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. 2023 Mar 27;3(3):136–142. doi: 10.1021/acsorginorgau.3c00008

On the Redox Properties of the Dimers of Thiazol-2-ylidenes That Are Relevant for Radical Catalysis

Ludivine Delfau †, Nadhrata Assani ‡, Samantha Nichilo †, Jacques Pecaut §, Christian Philouze †, Julie Broggi ‡, David Martin †,*, Eder Tomás-Mendivil †,*
PMCID: PMC10251502  PMID: 37303499

Abstract

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We report the isolation and study of dimers stemming from popular thiazol-2-ylidene organocatalysts. The model featuring 2,6-di(isopropyl)phenyl (Dipp) N-substituents was found to be a stronger reducing agent (Eox = −0.8 V vs SCE) than bis(thiazol-2-ylidenes) previously studied in the literature. In addition, a remarkable potential gap between the first and second oxidation of the dimer also allows for the isolation of the corresponding air-persistent radical cation. The latter is an unexpected efficient promoter of the radical transformation of α-bromoamides into oxindoles.

Keywords: Organocatalysis, N-Heterocyclic Carbenes, Reduction, Radical, Electrochemistry

Thiazol-2-ylidenes A (Scheme 1) are synthetic models for the active form of thiamine, a well-known enzymatic cofactor.1 These stabilized N-heterocyclic carbenes (NHCs) have been used for decades as efficient organocatalysts.2−7 They are generated in situ from the reaction of a base and a thiazolium salt. Indeed they cannot usually be isolated, as they readily dimerize. Arduengo et al. reported that the bulky 2,6-di(isopropyl)phenyl (Dipp) N-substituent slows down the dimerization for several hours at room temperature, thus allowing for the first isolation and characterization of such NHCs, including an X-ray diffraction study.8,9 The carbene is already too short-lived for isolation with a slightly smaller 2,4,6-trimethylphenyl N-substituent but could be observed by NMR spectroscopy at 0 °C. Furthermore, traces of Bronsted or Lewis acids catalyze fast dimerization, even for thiazol-2-ylidenes with a high steric hindrance.10−12 Therefore, dimers B are far more likely to accumulate than carbenes A in catalytic processes. Importantly, they react with aldehydes similarly to A to afford the key Breslow intermediates. They could be either resting-state reservoirs for A or catalysts on their own. Data exist in support and against these hypotheses for the benzoin condensation.13−22

Scheme 1. Thiazol-2-ylidenes A and Their Derivatives as Possible One-Electron Transfer Agents in Radical Catalysis or Chain Reactions.

Scheme 1

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In addition to ionic-type (2-electron) mechanisms, thiazol-2-ylidenes have also recently become privileged organocatalysts for radical transformations of aldehydes.23−58 In these reactions, the Breslow-type enolates C–, which result from the condensation of aldehydes with NHCs in basic conditions, are able to undergo spontaneous single-electron transfer (SET) to challenging substrates (Eox > −1.6 V vs SCE).59−62 In the absence of aldehydes, free NHCs are milder reducing reactants. For instance, imidazol-2-ylidenes perform stoichiometric reduction of the ferrocenium cation63 (E = +0.38 V vs SCE) and the trityl cation64 (E = +0.27 V vs SCE).65 Wang and co-workers recently proposed that thiazol-2-ylidenes A could promote radical transformations in the absence of aldehydes via SET to α-bromocarbonyl compounds and transient formation of radical A•+.66−69

Curiously, there is no consideration in the literature of the possible role of dimers B in redox NHC-catalyzed processes, although they belong to the large family of dithiadiazafulvalenes, which are known mild electron donors.70−72 In addition, electrochemical studies have been limited to electron-poor derivatives with benzo-fused or electron-withdrawing R-substituents.73−76 No data are available for a model that is relevant for catalysis. Thus, as part of ongoing efforts to establish a finer mechanistic comprehension of radical NHC catalysis,59−62 we underwent the synthesis, isolation, and electrochemical study of dimers B of catalytically relevant NHC A.

Thiazol-2-ylidenes featuring the 2,6-di(isopropyl)phenyl (Dipp) N-substituent, such as 1a (Scheme 2), stand out as polyvalent and efficient organocatalysts for the radical transformation of aldehydes. Therefore, our primary focus was on the dimer 2a of parent NHC 1a. We also considered dimer 2b with a smaller phenyl group in order to probe steric effects and dimer 2c because thiazol-2-ylidene with a neopentyl (Np) N-substituent found a niche application in radical catalysis for the activation of challenging aliphatic aldehydes.77

Scheme 2. Synthesis of Carbene Dimers 2a–c.

