence of an excess (5 equivalents) of phenyl N-tert-butylnitrone (PNB, a classical spin trap) at 80 °C. In the case of 2a′²⁺, the crude solution featured a broad EPR spectrum (Fig. 9a). The formation of undetermined radicals may result from decomposition of the radical adducts of PNB. In the case of 2h′²⁺, the EPR spectrum featured a triplet of doublet with hyperfine coupling constants of a(¹⁴N) = 38.2 MHz and a(¹H) = 5.1 MHz, that are typical of nitroxide radicals stemming from PNB.²⁹

Fig. 9 (a) Generation of radicals from 2a′²⁺ and 2h′²⁺; EPR spectra of crude mixture. (b) Generation of 2e˙⁺; simulated EPR spectrum with Lorentzian line-broadening parameter L_w = 0.24, hyperfine coupling constants a(¹⁴N) = 11.6 MHz (2 nuclei) and a(¹H) 6.0 MHz (6 nuclei).

In marked contrast, the EPR monitoring of a solution 2e²⁺ in acetonitrile indicated the formation of a radical within minutes at 80 °C. The hyperfine structure could be simulated with the same coupling constants as the known^4b radical cation 2e˙⁺ (Fig. 9b). No additional radical could be observed when heating in presence of excess PNB spin-trap. The identity of radical 2e˙⁺ was further supported by a strong UV-vis absorption at 450 nm and a remarkable air persistency.^4b

The formation of 2e˙⁺ could be due to the generation of 1e˙⁺ from the homolytic cleavage of 2e²⁺. Indeed 1e˙⁺ is prone to fast H˙ abstraction from the solvent, affording thiazolium 1e·H⁺. This latter could trap another transient radical cation 1e˙⁺, affording 2e˙⁺ after deprotonation (Fig. 10a). Note that the formal addition of H˙ provides for the reductive event that is required for the formation of 2e˙⁺ from 2e²⁺ (the carbenic carbon evolves from C^III in 1e˙⁺ to C^II in 1e·H⁺). We also considered an alternative: the heterolytic cleavage of 2e²⁺, which would afford a formal disproportionation of 2e²⁺ (C^III carbenic carbon) into the carbene 1e (C^II) and the carbene dication 1e²⁺ (C^IV). NHC 1e could lead to 2e˙⁺ by addition to 2e²⁺, followed by elimination of 1e˙⁺ (Fig. 10b).

Fig. 10 Possible reductive events for the formation of 2e˙⁺ from 2e²⁺: (a) H˙ abstraction from solvent by 1e˙⁺ to afford 1e·H⁺, (b) disproportionation of 2e²⁺ into 1e²⁺ and 1e. Energies are in kcal mol⁻¹ (B3LYP-GD3(BJ)/def2svp with SMD model for acetonitrile as solvent).

At first, the singularity of 2e²⁺ for the generation of radical seemed inconsistent with the high computed BDE (Fig. 2). When introducing the SMD model for acetonitrile as solvent, the homolytic cleavage was found very endothermic (139 kcal mol⁻¹ Fig. 10a). The heterolytic cleavage was found even less favoured (Fig. 10b). However, the DFT-optimized geometry of 2e²⁺ was unique among dimeric dications 2²⁺, which usually feature NHC units that are nearly perpendicular, in order to accommodate steric bulk around the central C–C bond. In contrast, in the case of 2e²⁺, the lack of steric hindrance around the sulphur atom allows both π-systems to be coplanar and conjugated. Importantly, we grew single crystals of a dichloride salt of 2e²⁺ and corroborated the DFT-predicted geometry with an experimental X-ray diffraction study (Fig. 11a). Overall, dication 2e²⁺ features a low-lying LUMO (−9.5 eV) with strong coefficients on the carbon atom of the central C–C bond, which is moderately sterically confined. In line with a superior electrophilicity of 2e²⁺, the reduction potential of this dication (−0.06 V vs. SCE)^4b is significantly higher than that of 2h′²⁺ (−0.8 V) and 2a′²⁺ (−1.4 V).²⁸

Fig. 11 (a) X-ray crystallographic structure of 2e²⁺ with 40% probability ellipsoids (Cl⁻ anions are omitted for clarity). (b) Representation of LUMO of 2e²⁺.

Considering that the resulting peculiar electrophilicity must be linked to its distinctive radical behaviour, we reacted 2e²⁺ with DMAP (a prototypical nucleophilic pyridine) at room temperature. The solution immediately turned red and EPR spectroscopy indicated the formation of 2e˙⁺ (Fig. 9b). Importantly, no formation of radicals was observed when adding DMAP to an acetonitrile solution of 2a′²⁺ or 2h′²⁺, even when heating up to 80 °C. This was in line with the lower electrophilicity of these dications.

