Redox-Neutral TEMPO Catalysis: Direct Radical (Hetero)Aryl C?H Di- and Trifluoromethoxylation

Article abstract of DOI:10.1002/anie.202009490

Applications of TEMPO^. catalysis for the development of redox-neutral transformations are rare. Reported here is the first TEMPO^.-catalyzed, redox-neutral C?H di- and trifluoromethoxylation of (hetero)arenes. The reaction exhibits a broad substrate scope, has high functional-group tolerance, and can be employed for the late-stage functionalization of complex druglike molecules. Kinetic measurements, isolation and resubjection of catalytic intermediates, UV/Vis studies, and DFT calculations support the proposed oxidative TEMPO^./TEMPO⁺ redox catalytic cycle. Mechanistic studies also suggest that Li₂CO₃ plays an important role in preventing catalyst deactivation. These findings will provide new insights into the design and development of novel reactions through redox-neutral TEMPO^. catalysis.

Full text of DOI:10.1002/anie.202009490

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Redox-Neutral TEMPO Catalysis Toward Direct Radical
(Hetero)Aryl C–H Di- and Trifluoromethoxylation
Authors: Johnny W. Lee, Sanghyun Lim, Daniel N. Maienshein, Peng
Liu, and Ming-Yu Ngai
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202009490
Link to VoR: https://doi.org/10.1002/anie.202009490

10.1002/anie.202009490
Angewandte Chemie International Edition
COMMUNICATION
Redox-Neutral TEMPO Catalysis Toward Direct Radical
(Hetero)Aryl C–H Di- and Trifluoromethoxylation
Johnny W. Lee,1‡ Sanghyun Lim,1‡ Daniel N. Maienshein,2 Peng Liu,2* and Ming-Yu Ngai1*
Dedicated to Professor Barry M. Trost on the occasion of his 80th birthday.
Abstract: Applications of TEMPO• catalysis for the development of
redox-neutral transformations are rare. Herein, we report the first
TEMPO•-catalyzed, redox-neutral C–H di- and trifluoromethoxylation
of (hetero)arenes. The reaction exhibits a broad substrate scope, has
high functional group tolerance, and can be employed for the late-
stage functionalization of complex drug-like molecules. Kinetic
measurements, isolation and resubjection of catalytic intermediates,
UV-Vis studies, and DFT calculations support the proposed oxidative
TEMPO•/TEMPO+ redox catalytic cycle. Mechanistic studies also
suggest that Li2CO3 plays an important role in preventing catalyst
deactivation. These findings will provide new insight into the design
and development of novel reactions through redox-neutral TEMPO•
catalysis.
its low turnover number (TON  3) renders the catalytic reaction
inefficient. To date, efficient redox-neutral TEMPO• catalysis that
proceeds through a TEMPO•/TEMPO+ redox cycle remains
elusive. The successful development of such a catalytic platform
could expand the reactivity profile of the aminoxyl radical’s redox
chemistry and advance fundamental knowledge in radical
chemistry.
In our quest for the establishment of redox-neutral TEMPO•
catalysis, we focused our attention on the development of
unprecedented TEMPO•-catalyzed intermolecular, redox-neutral
(hetero)aryl C–H functionalization. Herein, we report the first
success in this area, describe the experimental and
computational studies that support the TEMPO•/TEMPO+ redox
cycle, and outline a new approach for the preparation of di- and
trifluoromethoxylated (hetero)arenes (Figure 1). We looked to
TEMPO• (2,2,6,6-tetramethylpiperidine 1-oxyl radical) and its
derivatives have a rich history in the fields of biochemistry,
materials science, and organic chemistry.[1] These open-shell
species have diverse reactivity and can undergo reactions such
as a single-electron transfer (SET) process to access three
discrete oxidation states (i.e., TEMPO–/TEMPO•/TEMPO+) or
abstract hydrogen atoms from C–H/X–H bonds.[2] Their unique
redox properties and chemical reactivity render TEMPO• and
related aminoxyl radicals a versatile class of radical reagents to
achieve one/two-electron oxidation,[3] hydrogen atom transfer
(HAT),[4] proton-coupled electron transfer (PCET),[5] or radical
trapping reactions.[6] The majority of these transformations,
however, require either a stoichiometric amount of aminoxyl
radicals or the addition of external oxidants such as hypochlorite,
silver, or molecular oxygen (O2) to recycle aminoxyl radicals.[7] In
lieu of common external oxidants, elegant aminoxyl radical-
catalyzed reactions driven by electrooxidation have been recently
reported by Lei,[8] Lin,[9] Minteer,[10] Stahl,[11] and others.[12]
highly
sought-after
di-
and
trifluoromethoxylated
(hetero)arenes[15] as synthetic targets because of the unique
structural[16] and electronic properties[17] that make them an
important group of ethers in the pharmaceutical, agrochemical,
and materials sciences.[15a-c] Recently, we and others reported the
synthesis of di- and/or trifluoromethoxylated (hetero)arenes by
employing visible-light photoredox catalysts,[18] transition
metals,[18f] and/or stoichiometric oxidants/activators.[19] However,
utilizing TEMPO• as a catalyst for synthesis offers an attractive
alternative due to its low cost,[20] environmental friendliness,[21]
and thermodynamic[22] and kinetic stability.[23] Also, our findings
could provide new insight into the design and development of new
reactions through redox-neutral TEMPO• catalysis.