Scheme 2

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We synthesized NHC 1a as previously reported by Arduengo et al.8 After 2 days at room temperature in pentane, an orange precipitate was recovered by filtration, washed with pentane, extracted with toluene, and dried under vacuum, affording olefin 2a in 18% yield. Thiazolium salts 1b,c·H+PF6– were mixed with an excess of NaH and 10% potassium tert-butoxide to afford the desired electron-rich olefins 2b,c in 52 and 28% yield, respectively. The fast reaction likely involves a two-step process including the attack of transient carbene 1 on thiazoliums 1·H+ to afford protonated dimers 2·H+, followed by a second deprotonation. As a matter of fact, when applying this protocol to the Dipp-substituted thiazolium 1a·H+, the hexafluorophosphate salt of 2a·H+ was formed and isolated in 21% yield.

All new products were fully characterized. We obtained suitable single crystals of dimers 2b,c (Figure 1). A previous X-ray diffraction study showed that 2a features an almost planar structure in the solid state with a N–C–C–N dihedral angle of 177° and negligible pyramidalization around N atoms (average sum of angles: 359.6°).8 In the case of phenyl N-substituted 2b, the planarity of the olefin pattern is absolute (N–C–C–N dihedral angle: 180°), but lower steric bulk allows a pronounced pyramidalization at the nitrogen atoms (sum of angles: 350.9°). Dimer 2c also features pyramidalization at nitrogen atoms (sum of angles: 349°) but also a marked trans-bending of the central alkene pattern. It is worth mentioning that such distortion is not uncommon among NHC dimers: they have been reported for a bis(imidazolidin-2-ylidene)79,80 and a methyl N-substituted bis(thiazol-2-ylidene).8 Importantly, NMR spectra of the crude products showed the presence of only one isomer. However, whereas 2a,b are E, the Z-isomer of 2c was observed in the solid state. Accordingly, DFT calculations81 at the B3LYP-D3BJ/def2-SVP level of theory indicated a slight preference for the Z over the E configuration for 2c by 2 kcal·mol–1. Note that the variety of geometrical situations does not significantly affect the central C=C′ bond length, which remains almost unchanged within the series (2a: 134.4 pm; 2b: 134.6 pm; 2c: 134.5 pm).

Figure 1.

Figure 1

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Solid-state structures of dimers 2a–c. The structure of 2a is depicted with a ball-and-stick representation as CCDC 100053 (ref (8)) does not provide for thermal factors. Thermal ellipsoids for 2b,c are set at 50% probability. Selected sides views are also shown. Hydrogen atoms are omitted for clarity; N atoms are highlighted in blue, and S atoms are in yellow.

Cyclic voltammograms of 2a–c feature two consecutive reversible oxidations, which were attributed to the formation of the corresponding radical cations 2a–c•+ and dications 2a–c2+, respectively (Figure 2). The three dimers are better electron donors (Eox < −0.5 V vs SCE) than previously measured for other dithiadiazafulvalenes (Eox ∈ [+0.4; −0.5 V]).73−76 Olefin 2a is by far the strongest reducing agent of the series. We attributed its remarkably low oxidation potential of −0.8 V to the bulky Dipp substituent, which blocks the amino groups in a planar environment and thus forces them to act as strong +M donors. Munz and co-workers recently proposed that enforced planarity in NHC dimers must also result in radical cations with higher oxidation potentials, thus providing them for thermodynamic protection toward disproportionation.82 Electrochemical data of 2a–c obey this trend, as the separation between both redox events roughly correlates with the planarity at the N atom in the solid state (2a: ΔE = 0.74 V; 2b: ΔE = 0.35 V; 2c: ΔE = 0.21 V).

Figure 2.

Figure 2

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Cyclic voltammograms of 2a–c; 1 mM of each compound in 0.1 M nBu4NPF6 acetonitrile electrolyte at 100 mV·s–1 rates.

