Electrochemical benzylic oxidation of C-H bonds

Article abstract of DOI:10.1039/c8cc08768g

Oxidized products have become increasingly valuable as building blocks for a wide variety of different processes and fine chemistry, especially in the benzylic position. We report herein a sustainable protocol for this transformation through C-H functionalization and is performed using electrochemistry as the main power source and tert-butyl hydroperoxide as the radical source for the C-H abstraction. The temperature conditions reported here do not increase above 50 °C and use an aqueous-based medium. A broad substrate scope is explored, along with bioactive molecules, to give comparable and increased product yields when compared to prior reported literature without the use of electrochemistry.

Full text of DOI:10.1039/c8cc08768g

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Electrochemical benzylic oxidation of C–H
bonds†
Cite this: Chem. Commun., 2019,
55, 937
Jason A. Marko,
Anthony Durgham, Stacey Lowery Bretz
and Wei Liu
*
Received 2nd November 2018,
Accepted 19th December 2018
DOI: 10.1039/c8cc08768g
rsc.li/chemcomm
Oxidized products have become increasingly valuable as building coordination of heteroatoms to the metal catalysts. Furthermore,
blocks for a wide variety of different processes and fine chemistry, a relatively high temperature is usually required to initiate this
especially in the benzylic position. We report herein a sustainable transformation due to the inertness of benzylic C–H bonds23,24
protocol for this transformation through C–H functionalization and Other studies of benzylic oxidation have also suffered from a
is performed using electrochemistry as the main power source and narrow substrate scope.25,26 Due to the importance of benzylic
tert-butyl hydroperoxide as the radical source for the C–H abstrac- C–H oxidation reactions and the limitation of current protocols,
tion. The temperature conditions reported here do not increase a general method that can selectively oxidize benzylic C–H bonds
above 50 8C and use an aqueous-based medium. A broad substrate of substrates bearing various heterocycles using environmentally
scope is explored, along with bioactive molecules, to give compar- friendly solvents and reagents is highly desirable.
able and increased product yields when compared to prior reported
literature without the use of electrochemistry.
The use of electrochemistry in organic chemistry has provided
new avenues for synthetic transformation outside the ability of
the traditional methods. During electrochemistry, organic mole-
cules are able to gain or lose electrons upon interaction with the
electrodes, thus easily producing reactive reaction intermediates.
Consequently, electrochemical methods are inherently selective
and sustainable for the functionalization of organic molecules.
Therefore, electrochemical approaches are conceivably able to
overcome these limitations that their traditional counterparts
have and provide ‘‘greener’’ ways for direct benzylic oxidation.
The past few years have witnessed the resurrection of
electrochemistry in organic synthesis,27–38 especially electro-
chemical C–H activation.39–41 For example, the Baran group has
reported efficient and scalable protocols for allylic C–H oxidation39
and, more recently, unactivated Csp3–H bonds through electro-
chemical methods, with the use of organic mediators.40 Stahl
et al. have also recently developed electrochemical benzylic
oxidation reaction using NHPI as the mediator41 in organic
solvents, using pyridinium perchlorate as the electrolyte and a
high temperature of 100 1C. Compared to traditional synthetic
methods, electrochemical methods generally have higher overall
energy efficiency and offers the ability for milder conditions as
well as the generation of less toxic waste.42–44 Electrochemistry
also allows the regulation of the chemoselectivity by controlling
the applied current or potential.
Over the past few decades, the late-stage oxidation of organic
molecules via direct C–H activation has attracted substantial
interest among synthetic organic chemists.1–6 Methods using
environmentally friendly, cost-effective reagents and solvents
for transformations, especially regarding complex molecules,
have been in high demand.7–9 Among the many C–H function-
alization processes,10 the direct benzylic oxidation of alkylarenes
and heteroarenes is an important protocol to provide the
corresponding ketone compounds for uses as key intermediates
with a variety of commercial applications, such as the synthesis
of pharmaceuticals, flavor compounds, polyester fibers, and
agrochemicals.11,12
Although numerous methods have been developed for the
benzylic oxidation of C–H bonds, most of these methods suffer
from limitations. Traditional benzylic oxidation methods require
the use of stoichiometric amounts of toxic reagents, including
Cr(VI),13 Mn(IV)14 and Se(IV),15,16 and can also be achieved by
using transition metal catalysts, such as Bi,17 Rh,18 Ru,19 Mn,20
Co,21 and Pd22 in combination with excess amounts of oxidants.
