Electrosynthesis using a recyclable mediator-electrolyte system based on ionically tagged phenyl iodide and 1,1,1,3,3,3-hexafluoroisopropanol

Article abstract of DOI:10.1021/acs.orglett.6b02979

A new type of redox mediator for electrosynthesis based on the iodine(I)/iodine(III) redox couple is reported. It is demonstrated that the use of 1,1,1,3,3,3-hexafluoroisopropanol as solvent plays a crucial role for both the selective anodic generation of the active iodine(III) species and the subsequent chemical transformation. Furthermore, the supporting electrolyte is merged with the mediator by tethering the redox-active iodophenyl moiety to an alkylammonium group, allowing for straightforward recovery and reuse of both components.

Full text of DOI:10.1021/acs.orglett.6b02979

Letter
pubs.acs.org/OrgLett
Electrosynthesis Using a Recyclable Mediator−Electrolyte System
Based on Ionically Tagged Phenyl Iodide and 1,1,1,3,3,3-
Hexafluoroisopropanol
Timo Broese and Robert Francke*
Institute of Chemistry, Rostock University, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
S
* Supporting Information
ABSTRACT: A new type of redox mediator for electrosynthesis based on the
iodine(I)/iodine(III) redox couple is reported. It is demonstrated that the use of
1,1,1,3,3,3-hexafluoroisopropanol as solvent plays a crucial role for both the selective
anodic generation of the active iodine(III) species and the subsequent chemical
transformation. Furthermore, the supporting electrolyte is merged with the mediator by
tethering the redox-active iodophenyl moiety to an alkylammonium group, allowing for
straightforward recovery and reuse of both components.
he electrochemical conversion of organic compounds
(electroorganic synthesis) is considered to be a well-
context, Wirth et al. have accomplished the electrosynthesis of
T
diaryliodonium salts using a flow microreactor.25 However, only
few cases of their use as mediators in electrosynthesis have been
reported thus far, namely, in the anodic partial fluorination in
NR3·nHF-based ionic liquids (Fuchigami et al.)26−28 and in the
context of intramolecular C−N bond forming reactions in 2,2,2-
trifluoroethanol (Nishiyama et al.).29,30
established and useful method in organic synthesis.1−5 Among
several other advantages, it is recognized as a safe and
environmentally friendly methodology since dangerous and
toxic redox reagents can be replaced by electric current or
generated in situ in the course of electrolysis.6−8 Despite the
substantial progress that has been made, the potential of organic
electrosynthesis has yet to be fully exploited and expressed. This
is in part due to the fact that the necessity for excess amounts of
supporting electrolyte constitutes a severe drawback.9,10 Thus,
following the completion of a reaction, the supporting electrolyte
must be separated from the reaction mixture. Unless it is
recovered and reused, it constitutes a source of waste. Due to
their good solubility in organic solvents and high electrochemical
stability, tetraalkylammonium salts are often employed.11,12
However, the good solubility often leads to difficulties with
separation of the salts from the products after the reaction has
completed. A further separation issue is caused by the use of
redox mediators. Such mediators are often employed to facilitate
electron transfer between electrode and substrate and to
influence the selectivity of the electrosynthetic process.13 Since
both the supporting electrolyte and the mediator represents a
source of waste and a key-expense factor, their recovery and reuse
for multiple cycles is highly desirable for industrial applica-
tions.14,15
In the context of the aforementioned separation issues and the
yet unlocked potential of the iodine(I)/iodine(III) redox couple
with regard to electrosynthesis, we developed a mediator based
on compound 1 (see Scheme 1) containing a 4-iodophenyl
Scheme 1. Synthesis of the Redox-Active Supporting
Electrolyte 1
moiety as redox-active unit, which is tethered to a quaternary
ammonium group. The latter one serves both to provide ionic
conductivity (supporting electrolyte) and to facilitate separation
and reuse of the redox-active salt after completed conversion
with a substrate according to Scheme 2. Our elaborated synthesis
provides convenient access to 1 in three scalable steps from
inexpensive starting materials (phenyl iodide and 4-chloro
In conventional organic synthesis, hypervalent iodine
compounds represent a powerful and versatile class of reagents
with applications in C−C, C−Het, and Het−Het bond forming
reactions,16−20 rearrangements21,22 and as terminal oxidants in
transition metal catalyzed transformations.23,24 Instead of the
stoichiometric use of iodine(III) reagents, their electrochemical
in situ generation represents an intriguing alternative. In this
Received: October 3, 2016
© XXXX American Chemical Society
A
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Scheme 2. Concept for the Electrochemical Generation of an
Iodine(III) Species and the Subsequent Use for Chemical
Transformations
butyryl chloride) without the use of column chromatography
(Scheme 1, for details see Supporting Information (SI)).