We attempted the quantitative electrolysis of 2a–c in acetonitrile. The formation of the corresponding radicals 2a–c•+ could be characterized by UV–vis (see Supporting Information (SI)) and EPR spectroscopies (Figure 3a). As expected from the geometry of dimers and ΔE values,822c•+ slowly decomposes. Radicals 2a,b•+ could be synthesized through one-electron oxidation of 2a,b with NOPF6 in dichloromethane and isolated in 87 and 51% yield, respectively. Whereas 2b•+ is highly sensitive, we found the sterically protected radical 2a•+ remarkably air-persistent at room temperature, especially in the solid state. Dication 2a2+ was also synthesized from 2a employing 2 equiv of NOPF6 (see SI).

Figure 3.

Figure 3

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(a) Experimental X-band EPR spectra of 2a–c•+ in acetonitrile at room temperature and respective simulated spectra.83 (b) Solid-state structures of [2a•+]PF6 and [2b•+]PF6 with thermal ellipsoids set at 50% probability. Hydrogen atoms, PF6– anions, and cocrystallized solvent molecule(s) are omitted for clarity. (c) Representations of SOMO of 2a–c•+.

Single-crystal X-ray diffraction studies revealed fully planar dithiadiazafulvalene structures for radicals 2a,b•+ (Figure 3b). The central C=C′ bond lengths (2a•+: 1.403 Å; 2b•+: 1.391 Å) are about 6 pm longer than in the neutral dimer counterparts 2a,b. A simple molecular orbital analysis can account for this elongation. Indeed the oxidation process corresponds to the formation of the SOMO of 2•+ (Figure 3c) by removing an electron from the HOMO of 2, while both molecular orbitals are bonding combinations of π orbitals of two thiazol-2-ylidene fragments. The DFT-optimized structure of 2c•+ features a less conjugated π-system, with a 30° twist at the central C=C′ bond. In radicals 2a–c•+, the spin density is mainly distributed among N,S and central bridging C atoms (Table 1), with the twisted structure of 2c•+ resulting in a slight transfer of spin density from the heteroatoms to the carbon atoms.

Table 1. Redox Potentials, Isotropic EPR Hyperfine Coupling Constants, and Mulliken Spin Densities of Radicals 2•+.

R Dipp Ph Np
E1/2 (V)a
2/2•+ –0.80 –0.55 –0.56
2•+/22+ –0.06 –0.20 –0.35
isotropic EPR hyperfine coupling (MHz)
A(14Nx2) 11.8 11.3 9.9
A(1Hx6) 6.2 5.7 4.9
Mulliken spin density (%)b
on N (x2) 32 31 27
S (x2) 28 29 28
Ccentral (x2) 23 23 29
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a

E in acetonitrile vs SCE.

b

Computed at the B3LYP-D3BJ/def2-SVP level of theory.

The large potential gap between the first and second oxidations of 2a (ΔE = 0.74 V) indicates that it must behave as an efficient one-electron donor. It also stands out among bis(thiazol-2-ylidenes) as a remarkably strong reducing olefin (E(2a•+/2a) = −0.80 V vs SCE). Overall, these data suggest that dimer 2a might not be innocent in radical transformations allegedly involving the popular NHC 1a as a catalyst. For instance, recent works from Wang et al. attracted our attention. Methodological studies showed that α-bromoisobutyramides, such as 3 (see Table 2) can be activated with NHC radical catalysis to afford oxindoles, and free thiazol-2-ylidene 1a was proposed as a key single-electron donor.66

Table 2. Organocatalyzed Oxindole Synthesisa.

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entry variation from the standard conditions conv.b
1 none 62%
2 1b·H+ 49%
3 1c·H+ 4%
4 2a (5 mol %); 0.7 equiv of Cs2CO3 80%
5 2b (5 mol %); 0.7 equiv of Cs2CO3 38%
6 2c (5 mol %); 0.7 equiv of Cs2CO3 16%
7 [2a•+]PF6 (5 mol %); 0.7 equiv of Cs2CO3 90%
8 [2b•+]PF6 (5 mol %); 0.7 equiv of Cs2CO3 60%
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a

Standard reaction conditions: 3 (0.3 mmol), precatalyst [1a·H+]PF6 (0.03 mmol), Cs2CO3 (0.24 mmol), 1,4-dioxane (1.0 mL), Ar atmosphere, 100 °C (oil bath), 16 h.

b

Estimated from 1H NMR with 1,3,5-trimethoxybenzene (TMB) as internal standard.