However, most of these transition metal catalyzed benzylic
oxidation reactions do not tolerate heterocycles due to the strong
Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio, 45056,
USA. E-mail: wei.liu@miamioh.edu
Since one of our long-term goals is to develop efficient
electrochemical approaches for organic synthesis and energy
catalysis,45 we report herein an electrochemical method for
† Electronic supplementary information (ESI) available: General reaction proce-
dures, photographic guides of divided and undivided cells, supplemental figures
and NMR spectroscopic identification of products. See DOI: 10.1039/c8cc08768g direct oxidation of benzylic C–H bonds via the formation of the
This journal is ©The Royal Society of Chemistry 2019
Chem. Commun., 2019, 55, 937--940 | 937

View Article Online
Communication
ChemComm
tert-butyl peroxyl radical in aqueous conditions using an inexpen- trace amounts of products were observed when the reactions were
sive electrolyte and at relatively mild temperatures. Substrates conducted in the absence of tert-butyl hydroperoxide or without
containing common heterocycles, such as pyridines, benzimid- electricity (entries 1 and 2).
azoles and thiophenes are explored and their benzylic ketone
products are obtained in modest-to-excellent yields.
There were also a few other conditions taken into account
during the optimization that included the type of electrode
Peroxyl radicals have long been known to be reactive and used and the type of reaction cell. All of the products and yields
capable of abstracting moderately strong C–H bonds,46–50 as presented here were obtained using 100 PPI Reticulated Vitreous
the O–H BDE of tBuOOH is approximately 89 kcal molÀ1 51
.
Carbon (RVC) electrodes as both the working and counter
Traditional methods for the generation of peroxyl radicals electrode. Other working electrodes tested included glassy carbon
involve transition metal initiation and thermal heating.50,52,53 and graphite, with platinum counter electrodes. However, not
We hypothesize that the use of electrochemistry could serve as only were product yields considerably lower with the use of the
alternate methods for the generation of such a reactive species, different types of electrodes, but also the use of a precious metal,
allowing the C–H abstraction to occur in a controllable fashion. such as platinum, does not support our goal of being sustainable.
To test this hypothesis, we studied the electrochemical oxida- Additionally, much lower yields were observed when the reac-
tion of a model substrate, 4-benzylpyridine, 1, to phenyl-4- tions were conducted in an un-divided cell. For example, the yield
pyridinyl-methanone, 2, using tert-butyl hydroperoxide as the drops to 42% when the oxidation of 1 was conducted in an
oxidant in a divided cell (Table 1). The first condition optimized undivided cell. (Photographic guides for the set-up of both
was the applied voltage where four different voltages were tested: divided and undivided cells are located in the ESI.†)
0.7–1.0 V (entries 2–5) and compared to 1.1 V (entry 1, 64%) used
With the optimized reaction conditions in hand, we then
in the development stage. None of the lower voltages afforded a explored the substrate scope of this benzylic C–H oxidation
higher yield, (49%, 53%, 59%, 59%, respectively) when com- reaction, with a particular focus on pharmaceutically relevant
pared to 1.1 V and any voltages above 1.1 V were not explored in structural features (Scheme 1). In general, compounds con-
keeping with our goal of making this reaction green and taining different heterocycles, 2, 4–10, are well tolerated with
environmentally friendly, as well as the risk and possibility of moderate-to-excellent yields for all oxidized products. Mole-
over oxidation. The amount of tBuOOH that could be used cules containing different electron-donating, 11 and 12, and
was also explored during the development, as ratios of 0.5, 1, electron-withdrawing groups, 13 and 14, in the para position to
2 and 3 equivalents of tBuOOH-to-substrate were explored the benzylic C–H were all successfully oxidized. One result of
(entries 6–9) and compared to 6 equivalents (entry 1, 64%). particular note is in relation to the size of the cyclohexane ring,
The smaller ratios did effect the overall product yield (27%, when fused to a pyridine, and where the oxidation, and thus
47%, 60%, 62%, respectively), thus 6 equivalents were chosen the ketone, would be observed. With a cyclopentane ring, 9, the
as the desired ratio.
ketone was observed on the benzylic carbon opposite from the
Additionally, conversion to acetophenone, 3 (Fig. S1, ESI†), nitrogen within the pyridine. However, when a cyclohexane ring
was tested and at pH = 8, a NaHCO3 solution in a combination is present, 10, the ketone is observed on the benzylic carbon
of CH3CN and water was found to be the optimal electrolyte directly adjacent to the nitrogen in the pyridine. (Spectral data
while subsequent pHs with different electrolytes were found to is provided in the ESI.†) This electrochemical benzylic oxida-
be detrimental to the oxygenation reaction (entries 4–7). The tion reaction has also been applied for the late-stage function-
electrochemical oxidation reaction can also be conducted at room alization of bioactive molecules. For example, celestolide 29,
temperature albeit with a lower yield (entry 3) and furthermore, ibuprofen methyl ester 30, and papaverine 31 were able to be
oxidized at the benzylic position without affecting other func-
tional groups found in the molecules with synthetic useful yields.
