Catalysis Science &

A simple “reagent-free” thermal air treatment turns active carbon into a mildly oxidized material with an increased quinoidic content that catalytically dehydrogenates saturated N-heterocycles to the corresponding aromatic compounds. Additional thermal decarboxylation improves the activity of the catalyst further, making it overall more efficient compared to other widely used carbocatalysts such as oxidized carbon nanotubes, graphene oxide and untreated active carbons. The substrate scope covers 1,2,3,4-tetrahydroquinolines (THQ), 1,2,3,4-tetrahydro-  -carbolines and related N-heterocyclic structures. The developed protocol also successfully dehydrogenates 3-(cyclohexenyl)indoles to 3-aryl indoles, which opens a concise transition metal-free approach to (hetero)biaryls as exemplified with the synthesis of the core structure of progesterone receptor antagonist. Hammett plots, deuterium KIE measurements and computations at DFT level suggest that bimolecular hydride transfer mechanism is more likely to operate between THQs and o-quinoidic sites of the catalyst, than the addition-elimination hemiaminal route. Comparison of structural parameters and catalytic performance of various oxidized carbon materials, prepared by different oxidative and optional post treatments, revealed that quinoidic content and surface area correlates with the obtained yields, while carboxylic acid contents have a clear inhibiting effect for the studied oxidative dehydrogenations (ODHs) . The carbocatalyst itself can be prepared from inexpensive and environmentally benign starting materials and its catalytic activity can be enhanced by a simple thermal oxidation in air that produces no reagent waste. Furthermore, oxygen is used as terminal oxidant, and the carbocatalyst is recyclable for at least six times without a notable loss of results, writing-editing; T.W.: catalyst development, writing-editing, T.H.: XPS characterization; S.H.: Solid state NMR; L.R. and M.F.P.: BET and TPD analysis; J.H.: supervision, writing-editing,


2021

Lukas E
ders 
Department of Chemistry
University of Helsinki
A. I. Virtasen aukio 1P.O. Box 55

University of Helsinki
00014Finland

David S Casadio 
Department of Chemistry
University of Helsinki
A. I. Virtasen aukio 1P.O. Box 55

University of Helsinki
00014Finland

Santeri Aikonen 
Department of Chemistry
University of Helsinki
A. I. Virtasen aukio 1P.O. Box 55

University of Helsinki
00014Finland

Anna Lenarda 
Department of Chemistry
University of Helsinki
A. I. Virtasen aukio 1P.O. Box 55

University of Helsinki
00014Finland

Tom Wirtanen 
Department of Chemistry
University of Helsinki
A. I. Virtasen aukio 1P.O. Box 55

University of Helsinki
00014Finland

Tao Hu 
Faculty of Technology
Research Unit of Sustainable Chemistry
University of Oulu
90014OuluFinland

Sami Hietala 
Department of Chemistry
University of Helsinki
A. I. Virtasen aukio 1P.O. Box 55

University of Helsinki
00014Finland

Lucília S Ribeiro 
Faculty of Engineering
Laboratory of Separation and Reaction Engineering -Laboratory of Catalysis and Materials (LSRE-LCM)
University of Porto
4200-465PortoPortugal

Manuel Fernando 
R Pereira 
Faculty of Engineering
Laboratory of Separation and Reaction Engineering -Laboratory of Catalysis and Materials (LSRE-LCM)
University of Porto
4200-465PortoPortugal

Juho Helaja juho.helaja@helsinki.fi 
Department of Chemistry
University of Helsinki
A. I. Virtasen aukio 1P.O. Box 55