Despite recent advances, applications of aminoxyl radical
catalysis for the development of redox-neutral transformations[13]
without the aid of an external oxidant or electrooxidation are rare.
Baran et al. reported a seminal TEMPO•-mediated intramolecular,
redox-neutral, radical alkane desaturation reaction.[14] Although
they tested the catalytic activity of TEMPO•, they pointed out that
Figure 1. TEMPO•-Catalyzed redox-neutral aryl C-H functionalization.
[1]
J. W. Lee, S. Lim, Prof. M.-Y. Ngai
Department of Chemistry and Institute of Chemical Biology and
Drug Discovery, State University of New York, Stony Brook, New
York 11794, United States
E-mail: ming-yu.ngai@stonybrook.edu
Prof. P. Liu
Department of Chemistry, University of Pittsburgh, Pittsburgh,
Pennsylvania 15260, United States
E-mail: pengliu@pitt.edu
The mechanistic hypothesis of the proposed transformation is
outlined in Scheme 1. We envisioned that the reaction proceeds
through an oxidative redox cycle beginning SET between di- or
trifluoromethoxylating reagent 1a (Ep = +0.11 V vs SCE)[18g] or 1b
(Ep = +0.14 V vs SCE)[18e] and TEMPO• (E1/2 = +0.62 V vs
SCE),[12b] generating 2,2,6,6-tetramethyl-1-oxo-14-piperidine
(TEMPO+) and the di- or trifluoromethoxy radical (•ORF). Although
the SET operates against a moderate potential gradient of
[2]
[‡]
These authors contributed equally.
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.202009490
Angewandte Chemie International Edition
COMMUNICATION
Table 1. Deviation from the Optimized Conditionsa
approximately +0.5 V, such a redox process is possible if the
onward reaction following the electron transfer is irreversible.[24]
Addition of •ORF to an arene forms cyclohexadienyl radical Id (E1/2
= −0.10 V vs. SCE),[25] which is then oxidized by TEMPO+,
regenerating the TEMPO• catalyst and delivering cyclohexadienyl
cation Ie. Rearomatization of Ie via deprotonation should be highly
favored, affording the desired product If.
aReactions were performed using 1 equivalent of reagent and 10 equivalents of
benzene. bYields were determined by 19F NMR spectroscopy using
trifluorotoluene as an internal standard. RSM = remaining starting material (1a).
Scheme 1. Proposed mechanism for the TEMPO•-catalyzed di- and
trifluoromethoxylation of (hetero)arenes.
compatible and afforded the desired products in good yields.[26]
Arenes with other functional groups, including unprotected phenol
(3i, 3j, 3k), alkene (3j), cyano (3i), nitro (3j), aldehyde (3k), ketone
(3l, 3m), ester (3o), sulfone (3p), and carbonate (3p), were viable
substrates as well. Importantly, our protocol is amenable for late-
stage difluoromethoxylation reactions of medicinally relevant
molecules using one equivalent of substrates such as
Leflunomide® (antirheumatic drug, 3s), Efavirenz® (antiretroviral
drug for treating HIV, 3t), and derivatives of Diacetonefructose
(3u), Benzocaine® (pain killer, 3v), and trans-Androsterone (3w).