Finally, when the oxidation of 1 was conducted on a gram scale,
Table 1 Optimized reaction conditionsa
compound 2 was obtained at a similar yield (55%), thereby
supporting the possibility of large-scale use.
A possible mechanism (Fig. 1) can be proposed where the
electrochemical oxidation of tBuOOH on the anode results in
Entry tBuOOH (equiv.) Potentialb (V) Temperature (1C) Yieldc (%)
the formation of a tert-butyl peroxyl radical, which performs the
C–H abstraction in the benzylic position of the substrate,
thereby resulting the formation a benzylic radical. This radical
then reacts with tBuOOH yielding the corresponding oxygenated
products with tert-butanol as a side product. A few studies were
then conducted to understand the mechanism of this reaction,
especially the involvement of the tert-butyl peroxyl radical.
To further investigate the probability of this proposed
mechanism, a kinetic isotope effect study was performed under
standard reaction conditions with 1 and its deuterated iso-
topolgue (d10-ethyl benzene). The kH/kD was found to be 19.1 Æ 1
1
2
3
4
5
6
7
8
9
6
6
6
6
6
3
2
1
1.1
1.0
0.9
0.8
0.7
1.1
1.1
1.1
1.1
50
50
50
50
50
50
50
50
50
64
59
59
53
49
62
60
47
27
0.5
a
Reactions were run at 2 mmol scale using RVC working and counter
b
c
electrodes. vs. Ag/AgCl reference electrode. Yields are determined by
GC/MS using dodecane as the internal standard.
938 | Chem. Commun., 2019, 55, 937--940
This journal is ©The Royal Society of Chemistry 2019

View Article Online
ChemComm
Communication
Scheme 2 Kinetic isotope effect study using a mixture of ethylbenzene
and ethylbenzene-d10
.
Fig. 2 Cyclic voltammetry experiments. Glassy carbon as the working
electrode; scan rate: 100 mV sÀ1; 1 mM tBuOOH and 0.17 mM ethylbenzne.
When the system only contains the solvents (blue line) and
ethylbenzene (green line), near zero current is observed until
approximately 1.15 V, where water oxidation occurs. Interestingly,
in the presence of tBuOOH, oxidation current was observed
starting at B0.7 V vs. Ag/AgCl (red and yellow line). The irrever-
sibility of the CV suggests the formation of a reactive species,
presumably the tert-butyl peroxyl radical.
Scheme 1 Substrate scope of the electrochemical benzylic C–H oxida-
tion reaction. Isolated yields. aReactions were run on 2 mmol scale with
1 : 1 NaHCO3 : MeCN. bReactions were run on 0.5 mmol scale with 1 : 1
NaHCO3 : MeCN.
A comparison of the optimized electrochemical reaction
conditions reported here with previously reported benzylic
oxidization, which used heavy metals and other conditions, is
shown in Table S1 (ESI†). In these reported methods, the use of
heavy metal oxidants such as iron chloride,55 chromium(VI)
oxide,56 cobalt(II) perchlorate,57 bismuth,17 Co/NHPI-mediated41
and provided yields that either underperformed or were compar-
able to the yields obtained through this method. This comparison
not only highlights the potential utility of the new conditions
discussed here by providing comparable yields, but also providing
Fig. 1 Proposed mechanism for the tBuOOH-mediated electrochemical
oxidation of benzylic C–H bonds.
(Scheme 2) and the magnitude of this KIE suggests that the a more sustainable way to perform this transformation. Addition-
C–H abstraction is the rate-limiting step in the mechanism, ally, through the use of an aqueous solvent, a non-toxic electrolyte,
which supports our proposed mechanism. The kH/kD reported sodium bicarbonate, was able to be used, thus decreasing the
here matches closely to the isotope effect reported by Howard carbon footprint that this method would leave.
et al. of 14 Æ 5 for the C–H abstraction by a tert-butyl peroxyl
The results described here show the development of a
general method for benzylic C–H activation and oxidation. This
radical.54
Cyclic voltammetry was also performed to understand the reaction is performed using mild reaction temperatures, aqueous-
electrochemical behavior of tBuOOH (Fig. 2 and Fig. S2, ESI†). based solvents and electrochemistry to initiate formation of the
This journal is ©The Royal Society of Chemistry 2019
Chem. Commun., 2019, 55, 937--940 | 939

View Article Online
Communication
ChemComm
21 B. B. Wentzel, M. P. J. Donners, P. L. Alsters, M. C. Feiters and
R. J. M. Nolte, Tetrahedron, 2000, 56, 7797.
22 Y. Xie, Y. Yang, L. Huang, X. Zhang and Y. Zhang, Org. Lett., 2012,
14, 1238.