University of Helsinki
00014Finland


Catalysis Science & Technology Catalysis Science & Technology


Air Oxidized Activated Carbon Catalyst for Aerobic Oxidative Aromatizations of N-Heterocycles
26 July 2021A86204B08F4E21303A8C665F199032A410.1039/x0xx00000xReceived 00th January 20xx,
A simple "reagent-free" thermal air treatment turns active carbon into a mildly oxidized material with an increased quinoidic content that catalytically dehydrogenates saturated N-heterocycles to the corresponding aromatic compounds.Additional thermal decarboxylation improves the activity of the catalyst further, making it overall more efficient compared to other widely used carbocatalysts such as oxidized carbon nanotubes, graphene oxide and untreated active carbons.The substrate scope covers 1,2,3,4-tetrahydroquinolines (THQ), 1,2,3,4-tetrahydro--carbolines and related N-heterocyclic structures.The developed protocol also successfully dehydrogenates 3-(cyclohexenyl)indoles to 3-aryl indoles, which opens a concise transition metal-free approach to (hetero)biaryls as exemplified with the synthesis of the core structure of progesterone receptor antagonist.Hammett plots, deuterium KIE measurements and computations at DFT level suggest that bimolecular hydride transfer mechanism is more likely to operate between THQs and o-quinoidic sites of the catalyst, than the addition-elimination hemiaminal route.Comparison of structural parameters and catalytic performance of various oxidized carbon materia s, prepared by different oxidative and optional post treatments, revealed that quinoidic content and surface area correlates with the obtained yields, while carboxylic acid contents have a clear inhibiting effect for the studied oxidative dehydrogenations (ODHs) .The carbocatalyst itself can be prepared from inexpensive and environmentally benign starting materials and its catalytic activity can be enhanced by a simple thermal oxidation in air that produces no reagent waste.Furthermore, oxygen is used as terminal oxidant, and the carbocatalyst is recyclable for at least six times without a notable loss of activity.

Introduction

Activated carbons (ACs) are highly versatile materials with a wide range of applications from medicinal use to water purification and catalytic processes. 1Among ACs' many interesting properties, high surface area and extensive porosity are the epicenter of their success in these fields.][5] From sustainable chemistry perspective, carbocatalysis is becoming an increasingly interesting concept: heterogeneous materials derived from abundant second row elements can promote reactions that are usually either performed with stoichiometric reagents or catalysed by transition metals.As a result, both rea

nt waste and demand for
critical metals are reduced -both key aspects in green chemistry.Moreover, in oxidations, when (atmospheric) oxygen is employed to regenerate carbocatalyst's active sites, water and/or hydrogen peroxide is the only by-products generated. 6,7longside ACs, [3][4][5][6][7][8][9][10][11][12] other carbon allotropes such as carbon nanotubes (CNTs), [11][12][13][14][15] nanodiamonds (NDs), graphene oxides (GOs), [16][17][18] and nanohorns, have been employed as catalysts (Scheme 1) for organic transformations. 19,20Gas-phase dehydrogenations of hydrocarbons in particular have been extensively studied with these materials, with received yields comparable to those of AC. 21In gas-phase the oxidative catalysis at high temperatures causes combustion and "coking" of ACs and justifies the use of more resistant carbon nanomaterials. 22However, in a liquid-phase at low temperatures the degradation of AC is not an issue in oxidative carbocatalysis, which makes ACs highly appealing over the other allotropes (Scheme 1).ACs are, in fact, commercially available in many forms and much cheaper than the other carbon (nano)materials.In addition, they are available as a high volume bulk product 23 and they can be prepared from non-fossil feedstock (e.g., lignin, cellulose, agricultural waste). 1,24Furthermore, their catalytic activity can be enhanced by a simple, safe and ecological thermal treatment under air. 10In contrast, the preparation of graphene oxide from graphite usually requires highly corrosive acids and strong oxidants, which are not only hazardous, but also generate significant amounts of toxic waste. 25CNTs as well are usually treated, prior to their use in catalysis, by similarly strong oxidative conditions (i.e., refluxing nitric acid or HNO 3 :H 2 SO 4 ). 26According to our rationale, AC-based carbocatalysis deserves further investigation in organic synthesis.