Radical generation upon addition of DMAP to 2e²⁺ suggested that Lewis bases could ease the dissociation of the dication, mirroring the acid-catalysed generation of NHCs from their dimers 2 in the Wanzlick equilibrium. Without DMAP, radicals were generated but at a higher temperature. We presumed that the acetonitrile solvent was also able to add to 2e²⁺ and to promote the dissociation of the dication. We probed this hypothesis with DFT calculations with the SMD solvation model. The addition of acetonitrile to 2e²⁺ is endothermic by ΔH = 36 kcal mol⁻¹ and endergonic by ΔG = 48 kcal mol⁻¹ (Fig. 12). The heterolytic cleavage of the acetonitrile adduct is largely favoured over the homolytic cleavage (ΔG = 47 and 20 kcal mol⁻¹ respectively). These values can account for the formation of traces of 2e˙⁺ at high temperature, via the generation of free NHC 1e.

Fig. 12 DFT investigation of the facilitation of the homo- and hetero-dissociations of 2e²⁺ with Lewis bases (B3LYP-GD3(BJ)/def2svp with SMD model for acetonitrile as solvent. Energies are in kcal mol⁻¹).

In the case of DMAP, addition of the nucleophile and heterocyclic dissociation are significantly less endergonic (ΔG = 19 and 14 kcal mol⁻¹ respectively). These values are consistent with the generation of 2e˙⁺ at room temperature, which was evidenced experimentally. Once again, the homolytic dissociation of the adduct was found highly endergonic, but less than the dissociation of 2e²⁺ in absence of Lewis base. We failed to optimize with DFT the geometry of a DMAP adduct with 2a′²⁺ or 2h′²⁺. All attempts led to the dissociation of the two partners, supporting our assumption that such adducts are less relevant in the case of other dications 2²⁺.

In conclusion, the formation of 2e˙⁺ upon heating solution of 2e²⁺ likely involves the heterolytic cleavage of the dication and the formation of free NHC 1e. This process is promoted by Lewis bases, such as DMAP or the acetonitrile solvent.

Dications 2a′²⁺ or 2h′²⁺ are far less electrophilic. The generation of radicals from these dications required refluxing for hours. These latter cases may involve the homolytic dissociation of the dication to afford NHC radical cation 1e˙⁺. However, EPR is a very sensitive spectroscopy. The fact that harsh conditions are needed for several hours in order to detect radicals through trapping suggests that only insignificant traces are formed.

Dicationic dimers for the initiation of radical chains

NHC radical cations had been postulated as key catalytic intermediates for several parented radical reactions.² The formation of indole 7 through the intramolecular cyclisation of α-bromo amide 6·Br is a prototypical example (Fig. 13). The reaction can be performed in refluxing 1,4-dioxane in presence of 10% of thiazolium 1e·H⁺ and a base.^2a The customary mechanistic proposition involves the formation NHC 1e and the subsequent reduction of 6·Br to afford a bromide anion, NHC radical cation 1e˙⁺ and radical 6˙. The latter would undergo an intramolecular cyclisation to afford 7·H˙ and, then 7˙⁻, after deprotonation. Finally, the reduction of 1e˙⁺ by 7˙⁻ would afford the product 7 and regenerate the NHC catalyst 1e (Fig. 13b). However, in light of our findings, it seemed very unlikely that NHC radical cations could accumulate sufficiently to play the role of an electron shuttle. In addition, we previously reported that 2e˙⁺ was an efficient promoter of the reaction.^4b This was another indication that an alternative radical pathway may be at work.

Fig. 13 (a) Radical cyclisation of 6·Br into oxindole 7. (b) Customary mechanism involving a NHC catalyst. (c) Cyclic voltammetry of 6·Br and 7 in acetonitrile + 0.1M [Bu₄N]PF₆, scan rate: 100 mV s⁻¹. (d) Proposed radical chain propagation.

As a matter of fact, a radical chain could also account for the mechanism.³⁰ Both cyclic voltammograms of 6·Br and 7 features a reduction wave at around −1.9 V vs. SCE (Fig. 13c). This suggested that 7˙⁻ could enable the propagation of the radical chain by reducing substrate 6·Br to generate 6˙ (Fig. 13d).³¹ The fact that this transformation can occur in presence of radical initiators, such as AIBN and Bu₃SnH,³² also supports a radical chain pathway. This alternative mechanistic picture furthermore accounts for the efficiency of poor reducing agents. For instance, although 1e should undergo oxidative electron transfer above −0.2 V vs. SCE only,^4b the subsequent irreversible formation of 1·H⁺ may provide a thermodynamic drive and ultimately allow for the reduction of 6·Br. Similarly, alternative activation, such as irreversible Br-atom abstraction from 6·Br, could also benefit from further irreversible exergonic evolution of the initiator.