For several reasons we targeted fluorinated alcohols as solvents
for the mediated electrochemical process depicted in Scheme 2.
First, fluorinated solvents such as 1,1,1,3,3,3-hexafluoroisopro-
panol (HFIP) or 2,2,2-trifluoroethanol (TFE) are known to have
excellent electrochemical properties such as high conductivity
and excellent anodic stability (provided that an appropriate
supporting electrolyte is employed).31 Second, the alcohol is
expected to play an active role in the electrochemical generation
of the active form of the mediator by stabilizing iodine(III)
(structure 2 in Scheme 2). Furthermore, fluorinated alcohols
exhibit a positive influence on the rate and selectivity of
transformations containing radical and/or ionic intermedi-
ates32,33 and are therefore frequently employed in iodine(III)-
mediated reactions.34−36 Finally, selective proton reduction is
feasible as cathodic half-reaction due to the relatively low pKa
values of fluorinated alcohols, rendering H2 as the only
byproduct of the electrochemical process.
In order to study the feasibility of the process depicted in
Scheme 2, we started with cyclic voltammetry of 1 (2 mM) in
TFE (Figure 1, top, red line) and HFIP (Figure 1, bottom, red
line), each solution containing 0.1 M NBu4ClO4 as supporting
electrolyte. In both media, 1 is irreversibly oxidized at similar
peak potentials EP (2.12 V in TFE and 2.16 V in HFIP, all
potentials referenced vs Ag/AgNO3). Whereas in TFE this
anodic wave is superimposed with a further process, a selective
oxidation is observed in HFIP. The origin of this difference
becomes obvious upon considerations of the CVs of the blank
electrolytes (Figure 1, blue lines): Whereas the electrolyte based
on TFE is already significantly degraded at Elim = 2.04 V (with an
arbitrary stability criterion defined as jlim = 0.1 mA cm−1), the
HFIP-based electrolyte is about 0.6 V more stable toward anodic
oxidation (Elim = 2.65 V). Consequently, the Faradaic efficiency
for the oxidation of 1 is generally lower in TFE than in HFIP, and
therefore, we directed subsequent studies toward the use of the
latter solvent.
Figure 1. Cyclic voltammetry of mediator 1 (2 mM) in TFE (top) and
HFIP (bottom). The voltammograms for the blank electrolytes are
inserted for comparison (blue lines). Working electrode, glassy carbon;
supporting electrolyte, 0.1 M NBu4ClO4; reference electrode, Ag/0.01
M AgNO3 in 0.1 M NBu4ClO4; scan rate, 10 mV s−1.
We continued our studies with solubility tests and conductivity
measurements and found that 1 is soluble in HFIP at
concentrations well above 1 M. In contrast, the salt is only
sparsely soluble in polar aprotic organic solvents such as acetone
or acetonitrile and almost insoluble in less polar solvents such as
ethyl acetate and alkanes. This solubility behavior is beneficial for
the recovery of 1 from product mixtures and allows for
straightforward separation procedures (vide infra). With regard
to ionic conductivity, 1 exhibits a behavior comparable to
LiClO4, a frequently used supporting electrolyte in electro-
organic synthesis. For example, a 0.5 M solution of 1 in HFIP
renders a conductivity σ of 1.9 mS cm−1 (compared to 2.3 mS
cm−1 for a LiClO4 solution of the same concentration; a plot of σ
vs concentration is depicted in the SI). We note that this
observation is of fundamental importance with regard to cell
voltage and energy efficiency of the electrolysis since 1 is
supposed to serve both as supporting electrolyte and mediator.