This work:
H N Ph H N Ph R 2 R 2
In the present study, we focused on oxidative dehydrogenative aromatization of saturated N-heterocycles, which is a convenient and atom-economic way to prepare unsaturated heterocycles.Previously, this route has been studied with homogeneous (Ir, Ru, Fe, Rh, Pd, Cu, Co) and heterogeneous (Ru, Cu, Au, Pd, Pt, Ni, Mn) transition metals on various supports. 27Several metal-free approaches with graphene oxide (GO), 28 reduced graphene oxide (rGO), 29 mesoporous graphitic carbon nitride (mpg-C 3 N 4 ), 30 polymaleimide, 31 and polydopamine have been published as well. 32][35][36] Furthermore, they demonstrated that untreated AC delivers higher yields of quinolines and isoquinolines than Pd/C in MeCN. 37In this work, we show that the catalytic activity of untreated AC in oxidative dehydrogenative aromatizations can be significantly improved by an operationally easy thermal treatment, and we apply this sustainable synthetic protocol for the synthesis of the indole core structure of the progesterone receptor antagonists.


Results and discussion

We began our study by screening several carbon materials as catalysts for the ODH aromatization of 1-tert-butyl-1,2,3,4tetrahydro--carboline (1a) to the corresponding -carboline (2a) in toluene over 24 h at 90 °C under O 2 -atmosphere (Table 1).The use of HCl washed commercial active carbon (AC dm ) delivered 2a in 34% yield (entry 1).Surprisingly, yield increased only by 2% when HNO 3 -oxidized active carbon (oAC HNO3 ) was used as catalyst, as in previous studies we found this catalyst to be highly suitable for the homocoupling of heteroaryls (entry 2). 12Similarly, 57% of 2a was received when AC dm was oxidized thermally under static air (oAC air , entry 3).We then subjected this material to a thermal post-treatment under Ar at 425 °C, which is known to remove carboxylates selectively. 38The obtained material (oAC air() ) gave a slightly better yield of 59% (entry 4).The reaction conditions were optimized using a rather high, 896 mg • mmol -1 , catalyst loading, equal to fou weight equiv of 1a, which was the utmost limit that allowed efficient stirrability of the reaction suspension (0.25 M) using 24 h reaction time.Furthermore, widely used carbonaceous catalyst GO and its reduced form rGO delivered yields of 1% and 52%, respectively (entries 5 and 6).Previously, we have reported rather good results for ODH C-C couplings of aryls with HNO 3oxidized carbon nanotubes (oCNT, entry 7), 15 but for the current reaction, this catalyst delivered only 20% yield.Please do not adjust margins Please do not adjust margins received only 2% of 2a (entry 8).We then employed different model compounds that have been used before to mimic the active sites in carbocatalysts. 39,40Tetracene and anthraquinone delivered only marginal yields of 1% and 2% (entries 9-10).Remarkably, phenanthrenequinone produced 33% and 22% of 2a under O 2 and Ar atmospheres, respectively (entry 11).All the results suggest that the quinoidic groups function as the actives sites of the catalyst, which is in accordance with the characterization of the material (vide infra) and the literature. 2,11,20o expose the critical reaction parameters, the standard conditions were varied (Table 2).Decreasing the catalyst loading to one and two equivalents also decreased the yields to 30% and 42%, respectively (entries 2,3).Interestingly, increasing the reaction time to 72 h increased the yield to 67%, while decreasing the time to 3 h resulted in 44% yi ld (entries 4 and 5).Drastic differences were also observed upon changing the temperature.At room temperature, the reaction proceeded poorly with a low yield of 26% (entry 6), while in contrast we obtained 2a in 67% yield when we raised the temperature to 140 °C (entry 7).We performed the latter experiment in anisole, which in addition to its higher boiling point, also has complementary value both in terms of safety and environmental profile. 41,42Based on literature, [6][7][8]11 we supposed that molecular oxygen was acting as the terminal oxidant, so we investigated its role by running the reaction under inert atmosphere (Table 2, entry 8). Suprisingly, we obtained 24% yield, despite thorough removal of oxygen from the reaction mixture.This modest activity suggests a possible stoichiometric interaction occurring under Ar atmosphere with the presumed quinoidic active sites (vide infra).An addition of MsOH (entry 9), which was previously crucial for the carbocatalysed coupling of benzofused heterocycles, 12 decreased the yield drastically to 22%.In the absence of carbocatalyst, only 2% yield was received (entry 10).