We tested our hypothesis and obtained the desired
difluoromethoxylated product (3a) in 83% yield when a mixture of
benzene (2a), difluoromethoxylating reagent (1a), Li2CO3, and
TEMPO• (5 mol%) was heated at 60 °C for 20 hours (Table 1,
entry 1). Control experiments indicated that both TEMPO• and
Li2CO3 are critical. The absence of either one of these
components led to either no desired reaction or low yield (entries
2 and 3). Mechanistic studies suggested that Li2CO3 prevents
catalyst deactivation (vide infra). Replacement of Li2CO3 with
more soluble bases such as Cs2CO3 or 2,6-di-tBu-4-me-pyridine
resulted in reagent decomposition, decreasing the yields to 29%
and 39%, respectively (entries 4 and 5). When we conducted the
reaction at room temperature or under diluted conditions (0.10 M),
we obtained lower yields of 50% and 49%, respectively (entries 6
and 7). The use of a MeCN/DCE solvent mixture (1:1) is essential
as the absence of either solvent led to poor yields (entries 8 and
9). Presumably, the partial solubility of reagent 1a in the solvent
mixture allows the slow introduction of 1a and so maintains its
integrity. While using 1 equivalent of benzene afforded the
product in a lower yield, the reaction proceeded with similar
efficiency in the presence of water or air (entries 10-12).
To further demonstrate the synthetic utility of redox-neutral
TEMPO• catalysis, we successfully achieved radical
trifluoromethoxylation of a broad range of (hetero)arenes using
trifluoromethoxylating reagent 1b (Table 2b). Again, the reaction
tolerated a wide array of functionalities such as benzylic C–H
bond (4c), carbonyl and cyano (4c-4g, 4l), phosphine oxide (4h),
sulfone (4i), carbonate (4j) and imide (4k) groups. The selectivity
of the TEMPO•-catalyzed (hetero)aryl C–H di- and
trifluoromethoxylation reactions is governed by the radical nature
of the process, which provides rapid access to multiple
regioisomeric products without labor-intensive, parallel multistep
analog synthesis,[27] conveniently generating promising new
candidates that might have never been evaluated otherwise.
Our mechanistic hypothesis for the TEMPO•-catalyzed redox-
neutral reaction depicted in Scheme 1 is supported by kinetic
measurements, catalytic intermediate isolation and resubjection,
UV-Vis studies, EPR measurements, and DFT calculations. The
Having identified the optimal reaction conditions, we explored
the scope of TEMPO•-catalyzed redox-neutral (hetero)aryl C–H
difluoromethoxylation (Table 2a). We found that this protocol has
a broad substrate scope and high functional group compatibility.
For example, the reaction tolerated halide substituents (3b, 3c,
3g, 3r), which provide useful handles for further structural
elaborations through metal-catalyzed coupling reactions. Notably,
substrates containing benzylic C–H bonds (3d, 3e, 3f, 3g), which
are often sites for undesired reactivity in radical processes, were
intermolecular
kinetic
isotope
effect
(KIE)
of
the
difluoromethoxylation reaction using equimolar amounts of
benzene and benzene-d6 was found to be 1, implying that the
cleavage of the aryl C–H takes place after the rate-determining
step (Figure 2a). Kinetic studies using Burés’ method[28]
suggested a first-order dependence on TEMPO• (Figure S3). To
understand the role of the TEMPO• catalyst, we synthesized
This article is protected by copyright. All rights reserved.

10.1002/anie.202009490
Angewandte Chemie International Edition
COMMUNICATION
Table 2. Selected Examples of Di- and Trifluoromethoxylation of (Hetero)Arenes.
aReactions were performed using 1 equivalent of reagent 1a or 1b and 10 equivalents of (hetero)arene. The asterisk (*) denotes the functionalization of minor
regioisomeric products. Due to the high volatility of the products, overall yields and the ratio of the constitutional isomers were determined by 19F NMR
spectroscopy using trifluorotoluene as an internal standard. bReactions were performed with 10.0 mol% of TEMPO. cReactions were performed with 20 mol%
of TEMPO. dReactions were performed using 2.00 equivalents of reagent 1a, 1.0 equivalent of (hetero)arene and 50 mol% TEMPO• in MeCN:DCE 1:1 (0.200
M). eOverall yields were determined based on the recovered starting material. fIsolated yield.