As dications 2²⁺ could generate radicals in refluxing solutions, we tested 2a′²⁺, 2h′²⁺ and 2e²⁺ as radical initiators for the intramolecular cyclisation of 6·Br. The reaction performed well in presence of 5% of bis(hexafluorophosphate) salt of 2e²⁺ (95% conversion, Fig. 13a). Of course, prior to this study, it would have been tempting to interpret these results as evidence for the transient formation of 1e˙⁺. However, it is now clear that 2e²⁺ does not undergo homolytic cleavage, but instead generates NHC 1e, as well as radical 2e˙⁺, which are both efficient promoters of the reaction.

No conversion was obtained with 2h′²⁺ as initiator. Dication 2a′²⁺ afforded a modest 38% conversion. In the latter case, it is not possible to totally rule out the homo-dissociation of the dication and the involvement of radical cation 1a′˙⁺.

Conclusions

Our results showcase the high reactivity and elusiveness of radicals 1˙⁺. Typical NHC radical cations are C_sp²-centered. They are predicted to be extremely short-lived, even in the gas phase, as they can undergo nearly barrierless rearrangements through H atom migration. Spin density delocalization can be achieved with NHC 1f and 1g, which feature electron-rich patterns: a bis(dimethylamino)-substituted ethylene and oxyallyl, respectively. However, the radical cations 1f˙⁺ and 1g˙⁺ remain too reactive for direct observation in solution, despite their redox-active ancillary frameworks.

It is clear that the geometric constraints of the N-heterocyclic structure in 1˙⁺ preclude any efficient stabilisation by +M substituents. Future observation or isolation of a radical cation with divalent C^III centres will certainly require acyclic structures. Incidentally, Bertrand and co-workers recently reported a stable carbene dication stemming from an acyclic framework.³³ This compound undergoes 2-electron reductions to afford the corresponding neutral form. Although the radical cation may disproportionate in this specific case, one could foresee that a stable version could be designed through structural tuning.

In the course of our study, radicals were observed by EPR on several occasions, when attempting the oxidation of 1g or the cleavage of dicationic dimers 2²⁺. Furthermore, 2e²⁺ is an efficient initiator for the radical intramolecular cyclisation of 6·Br. Each time, it would have been tempting to infer the formation of the desired NHC radical cation 1˙⁺. However, each time, the formation and/or observation of 1˙⁺ could be dismissed. Indeed, we showed that the oxidation of 1g afforded oxyallyl radical 3˙⁺. In addition, bond dissociation energies of dicationic dimers are very high. Although 2a′²⁺ or 2h′²⁺ may undergo homolytic dissociation in harsh conditions, only the formation of trace amounts of unidentified radicals could be evidenced. Finally, Lewis bases considerably ease the heterolytic dissociation of 2e²⁺, which leads ultimately to reduced products 1e and 2e˙⁺ (which promote the formation of 7), and not to the desired NHC radical cation 1˙⁺.

In 2023, Song and Lee proposed an alternative mechanism for the reduction of the trityl cation by NHC 1a and showed that the formal oxidation of the NHC 1 into 1·H⁺ does not necessarily imply the formation of the radical intermediate 1˙⁺.¹⁰ Our study clearly drives the point home: N-heterocyclic carbene radical cations 1˙⁺ are certainly irrelevant in most radical transformations. Future mechanistic considerations on reductive processes involving free NHCs should systematically look for alternative pathways.

Author contributions

E. T.-M., J. B. and D. M.: conceived the project and acquired funding, provided resources and supervised the project; P. S., L. D., S. B., F. M.: (advanced electrochemical analysis); J. P.: (X-ray diffraction analysis) and D. M.: (DFT calculations) conducted the investigation and formal analysis of the methodology.

All authors contributed to the reviewing and editing of the manuscript.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the supplementary information (SI). Supplementary information is available. See DOI: https://doi.org/10.1039/d5qo01285f.

CCDC 2475077 (2e·Cl₂) contains the supplementary crystallographic data for this paper.³⁴

Acknowledgements

This work was funded by the French National Agency for Research (ANR-20-CE07-0010). P. Smits acknowledges Labex Arcane and CBHEUR-GS (ANR-17-EURE-0003) for funding. We thank the CECCIC centre of Grenoble for computer resources and the ICMG analytic platform (FR 2607).

References

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