a 896 mg • mmol -1 of SM (0.25 M);

With the optimized conditions at hand, we studied the scope of ODH aromatization with 1,2,3,4-tetrahydro-carbolines, 1,2,3,4-tetrahydroquinolines and related tetrahydroaryl N-heterocyclic structures (Scheme 2).Due to the observed difference in reactivity between oAC HNO3 and oAC air() during the synthesis of 1-tert-butyl--carboline (2a, Table 1), we screened the dehydrogenation of various tetrahydro Nheterocycles with the both catalysts.The complete list is presented in Table S1 (SI), but for the most of the substrates oAC air() was more active (Scheme 2).

We first explored the preparation of -carboline substructures within the well-known harmala alkaloid family (Table 3, entries 1-5), as well as 6-methoxy--carboline.We observed that upon addition of a methoxy substituent at C6 and removal of tBu from C1, the yield dropped from 59% (2a) to 38% (6-methoxy--carboline, 2b).The yield was lowered even more drastically for harmine 2c (12%) and isoharmine 2d (7%).Additionally, for the substrates 1a-1d the dihydro-imine intermediates could be isolated (see SI).On the other hand, 1phenyl-substituted substrate 1x exhibited higher reactivity, and was converted with 75% yield to 2x in 24h (86% yield in 72h).We then moved to study various quinoline-derivatives.All 6-substituted 1,2,3,4-tetrahydroquinolines (THQs) were dehydrogenated in excellent to quantitative yields.Notable exceptions were 6-bromo and 6-chloro derivatives that were obtained in 66% and 72% yields, respectively (Table 3, entry 6).Quinoxaline (2o) was dehydrogenated from its 1,2,3,4tetrahydro precursor in 67% yield and 1,2,3,4tetrahydroisoquinoline (1q, THIQ) was converted to isoquinoline in 40% yield.The yield of isoquinoline could be further improved to 67% by extending the reaction time to 72 h and raising the temperature from 90 °C to 100 °C.Slightly better yields were received with oAC HNO3 (56 % and 55 %) than with oAC air) (53% and 47%) for quinaldine (2m) and 2,6dihydroxyquinoline (2n), respectively.