and compared the catalytic activity of TEMPO+ and TEMPO–
with TEMPO• under standard reaction conditions (Figure
2b).[29] In the presence of Li2CO3, while TEMPO– failed to
promote the reaction, TEMPO• and TEMPO+ afforded the
desired product in 83% and 51% yield, respectively. In the
absence of Li2CO3, the reactivity dropped dramatically in all
cases, and only 3% of product 3a was obtained using
TEMPO•. These data showed that (i) Li2CO3 is critical for
catalytic activity, (ii) TEMPO– is catalytically inactive, and (iii)
TEMPO• and TEMPO+ are catalytically active only in the
presence of Li2CO3. Given that our di- and
trifluoromethoxylation reactions generate one equivalent of
acid and that acid can promote disproportionation of TEMPO•
(K = 3.3 x 104 M-2) to produce catalytically inactive TEMPO+
and TEMPOH2+ species,[30] it may explain the lack of catalytic
turnover of TEMPO• in the absence of base. UV-Vis
measurements of TEMPO+ (abs = 290 nm)[31] showed a new
peak with abs = 245 nm after the addition of Li2CO3 (Figure
2c). Since carbonate can serve as a reductant and engage in
SET with both inorganic complexes and organic molecules,[32]
the UV-Vis data indicate that carbonate reduces TEMPO+ to
the putative TEMPO• (abs = 245 nm).[31] This unprecedented
This article is protected by copyright. All rights reserved.

10.1002/anie.202009490
Angewandte Chemie International Edition
COMMUNICATION
Figure 2. Mechanism Studies: a The reaction was performed using 5.0 equivalents of 2a/2a-d6, respectively. DFT and Marcus theory calculations were performed at
the M06-2X/6-311++G(d,p)/SMD(MeCN)//M06-2X/6-31+G(d) level of theory using benzene as the substrate. All energies are in kcal/mol and are with respect to Ia
and 1a. See SI for details. DET = dissociative electron transfer; SET = single electron transfer; and HAT = hydrogen atom transfer.
observation is further supported by EPR studies.[33] Taken
together, these results suggested that Li2CO3 plays a dual role as
a base and a sacrificial reductant to prevent catalyst deactivation.
trifluoromethoxylation of (hetero)arenes. Our strategy uses the
readily available and inexpensive TEMPO• catalyst, exhibits high
functional group tolerance, and offers flexible late-stage
functionalization of drug-like molecules. Detailed experimental
and computational studies suggest that (i) the reaction proceeds
through an oxidative TEMPO•/TEMPO+ redox cycle, and (ii)
Li2CO3 prevents catalyst deactivation. We anticipate that these
new findings and mechanistic insights will aid in the development
of a new class of reactions in the area of nitroxyl radical chemistry.
We performed computational studies to evaluate the energy
profiles of the proposed SET reaction mechanism and another
plausible catalytic cycle involving HAT by TEMPO• (Figure 2d).
DFT and Marcus theory calculations suggested that the formation
of the difluoromethoxyl radical (•OCF2H) and TEMPO+ via the
dissociative electron transfer (DET)[34] is feasible with an
activation free energy of +12.8 kcal/mol and is exergonic by –11.2
kcal/mol. The addition of the •OCF2H to an arene to give
cyclohexadienyl radical IIa is slightly exergonic with a ΔG° of –2.6
kcal/mol. Single-electron oxidation of IIa by TEMPO+ to form
cyclohexadienyl cation IIb and regenerate TEMPO• catalyst is
kinetically favored by –8.5 kcal/mol as compared to the sterically
challenging HAT (ΔG‡ = 18.7 kcal/mol with respect to IIa).[35],[36]
Deprotonation of IIb to form the desired product 3a is highly
favorable with a ΔG° of –82.2 kcal/mol. Collectively, the
experimental and computational studies support the proposed
catalytic cycle shown in Scheme 1.
Acknowledgements
Financial support for this work was provided by the NIH
(R35GM119652 to M.-Y. N.) and the NSF (CHE-1654122 to P. L.).
Calculations were performed at the Center for Research
Computing at the University of Pittsburgh, the TACC, and the
Extreme Science and Engineering Discovery Environment
(XSEDE) supported by the NSF (ACI-1053575). We thank Prof.
Tianning Diao and Ms. Qiao Lin at New York University for the
EPR measurement. The EPR instrument at NYU is supported by
the NSF (CHE-1827902). We acknowledge Dr. Katarzyna N. Lee
and Mr. Chaudhary Harris for proofreading this manuscript. We
In summary, we have developed the first application of redox-
neutral TEMPO• catalysis to achieve intermolecular di- and
This article is protected by copyright. All rights reserved.

10.1002/anie.202009490
Angewandte Chemie International Edition
COMMUNICATION
[15] a) F. Leroux, P. Jeschke, M. Schlosser, Chem. Rev. 2005, 105, 827; b)
P. Jeschke, E. Baston, F. R. Leroux, Mini-Rev. Med. Chem. 2007, 7,
1027; c) B. Manteau, S. Pazenok, J. P. Vors, F. R. Leroux, J. Fluorine
Chem. 2010, 131, 140; d) T. Liang, C. N. Neumann, T. Ritter, Angew.