23 W. R. Gutekunst and P. S. Baran, Chem. Soc. Rev., 2011, 40, 1976.
24 L. Ren, L. Wang, Y. Lv, G. Li and S. Gao, Org. Lett., 2015, 17, 2078.
25 J. De Houwer, K. A. Tehrani and B. U. W. Maes, Angew. Chem.,
Int. Ed., 2012, 51, 2745.
26 S. Cacchi, G. Fabrizi, A. Goggiamani, A. Iazzetti and R. Verdiglione,
Synthesis, 2013, 1701.
27 M. Yan, Y. Kawamata and P. S. Baran, Chem. Rev., 2017, 117, 13230.
28 A. G. O’Brien, A. Maruyama, Y. Inokuma, M. Fujita, P. S. Baran and
D. G. Blackmond, Angew. Chem., Int. Ed., 2014, 53, 11868.
29 B. R. Rosen, E. W. Warner, A. G. O’Brien and P. S. Baran, J. Am.
Chem. Soc., 2014, 136, 5571.
30 P. Qian, M. Bi, J. Su, Z. Zha and Z. Wang, J. Org. Chem., 2016,
81, 4876.
31 W.-B. Wu and J.-M. Huang, J. Org. Chem., 2014, 79, 10189.
32 H. Ding, P. L. DeRoy, C. Perreault, A. Larivee, A. Siddiqui, C. G.
Caldwell, S. Harran and P. G. Harran, Angew. Chem., Int. Ed., 2015,
54, 4818.
tert-butyl peroxyl radical to perform the C–H activation step,
which is shown as the rate-limiting step in the proposed
mechanism based on its KIE value. The broadness of the sub-
strate scope highlights the practicality of this method to be
adapted and employed for large-scale synthesis. Additionally,
by showing the effectiveness of this method on bioactive
molecules, this method may be adaptable by medicinal chemists
to generate oxidized analogues and allow for the evaluation in a
clinical setting.
WL thanks Miami University for the start-up fund. SLB
thanks financial support by the NSF (DUE-1432466). Any
opinions, findings, and conclusions expressed in this material
are those of the authors and do not necessarily reflect the views
of the National Science Foundation.
33 L.-J. Li, Y.-Y. Jiang, C. M. Lam, C.-C. Zeng, L.-M. Hu and R. D. Little,
J. Org. Chem., 2015, 80, 11021.
Conflicts of interest
34 N.-N. Lu, N.-T. Zhang, C.-C. Zeng, L.-M. Hu, S. J. Yoo and R. D. Little,
J. Org. Chem., 2015, 80, 781.
There are no conflicts to declare.
35 M. Rafiee, K. C. Miles and S. S. Stahl, J. Am. Chem. Soc., 2015,
137, 14751.
36 A. Das and S. S. Stahl, Angew. Chem., Int. Ed., 2017, 56, 8892.
Notes and references
1 M. D. Hughes, Y.-J. Xu, P. Jenkins, P. McMorn, P. Landon, 37 A. Badalyan and S. S. Stahl, Nature, 2016, 535, 406.
D. I. Enache, A. F. Carley, G. A. Attard, G. J. Hutchings, F. King, 38 X.-Y. Qian, S.-Q. Li, J. Song and H.-C. Xu, ACS Catal., 2017, 7, 2730.
E. Hugh Stitt, P. Johnston, K. Griffin and C. J. Kiely, Nature, 2005, 39 E. J. Horn, B. R. Rosen, Y. Chen, J. Tang, K. Chen, M. D. Eastgate and
437, 1132.
P. S. Baran, Nature, 2016, 533, 77.
2 J.-E. Backvall, Modern Oxidation Methods, Wiley-VCH, Weinheim, 40 Y. Kawamata, M. Yan, Z. Liu, D. H. Bao, J. Chen, J. T. Starr and
¨
2nd edn, 2010.
P. S. Baran, J. Am. Chem. Soc., 2017, 139, 7448.
41 D. P. Hruszkewycz, K. C. Miles, O. R. Thiel and S. S. Stahl, Chem. Sci.,
2017, 8, 1282.