To prove the catalytic nature of the carbon material, we performed an additional test with 1-phenyl-1,2,3,4-tetrahydroβ-carboline (1x) ODH to 2x.At the first stage, the reaction was run for 24 h under argon at otherwise standard conditions (Table 2).Thereafter, at the second phase, the atmosphere was exchanged to O 2 and the reaction was stirred for an additional 24 h.After the first step, the reaction delivered only 35% yield, however, when the second stage was completed, 71% of 2x was received.The test proves that the oxygen reactivates the consumed catalyst, reinitiating the catalytic cycle.Next, we became curious whether we could extend the ODH method to the aromatization of 2-phenyl-3-(cyclohexenyl)indoles to the corresponding 2,3-diphenylindole derivatives.Initially, when the optimized conditions for the previous ODH aromatizations were used, we could only obtain products in low yields.However, when we changed the solvent to anisole and raised the temperature to 140 °C we obtained 1H-2,3diphenylindole in 61% yield.The scope of the reaction was explored using 2-phenyl-indole as the backbone structure and varying the 3-tetrahydroaryl substituent (Table 4).Overall, the yields for most 3-aryl-2-phenyl-i doles were moderate, varying between 49-72% with 24-72 h reaction time.Interestingly, 3-(4-methoxy-tetrahydroaryl)-2-phenyl-indole (3d) yielded mainly the elimination product 2,3-diphenyl-indole (4a).Interestingly, a control test in the absence of carbocatalyst yielded only 4% of 3b after 72 h reaction time.As 3-tetrahydroaryl indoles can be straightforwardly prepared via a condensation reaction between indoles and the cyclohexanones (see SI), the developed methodology does not only open a concise synthetic route, but also a transition metalfree access to biaryl compounds that are typically prepared with Pd-mediated couplings (in this case by Suzuki-Miyaura couplings) from halide and boronic acid (or ester) functionalized aryls. 43Importantly, the developed method allows the employment of unprotected (NH)-indoles as substrates that are often not tolerated in Pd-coupling reactions. 44The development of this protocol is of significant synthetic relevance as many 3-aryl indoles are core structures of active pharmaceutical ingredients of marketed drugs. 44In order to test the viability of the concept, we synthesized 3-aryl indole 7 that is the core structure of the progesterone receptor antagonists (Scheme 2). 45The synthesis was carried out in only 4 Kinetic monitoring of 1a with 1 H NMR, performed with both oAC HNO3 and oAC air(Δ) catalysts, indicates that the dehydrogenation reaction to 2a proceeds via 3,4-dihydro intermediate (Fig. 1a).The reaction monitoring also quantifies the better catalytic activity of the air oxidized catalyst compared to the HNO 3 oxidized one (Fig. 1b).Based on our previous oAC studies, 12 and reference compound stoichiometric experiments (see phenanthrenequinone in Table 1), we presume that the quinoidic groups are the active sites in oAC catalysts.To support this hypothesis, we analysed the employed carbocatalysts with X-ray photoelectron spectroscopy (XPS) to evaluate their surface properties (see SI). From the survey spectra it was possible to determine the O% of each sample, and evaluate the efficacy of each catalyst preparation protocol in introducing Ocontaining groups (Table S2 and S3).When compared to AC dm (Fig. 2a), oAC HNO3 exhibits a higher amount of C=O groups, as well as abundant C-OH and O-C=O groups, while the oxidation occurs with concurrent deterioration of the graphitic surface C(sp 2 , π-π*).In contrast, the thermal air-oxidation (oAC air ) is gentler for the π-surface, but also produces less oxygen containing functional groups.Raman measurements (SI) support this assumption, as higher I D /I G ratio was calculated for oAC HNO3 (1.02) than for oAC air() (0.97), indicating increased defectivity and reduction of graphene-type domains in the HNO 3 -oxidized carbon.
oAC air() * 90 °C toluene, 24-72 h (Het) (Het) N-heterocycle N-heterocycle O 2 R 1 R 2 R 1 R 2 Entry Substrate Product(s) Time (h) Isolated Yield (%)N H NH O 1c N H N O 2c C4 C3 [3,4-dihydro-2c] 24 9 b [15] b 5 N H NH O 1d N H N O 2d [3,4-dihydro-2d] 24 11 [9] 6 N H R 2e R = H 2f R = OMe 2h R = F 2j R = Br 2k R = CO 2 Me 2i R = Cl 2l R = CN 2g R = Me N R24
The thermal decarboxylative post-treatment under N 2 notably increases the relative C=O content i the oAC air(∆) material.Based on combined material characterization, the nitric acid treatment is more efficient in promoting the formation of oxygen functionalities.However, the O1s peak deconvolution (Table 5) reveals that there is a significant difference in acidic group abundance between oAC HNO3 and oAC air() , which seems to be critical for the catalytic activity towards the explored reactions.Similar poor reactivity was also demonstrated for GO (Table 1), where the high degree of oxidation and abundance of -COOH groups are both characteristic features. 46The oxygen containing functional group content was also examined with temperatureprogrammed desorption (TPD).The CO 2 desorption curve (Fig. 2c) highlights the divergent abundance of carboxylic acid groups in the two different materials; absence in oAC air() and high distribution in oAC HNO3 , confirming the XPS results.From the CO desorption curves (Fig. 2d), it is noticeable how both materials are rich in carbonyls, although oAC air() displays an additional shoulder at higher temperature (>800 °C) that can be associated with quinones and basic functionalities such as chromenes and pyrones (deconvolution of the TPD curves are presented in SI).This feature was confirmed by MAS NMR (Fig. 2b): the broad peak appearing around 190-200 ppm in oAC air() spectrum is further evidence of higher abundance of quinones.