Chem. Int. Ed. 2013, 52, 8214; Angew. Chem. 2013, 125, 8372; e) C. Ni,
J. Hu, Synthesis 2014, 46, 842; f) A. Tlili, F. Toulgoat, T. Billard, Angew.
Chem. Int. Ed. 2016, 55, 11726; Angew. Chem. 2016, 128, 11900; g) T.
Besset, P. Jubault, X. Pannecoucke, T. Poisson, Org. Chem. Front. 2016,
3, 1004; h) K. N. Lee, J. W. Lee, M.-Y. Ngai, Tetrahedron 2018, 74, 7127;
i) X. Zhang, P. Tang, Sci. China Chem. 2019, 62, 525; j) J. W. Lee, K. N.
Lee, M. Y. Ngai, Angew. Chem. Int. Ed. 2019, 58, 11171; Angew. Chem.
2019, 131, 11289; k) L. Gregory, P. Armen, R. L. Frederic, Curr. Top.
Med. Chem. 2014, 14, 941; l) J. W. Lee, K. N. Lee, M. Y. Ngai, in
Emerging Fluorinated Motifs, 10.1002/9783527824342.ch8 (Eds.: D.
Cahard, J. A. Ma), Wiley‐VCH Verlag GmbH & Co. KGaA., 2020, pp. 225.
[16] a) D. Federsel, A. Herrmann, D. Christen, S. Sander, H. Willner, H.
Oberhammer, J. Mol. Struct. 2001, 567, 127; b) K. Müller, Chimia 2014,
68, 356; c) Q. A. Huchet, N. Trapp, B. Kuhn, B. Wagner, H. Fischer, N.
A. Kratochwil, E. M. Carreira, K. Müller, J. Fluorine Chem. 2017, 198, 34.
[17] M. A. McClinton, D. A. McClinton, Tetrahedron 1992, 48, 6555.
[18] a) J. W. Lee, D. N. Spiegowski, M. Y. Ngai, Chem. Sci. 2017, 8, 6066; b)
J. Yang, M. Jiang, Y. Jin, H. Yang, H. Fu, Org. Lett. 2017, 19, 2758; c)
W. J. Zheng, C. A. Morales-Rivera, J. W. Lee, P. Liu, M. Y. Ngai, Angew.
Chem. Int. Ed. 2018, 57, 9645; Angew. Chem. 2018, 130, 9793; d) B. J.
Jelier, P. F. Tripet, E. Pietrasiak, I. Franzoni, G. Jeschke, A. Togni,
Angew. Chem. Int. Ed. 2018, 57, 13784; Angew. Chem. 2018, 130, 9793;
e) W. J. Zheng, J. W. Lee, C. A. Morales-Rivera, P. Liu, M. Y. Ngai,
Angew. Chem. Int. Ed. 2018, 57, 13795; Angew. Chem. 2018, 130,
13991; f) S. Yang, M. Chen, p. Tang, Angew. Chem. Int. Ed. 2019, 58,
7840; Angew. Chem. 2018, 131, 7922; g) J. W. Lee, W. J. Zheng, C. A.
Morales-Rivera, P. Liu, M. Y. Ngai, Chem. Sci. 2019, 10, 3217.
[19] a) C. Huang, T. Liang, S. Harada, E. Lee, T. Ritter, J. Am. Chem. Soc.
2011, 133, 13308; b) J.-B. Liu, C. Chen, L. Chu, Z.-H. Chen, X.-H. Xu,
F.-L. Qing, Angew. Chem. Int. Ed. 2015, 54, 11839; Angew. Chem. 2015,
127, 12005; c) M. Zhou, C. F. Ni, Z. B. He, J. B. Hu, Org. Lett. 2016, 18,
3754; d) Q. W. Zhang, A. T. Brusoe, V. Mascitti, K. D. Hesp, D. C.
Blakemore, J. T. Kohrt, J. F. Hartwig, Angew. Chem. Int. Ed. 2016, 55,
9758; Angew. Chem. 2016, 128, 9910; e) Q.-W. Zhang, J. F. Hartwig,
Chem. Commun. 2018, 54, 10124; f) M. Zhou, C. Ni, Y. Zeng, J. Hu, J.