In order to evaluate the reducing ability of thiazol-2-ylidenes, we considered their precursors 1a–c•H+. Their cyclic voltammograms feature an irreversible reduction wave around −1.5 V, which corresponds to an EC process84,85 generating free carbenes 1, through the formation of radical 1·H•, followed by the fast loss of H•. The reoxidation wave allowed thiazol-2-ylidenes 1a–c to feature oxidation potentials Epox (1/1•+) higher than −0.2 V vs SCE (see SI).

Not only is thiazol-2-ylidene 1a a very weak reducing agent, but the NHC is also prone to fast dimerization in the reaction conditions. Therefore, we naturally hypothesized that olefin 2a was the relevant electron donor in the transformation of 3 into oxindole 4, and we ran a few control experiments (Table 2). We first reproduced results from the literature66 employing [1a·H+]PF6 as a precatalyst (entry 1). Oxindole 4 was formed in 62% conversion (reported: 63%). Phenyl N-substituted 1b•H+ was less performant (entry 2) and 1c•H+ barely promoted the reaction (4% conversion, entry 3). As expected, the corresponding dimers 2a–c gave similar or higher conversions (entries 4–6).

The reduction potential of ethyl α-bromoisobutyrate 5, which is electronically similar to 3, is reported to be Epred (5/5•–) = −0.77 V in DMSO.35 This value would support a spontaneous SET from 2a (Eox = −0.80 V) to 5. However, α-bromoisobutyryl derivatives may be in fact more challenging to reduce than previously proposed. Indeed, we found a different value, Epred (5/5•–) = −1.89 V in acetonitrile (see SI), which prompted us to measure Epred (3/3•–) which was found at to be −1.94 V vs SCE in acetonitrile. Even more, we tested hexafluorophosphate salts of 2a,b•+ as catalysts (entries 7 and 8). Surprisingly, the radical cations were more efficient than the corresponding electron-donating olefins 2a,b. These data suggest that the hypothesis of a simple SET process is not valid.

In conclusion, bis(thiazol-2-ylidene) 2a, stemming from the popular NHC organocatalyst 1a, presents three stable redox states. The bulky Dipp N-substituent forces planar geometries, thus resulting in an unusually low oxidation potential and a comparatively high second oxidation potential, allowing for the isolation of air-persistent radical 2a•+. Olefin 2a is not strong enough to compete as a reducing agent with Breslow-type enolates. However, it remains a potential electron donor, which can interfere in radical reactions that are allegedly catalyzed by 1a and does not involve aldehyde derivatives as substrates. In the specific case of the activation of α-bromoisobutyramides, we unexpectedly found that radical 2a•+ is the most efficient redox form as a catalyst. This surprising result suggests that the NHC derivatives are unlikely to promote this radical reaction through a simple SET, as initially proposed. We are actually undergoing further experimental and theoretical studies, in an attempt to decipher and better understand such process.

Acknowledgments

We thank the CECCIC centre of Grenoble for computer resources and the ICMG analytic platform (FR 2607), especially P. Girard, D. Gatineau, R. Sanahuges, and N. Altounian for their outstanding service.

Data Availability Statement

The data underlying this study are available in the published article and its online Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsorginorgau.3c00008.

  • Experimental procedures, X-ray crystallographic data, computational details, 1H and 13C NMR spectra of all new compounds (PDF)

Author Contributions

CRediT: Ludivine Delfau investigation (lead), writing-original draft (supporting), writing-review & editing (supporting); Nadhrata Assani investigation (supporting); Samantha Nichilo investigation (supporting); Jacques Pecaut investigation (supporting); Christian Philouze investigation (supporting); Julie Broggi conceptualization (equal), funding acquisition (equal), supervision (equal), writing-review & editing (supporting); David Martin conceptualization (equal), funding acquisition (equal), investigation (supporting), supervision (equal), writing-review & editing (equal); Eder Tomás-Mendivil conceptualization (equal), investigation (supporting), supervision (equal), writing-original draft (lead), writing-review & editing (equal).

This work was funded by the French National Agency for Research (ANR-20-CE07-0010). We acknowledge the CNRS and the University of Grenoble Alpes for a frictionless environment in the context of the Labex Arcane and CBHEUR-GS (ANR-17-EURE-0003).

The authors declare no competing financial interest.

Supplementary Material

gg3c00008_si_001.pdf (2.6MB, pdf)

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The data underlying this study are available in the published article and its online Supporting Information.

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