Textural properties were analyzed with N 2 physisorption (Fig. S26).Both catalysts present adsorption isotherms of the type I plus II that implies the presence of micro and mesopores within the materials.The hysteresis loops of type H4 are associated with a narrow slit-like mesopores.The BET surface area appears to slightly decrease with the nitric acid treatment, while it increases in the case of air oxidation (Table S8).The increased available surface can be recognized as another feature contributing to the better catalytic performance of oAC air() .Next, we analyzed the combined effect of high surface area and carbonyl content on the catalyst activity for the dehydrogenation of both 1-tert-butyl-1,2,3,4-tetrahydro-carboline (1a) and 1,2,3,4-tetrahydroquinoline (1e) (Fig. 3).For both reactions, a direct correlation between these parameters can be noticed: the highest yields are obtained when there is a combination of high surface area and high carbonyl content.One exception to this trend is oAC HNO3 , which stands out due to its lower catalytic activity, despite having the highest C=O % and high surface area.The moderate obtained yields can be ascribed to its high carboxylic acid content, which appears to inhibit the studied reactions.To gain further proof of this, oCNTs and oAC HNO3 were subjected to the same decarboxylation treatment as oAC air() (450 °C for 24 h under Ar atmosphere), which caused only minor changes in the materials' carbonyl conte t and surface area (see Fig. 3 and SI).These decarboxylated materials delivered remarkably increased yields for both reactions, proving that the high acid content has a detrimental effect for the studied ODH carbocatalysis.

Finally, the recyclability of the catalysts was tested to determine their robustness, as well as their catalytic nature.For this purpose, both oAC HNO3 and oAC air() were used for six sequential cycles of 1-tert-butyl-1,2,3,4-tetrahydro--carboline (1a) dehydrogenation.Between the cycles, the carbocatalysts were filtered off and thoroughly washed with CH 2 Cl 2 /MeOH (93/7%).As shown in Fig. 1b, no major decrease in catalytic activity was observed, indicating robustness of both carbocatalysts.Therefore, we can state that the carbon materials act mainly as catalysts, only marginally taking part in the reaction in a stoichiometric way.This contrasts the recent report that casts some doubts over the catalytic nature of GO in (alcohol) oxidation reactions. 47To further enforce our statement, the two carbocatalysts were analysed by XPS after the recycling experiments and the oxygen peaks were compared to the ones measured before the catalysis (Table 5).As summarized in Table 5, the changes in the oxygen groups' distribution is almost negligible in the both cases.Noticeably, a peak associated to pyrrolic Ns appears after the recycling, which can indicate a possible partial stoichiometric reactivity between the carbon and the substrate.Inductively coupled plasma mass spectrometry (ICP-MS) was used to investigate the possible presence of residual metal impurities.The study revealed that the carbon materials examined contain a maximum of 600 ppm level of Fe and notably lower amounts of other metal impurities (e.g., in oAC air() : Ni < 30 ppm, Mn = 40 ppm, Cu = 20 ppm, Co < 3 ppm and Pd < 0.2 ppm; Table S4), which makes trace metal impurity catalysis unlikely.The high carbon material loadings used in the catalytic runs may raise questions about the actual catalytic nature of oACs.TPD analysis of oAC air() shows that the total concentration of carbonyls and quinones is 1861 mol/g, which makes the loading for each catalytic cycle appear quite high (416 mol for 250 mol of starting material).Anyhow, this theoretical maximum of catalytically active quinone sites is calculated presuming that all the carbonyls are in quinone-type configurations and that they are accessible by the substrates, which is questionable, as ACs have high microporous surface areas (see BET analysis Fig. S32).The model compound studies strongly suggests that only some quinone configurations are active in the catalytic process.Considering that TPD analysis does not discriminate the different configurations of quinones and carbonyls, we can assume that the actual number of redox active sites for each run is considerably lower.This consideration, together with the good recyclability of the carbocatalyst shines a light on the reason why such high catalyst loading is required, mitigating the doubts on the actual catalytic nature of the material.