Am. Chem. Soc. 2018, 140, 6801; g) Y.-M. Yang, J.-F. Yao, W. Yan, Z.
Luo, Z.-Y. Tang, Org. Lett. 2019, 21, 8003; h) M. Yoritate, A. T.
Londregan, Y. Lian, J. F. Hartwig, J. Org. Chem. 2019, 84, 15767; i) Z.
Deng, M. Zhao, F. Wang, P. Tang, Nat. Commun. 2020, 11, 2569.
[20] $25/mol at BioSynth CarboSynth (https://www.carbosynth.com/, as of
9th July, 2020)
also thank reviewers for their insightful suggestions and
comments.
Keywords: TEMPO catalysis • difluoromethoxylation •
trifluoromethoxylation • radical • arenes
[1]
[2]
a) E. E. Voest, E. v. Faassen, J. J. M. Marx, Free Radical Bio. Med. 1993,
15, 589; b) H. Fischer, Chem. Rev. 2001, 101, 3581; c) A. Studer, Chem.
- Eur. J. 2001, 7, 1159; d) A. Studer, Chem. Soc. Rev. 2004, 33, 267; e)
J. E. Nutting, M. Rafiee, S. S. Stahl, Chem. Rev. 2018, 118, 4834; f)
Hongfeng Zhuang, Heng Li, Shuai Zhang, Yanbin Yin, Feng Han, Chao
Sun, C. Miao, Chin. Chem. Lett. 2020, 31, 39; g) D. Leifert, A. Studer,
Angew. Chem. Int. Ed. 2020, 59, 74; Angew. Chem. 2020, 132, 74.
a) J. E. Babiarz, G. T. Cunkle, A. D. DeBellis, D. Eveland, S. D. Pastor,
S. P. Shum, J. Org. Chem. 2002, 67, 6831; b) S. Coseri, K. U. Ingold,
Org. Lett. 2004, 6, 1641; c) J.-L. Zhan, M.-W. Wu, D. Wei, B.-Y. Wei, Y.
Jiang, W. Yu, B. Han, ACS Catal. 2019, 9, 4179.
[3]
[4]
a) J. M. Hoover, S. S. Stahl, J. Am. Chem. Soc. 2011, 133, 16901; b) T.
Kano, F. Shirozu, K. Maruoka, J. Am. Chem. Soc. 2013, 135, 18036; c)
A. Badalyan, S. S. Stahl, Nature 2016, 535, 406.
a) E. A. Mader, A. S. Larsen, J. M. Mayer, J. Am. Chem. Soc. 2004, 126,
8066; b) T. Gunasekara, G. P. Abramo, A. Hansen, H. Neugebauer, M.
Bursch, S. Grimme, J. R. Norton, J. Am. Chem. Soc. 2019, 141, 1882.
C. T. Saouma, W. Kaminsky, J. M. Mayer, J. Am. Chem. Soc. 2012, 134,
7293.
[5]
[6]
a) T. Iwamoto, H. Masuda, S. Ishida, C. Kabuto, M. Kira, J. Am. Chem.
Soc. 2003, 125, 9300; b) J. L. Pitters, R. A. Wolkow, J. Am. Chem. Soc.
2005, 127, 48; c) P. H. Fuller, J.-W. Kim, S. R. Chemler, J. Am. Chem.
Soc. 2008, 130, 17638.
[7]
a) M. F. Semmelhack, C. R. Schmid, D. A. Cortes, C. S. Chou, J. Am.
Chem. Soc. 1984, 106, 3374; b) R. Liu, X. Liang, C. Dong, X. Hu, J. Am.
Chem. Soc. 2004, 126, 4112; c) J. M. Bobbitt, C. BrüCkner, N. Merbouh,
Org. React. 2004, 103; d) M. Shibuya, M. Tomizawa, I. Suzuki, Y.
Iwabuchi, J. Am. Chem. Soc. 2006, 128, 8412; e) Y.-X. Chen, L.-F. Qian,
W. Zhang, B. Han, Angew. Chem. Int. Ed. 2008, 47, 9330; ; Angew.
Chem. 2008, 120, 9470; f) S. Maity, S. Manna, S. Rana, T. Naveen, A.
Mallick, D. Maiti, J. Am. Chem. Soc. 2013, 135, 3355; g) X. Xie, S. S.
Stahl, J. Am. Chem. Soc. 2015, 137, 3767; h) D. Gangaprasad, J. Paul
Raj, T. Kiranmye, K. Karthikeyan, J. Elangovan, Eur. J. Org. Chem. 2016,
2016, 5642; i) X.-Q. Hu, J. Chen, J.-R. Chen, D.-M. Yan, W.-J. Xiao,
Chem. - Eur. J. 2016, 22, 14141.