3 S. Wertz and A. Studer, Green Chem., 2013, 15, 3116.
4 K. Chen, P. Zhang, Y. Wang and H. Li, Green Chem., 2014, 16, 2344.
5 K. Jahnisch, V. Hessel, H. Lowe and M. Baerns, Angew. Chem., 42 C. A. C. Sequeira and D. M. F. Santos, J. Braz. Chem. Soc., 2009,
Int. Ed., 2004, 43, 406. 20, 387.
6 Z. Shi, C. Zhang, C. Tang and N. Jiao, Chem. Soc. Rev., 2012, 41, 3381. 43 N. Fu, G. S. Sauer, A. Saha, A. Loo and S. Lin, Science, 2017, 11, 575.
7 H. Huang, X. Ji, W. Wu and H. Jiang, Chem. Soc. Rev., 2015, 44, 1155. 44 R. A. Sheldon, Chem. Soc. Rev., 2012, 41, 1437.
8 C. L. Hill, Nature, 1999, 401, 436.
9 A. Dos Santos, L. El Kaim and L. Grimaud, Org. Biomol. Chem., 2013,
11, 3282.
10 A. Shilov and G. B. Shul’pin, Chem. Rev., 1997, 97, 2879.
11 T. Punniyamurthy, S. Velusamy and J. Iqbal, Chem. Rev., 2005,
105, 2329.
45 Z. Cao, S. B. Zacate, X. Sun, J. Liu, E. M. Hale, W. P. Carson,
S. B. Tyndall, J. Xu, X. Liu, X. Liu, C. Song, J. Luo, M. Cheng, X. Wen
and W. Liu, Angew. Chem., Int. Ed., 2018, 57, 12675–12679.
46 A. Bravo, H.-R. Bjorsvik, F. Fontana, L. Ligouri and F. Minisci, J. Org.
Chem., 1997, 62, 3849.
47 J.-Q. Yu and E. J. Corey, J. Am. Chem. Soc., 2003, 125(11), 3232.
48 J.-Q. Yu and E. J. Corey, Org. Lett., 2002, 4(16), 2727.
12 F. Recupero and C. Punta, Chem. Rev., 2007, 107, 3800.
13 G.-J. ten Brink, I. W. C. E. Arends and R. A. Sheldon, Science, 2000, 49 D. W. Snelgrove, J. Lusztyk, J. T. Banks, P. Mulder and K. U. Ingold,
287, 1636. J. Am. Chem. Soc., 2001, 123, 469.
14 H. C. Ooi and H. Suschitzky, J. Chem. Soc., Perkin Trans. 1, 1982, 2871. 50 A. J. Catino, R. E. Forslund and M. P. Doyle, J. Am. Chem. Soc., 2004,
15 E. Alcalde, M. Gisbert, J. M. Pons and L. Perez-Garcia, Tetrahedron,
1996, 52, 15197.
126(42), 13622.
51 H. Gao and J. T. Groves, J. Am. Chem. Soc., 2017, 139, 3938–3941.
´
16 J. Mlochowski and H. Wojtowicz-Mlochowski, Molecules, 2015, 20, 52 E. C. McLaighlin, H. Choi, K. Wang, G. Chiou and M. P. Doyle, J. Org.
10205.
Chem., 2009, 74, 730.
17 Y. Bonvin, E. Callens, I. Larrosa, D. A. Henderson, J. Oldham, A. J.
Burton and A. G. M. Barrett, Org. Lett., 2005, 7, 4549.
18 A. J. Catino, J. M. Nichols, H. Choi, S. Gottipamila and M. P. Doyle,
Org. Lett., 2005, 7, 5167.
53 H. Choi and M. P. Doyle, Org. Lett., 2007, 9(62), 5349.
54 J. A. Howard, K. U. Ingold and M. Symonds, Can. J. Chem., 1968,
46, 2661.
55 H. Sterckx, J. De Houwer, C. Mensch, W. Herrebout, K. A. Tehrani
and B. U. W. Maes, Beilstein J. Org. Chem., 2016, 12, 144.
19 D. Zhang and C. Pan, Catal. Commun., 2012, 20, 41.
20 D. Shen, C. Miao, S. Wang, C. Xia and W. Sun, Org. Lett., 2014, 56 S. Yamazaki, Org. Lett., 1999, 13, 2129.
16, 1108.
57 Y. Yang and H. Ma, Tetrahedron Lett., 2016, 57, 5278.
940 | Chem. Commun., 2019, 55, 937--940
This journal is ©The Royal Society of Chemistry 2019