Catalysis Science & Technology Accepted Manuscript

We then turned our attention to the reaction mechanism of the oxidative carbocatalyzed aromatizations.We chose THQs as mechanistic probes as they were the most reactive substrates, and different 6-R-THQs (see Scheme 2) can be easily prepared or they are commercially available.

Quinoidic groups have been pinpointed by various studies as the mediators of carbon catalysed dehydrogenations in both gas 14 and liquid phase. 36Furthermore, they have been als identified as active sites in ODH C-C couplings of various (hetero)aryl substrates. 13,48,49Usually, hydrogen abstraction is proposed as a reasonable mechanistic route in the gas-phase dehydrogenative reactions. 49However, in the liquid phase more mechanistic pathways become possible and the dehydrogenation does not necessarily need to proceed via neutral radical intermediates.The commonly proposed reaction mechanisms in homogeneous quinone-promoted oxidations include sequential electron-proton transfer, hydrogen atom transfer, and hydride transfer. 50In addition, Stahl and coworkers have reasoned that the oxidation of THIQ with phenanthroline could take plac

via a hemiaminal pathway. 51,52uilding on t
ese mechanistic proposals for both heterogeneous and homogeneous quinones, we consider the following alternatives: i) H-abstraction, ii) bimolecular hydride transfer, and iii) hemiaminal pathway.Firstly, we performed the reaction in the presence of 1 equiv of radical scavenger 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO).Interestingly, TEMPO did not trap any radicals and neither had any influence on the received yields.

We then performed a Hammett plot study by varying the substituent at THQ's 6-position (Fig. 4).The observed negative ρ-value (−0.45 or −0.43, see Fig. 3a) suggested the formation of a positive charge in the transition state of the rate-limiting step. 53Linear fitting without the halogen substituted substrates shows excellent correlation in Fig. 4a (R 2 = 0.999) between the σ para values and log(k X /k H ). The divergent results with the halogenated THQs can arise from the resonance effects not captured by the Hammett σ para values.After this, we considered direct bimolecular hydride transfer and the hemiaminal pathway, see Fig. 5 and Figs S1-S2, which have been suggested for homogeneous quinones.To distinguish between the two different mechanisms, and to identify whether the firs

hydride abstraction takes place from the 2-or 4-position (Scheme
3), we synthesized deuterated analogues of 1e and measured the kinetic isotope effects.Comparison of the intermolecular KIEs between 1e, 1e-2-2 H 2 , and 1e-4-2 H 2 revealed that there is no observable 1 H/ 2 H KIE on C4, whereas C2 exhibited KIE of 1.8.Therefore, the ratedetermining H-abstraction occurs from the C2-position.Additionally, the observed KIE rules out a rate-determining electron transfer followed by fast deprotonation

54,55However
the intramolecular KIE with 1e-2-2 H 1 was higher than the intermolecular KIE; 3.7 versus 1.8, respectively (Scheme 4).Stahl and coworkers have earlier argued that the divergent intra-/intermolecular KIE values support the formation of a preequilibrium transient covalent adduct prior to the hydride transfer. 55However, it has also been debated that the said preequilibrium adduct is an off-cycle species 56 or even contradicts high intermolecular KIE values in related reduction reactions of dihydropyrans with PhC(O)CF 3 . 57Scheme 3. Kinetic isotopic effect measurements for 1e to 2e conversions.

We then decided to compute the activation free energies for the dehydrogenation reaction for both hydride transfer and hemiaminal pathway mechanisms.We selected phenanthrenequinone (PQ) and ortho-benzoquinone (o-BQ) as the model quinoidic fragments 15 and 1e as the model substrate.The computed activation free energy barriers indicate that the rate-determining steps for both mechanisms -hydride transfer (TS1) and hemiaminal pathway (TS5) -are energetically close (see Fig.  Therefore, we compared the THQs' and hemiaminals' partial charges with the experimental reaction rates in Fig. 4b and Fig. S3 (SI).The NBO charge on THQs' nitrogen correlated well (R 2 = 0.9523) with the measured reaction rates, including the halogenated substrates, while the hemiaminals'

itrogen NBO charges ga
e poor correlations with the experi