[8]
[9]
Y. Wu, H. Yi, A. Lei, ACS Catal. 2018, 8, 1192.
a) J. C. Siu, G. S. Sauer, A. Saha, R. L. Macey, N. Fu, T. Chauviré, K.
M. Lancaster, S. Lin, J. Am. Chem. Soc. 2018, 140, 12511; b) J. C. Siu,
J. B. Parry, S. Lin, J. Am. Chem. Soc. 2019, 141, 2825.
[21] K. Sakuratani, H. Togo, Synthesis 2003, 1, 21.
[22] Resonance stabilization energy of TEMPO is 29 kcal/mol, see: I.
Novak, L. J. Harrison, B. Kovač, L. M. Pratt, J. Org. Chem. 2004, 69,
7628.
[10] a) D. P. Hickey, M. S. McCammant, F. Giroud, M. S. Sigman, S. D.
Minteer, J. Am. Chem. Soc. 2014, 136, 15917; b) D. P. Hickey, R. D.
Milton, D. Chen, M. S. Sigman, S. D. Minteer, ACS Catal. 2015, 5, 5519.
[11] a) M. Rafiee, Z. M. Konz, M. D. Graaf, H. F. Koolman, S. S. Stahl, ACS
Catal. 2018, 8, 6738; b) M. Rafiee, M. Alherech, S. D. Karlen, S. S. Stahl,
J. Am. Chem. Soc. 2019, 141, 15266; c) F. Wang, S. S. Stahl, Acc. Chem.
Res. 2020, 53, 561.
[23] A. Nilsen, R. Braslau, J. Polym. Sci. A Polym. Chem. 2006, 44, 697.
[24] a) V. G. Mairanovsky, Angew. Chem. Int. Ed. 1976, 15, 281; Angew.
Chem. 1976, 88, 283; b) W. Schmidt, E. Steckhan, J. Electroanal. Chem.
Interf. Electrochem. 1978, 89, 215; c) E. Steckhan, Angew. Chem. Int.
Ed. 1986, 25, 683; Angew. Chem. 1986, 98, 681; d) M. Majek, A. Jacobi
von Wangelin, Acc. Chem. Res. 2016, 49, 2316.
[12] a) H. G. Cha, K.-S. Choi, Nat. Chem. 2015, 7, 328; b) X.-Y. Qian, S.-Q.
Li, J. Song, H.-C. Xu, ACS Catal. 2017, 7, 2730; c) H. B. Zhao, P. Xu, J.
Song, H. C. Xu, Angew. Chem. Int. Ed. 2018, 57, 15153; Angew. Chem.
2018, 130, 15373; d) A. C. Cardiel, B. J. Taitt, K.-S. Choi, ACS Sustain.
Chem. Eng. 2019, 7, 11138.
[25] K. Bahtia, R. H. Schuler, J. Phys. Chem. 1974, 78, 2335.
[26] The addition of electrophilic O-centered radical to arenes is faster than
hydrogen atom abstraction, see: a) M. P. DeMatteo, J. S. Poole, X. Shi,
R. Sachdeva, P. G. Hatcher, C. M. Hadad, M. S. Platz, J. Am. Chem.
Soc. 2005, 127, 7094; b) J. S. Poole, X. Shi, C. M. Hadad, M. S. Platz, J.
Phys. Chem. A, 2005, 109, 2547.
[13] In a redox neutral reaction, the substrate or substrates undergo both
single-electron oxidation and single-electron reduction at different points
of the catalytic cycle. For examples, see: a) N. Z. Burns, P. S. Baran, R.
W. Hoffmann, Angew. Chem. Int. Ed. 2009, 48, 2854; Angew. Chem.
2009, 121, 2896; b) T. Newhouse, P. S. Baran, R. W. Hoffmann, Chem.
Soc. Rev. 2009, 38, 3010; c) L. Ma, W. Chen, D. Seidel, J. Am. Chem.
Soc. 2012, 134, 15305; d) C. K. Prier, D. A. Rankic, D. W. C. MacMillan,
Chem. Rev. 2013, 113, 5322.
[27] a) D. A. Nagib, D. W. MacMillan, Nature 2011, 480, 224; b) T. Cernak, K.
D. Dykstra, S. Tyagarajan, P. Vachal, S. W. Krska, Chem. Soc. Rev.
2016, 45, 546.
[28] J. Burés, Angew. Chem. Int. Ed. 2016, 55, 2028; Angew. Chem. 2016,
128, 2068.
[29] a) M. Shibuya, M. Tomizawa, Y. Iwabuchi, J. Org. Chem. 2008, 73, 4750;
b) N. A. Giffin, M. Makramalla, A. D. Hendsbee, K. N. Robertson, C.
[14] A.-F. Voica, A. Mendoza, W. R. Gutekunst, J. O. Fraga, P. S. Baran, Nat.
Chem. 2012, 4, 629.
This article is protected by copyright. All rights reserved.

10.1002/anie.202009490
Angewandte Chemie International Edition
COMMUNICATION
Sherren, C. C. Pye, J. D. Masuda, J. A. C. Clyburne, Org. Biomol. Chem.
2011, 9, 3672.
[30] a) V. A. Golubev, V. D. Sen', I. V. Kulyk, A. L. Aleksandrov, Bull. Acad.
Sci. USSR, Div. Chem. Sci. 1975, 24, 2119; b) V. D. Sen, V. A. Golubev,
J. Phys. Org. Chem. 2009, 22, 138.
[31] A. Israeli, M. Patt, M. Oron, A. Samuni, R. Kohen, S. Goldstein, Free
Radical Bio. Med. 2005, 38, 317.
[32] a) T. Xu, C. W. Cheung, X. Hu, Angew. Chem. Int. Ed. 2014, 53, 4910;
Angew. Chem. 2014, 126, 5010; b) B. Zhang, A. Studer, Org. Lett. 2014,
16, 3990; c) M. Bühl, P. DaBell, D. W. Manley, R. P. McCaughan, J. C.
Walton, J. Am. Chem. Soc. 2015, 137, 16153; d) J. Rong, L. Deng, P.
Tan, C. Ni, Y. Gu, J. Hu, Angew. Chem. Int. Ed. 2016, 55, 2743; Angew.
Chem. 2016, 128, 2793.
[33] The addition of Li2CO3 to a TEMPO+ solution increases the TEMPO•
concentration by 10 times (see SI for details). It is known that TEMPO+
salts always have a trace amount of TEMPO•: J. M. Bobbitt, N. A. Eddy,
C. X. Cady, J. Jin, J. A. Gascon, S. Gelpí-Dominguez, J. Zakrzewski, M.
D. Morton, J. Org. Chem. 2017, 82, 9279.
[34] J. M. Saveant, J. Am. Chem. Soc. 1992, 114, 10595.
[35] A radical chain reaction between IIa and reagents 1a & 1b cannot be
ruled out, but it is unlikely because oxidation of IIa (E1/2 = –0.10V vs SCE)
by TEMPO+ (E1/2 = +0.62 V vs SCE) is more favorable than that by the
reagents 1a & 1b (Ep = +0.11V vs SCE for 1a; Ep = +0.14V vs SCE for
1b). The conclusion agrees with our previous report (ref. 18g).
[36] Another possible reaction mechanism involves trapping of IIa with
TEMPO to form a 1-OCF2H-2-TEMPO-cyclohexadienyl intermediate,
which then undergoes TEMPO-/H+ elimination to form the desired Ph-
OCF2H product and TEMPOH. However, this mechanism is unlikely
because DFT calculations suggested that such a reaction mechanism is
less favorable than OCF2H-/H+ elimination to form side product of
TEMPOPh, see SI for details. For TEMPO trapping of cyclohexadienyl
radicals, see: A. Teichert, K. Jantos, K. Harms, A. Studer, Org. Lett. 2004,
6, 3477.
This article is protected by copyright. All rights reserved.

10.1002/anie.202009490
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
Johnny W. Lee,† Sanghyun Lim,† Daniel
N. Maienshein, Peng Liu,* and Ming-Yu
Ngai*
Page No. – Page No.
Title: Redox-Neutral TEMPO
Catalysis Toward Direct Radical
(Hetero)Aryl C–H Di- and
Trifluoromethoxylation
Text for Table of Contents
TEMPO-catalyzed redox-neutral di- and trifluoromethoxylation of arenes
and heteroarenes. The strategy exhibits high functional group tolerance
and offers flexible late-stage functionalization of drug-like molecules.
Mechanistic studies suggest an oxidative TEMPO•/TEMPO+ redox
catalytic cycle and that Li2CO3 plays an important role in preventing
catalyst deactivation.
This article is protected by copyright. All rights reserved.