We then proceeded with the exploration of the reactivity and
the identity of the species formed upon anodic oxidation of the
phenyl iodide derivative. As a proof of the concept presented in
Scheme 2, we added hydroquinone to a pre-electrolyzed solution
of 1 in HFIP (undivided cell, no additional supporting
electrolyte) and found quantitative conversion to 1,4-benzoqui-
none after approximately 15 min stirring at room temperature.
Remarkably, no decomposition products were detected after
completed reaction, and mediator salt 1 was almost fully
recovered by a simple solid phase extraction. However, the
characterization of the active iodine species turned out to be less
straightforward. Whereas the oxidation product of 1 is stable in
HFIP for several days (more details: see SI), the active species
slowly decomposes as soon as HFIP is removed, and our
attempts for isolation and the usual characterization were
therefore unsuccessful. 1H NMR spectroscopy of an electrolyzed
solution of 1 in HFIP (20 vol % CDCl3 added) reveals an
additional set of aromatic signals with a downfield displacement,
consistent with the selective formation of a more electron-
The results depicted in Figure 1 allow for a further conclusion
with regard to the use of 1 as mediator: Due to the relatively high
redox potential of the 1/2b couple, most of the substrates of
interest have to be added to the electrolyte after completed
anodic conversion of 1 to 2b (“ex-cell process”).13 In contrast, a
continuous regeneration of iodine(III) in a one-pot approach
(“in-cell process”) would lead to direct anodic oxidation of the
substrate.
B
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1
deficient iodine(III) species (see Figure 2; for full H and 13C
Scheme 3. Intra- and Intermolecular C−N Bond Forming
spectra see SI). On the basis of this observation, the 19F NMR
a
Reactions Using Electrolyzed Salt 1 in HFIP
Figure 2. Aromatic range of the 1H NMR spectrum of a solution of 1 in
HFIP (20 vol % CDCl3 added) after electrolysis (red line) and prior to
electrolysis (black line).
spectrum (single signal at −75.2 ppm, see SI) and the general
preference of iodine(III) toward a T-shaped structure with a
trans configuration of the electron withdrawing substituents18,19
we propose structure 2b (Scheme 2) for the anodically generated
species.
1
Monitoring the conversion of 1 to 2b in HFIP via H NMR
spectroscopy, we optimized the electrolysis conditions with
regard to electrode material, concentration of 1, and current
density (see SI). We found that an optimum Faradaic efficiency
of 70% is achieved when a glassy carbon working electrode in
combination with a platinum counter electrode is used in an
undivided cell applying a current density of 15 mA cm−2 (0.2 M
solution of 1 in HFIP). With these optimized parameters in hand,
we proceeded with investigating the scope of applications,
starting with direct oxidative C−N bond forming reactions,
which have been previously reported in the context of other
hypervalent iodine reagents. With regard to our focus on the
electrochemical construction of heterocycles,37 we were
particularly interested in the synthesis of N-acetyl carbazoles
4a−d via intramolecular cyclization of 2-(N-acetylamino)-
biphenyls 3a−d (see Scheme 3). Similar transformations of
biaryls to carbazoles have been previously reported using
PhI(OAc)2/Pd(OAc)2,38 PhI(OAc)2/Cu(OTf)2,39 and under
metal-free conditions with PhI(OCH2CF3)2.29 In our case, the
carbazole formation proceeds cleanly upon addition of 3 to the
electrolyzed solution of 1 in HFIP. During the electrolysis, 3
equiv of charge per mol 3 (3 F mol−1) are passed, which
corresponds to 1.05 equiv of active species 2b (2e− oxidation,
70% Faradaic efficiency). After addition of 3 to the electrolyte
and stirring for 21 h at room temperature, 4a−d are obtained in
66−94% isolated yield. A limitation of the scope is represented
by biphenyl substrates bearing electron withdrawing substitu-
ents. For R = CN, only 4% conversion could be observed after 24
h reaction time (determined via 1H NMR spectroscopy). We also
note that direct anodic cyclization is not possible. The
electrolysis of 3a−d in HFIP containing 0.1 M NBu4ClO4 in
absence of mediator 1 (j = 15 mA cm−2, 2 F mol−1) leads to a
complex reaction mixture with no detectable amounts of
cyclization product 4a−d. In all cases presented in Figure 3,
both the solvent HFIP and 1 were almost entirely recovered.
Whereas HFIP is removed from the reaction mixture by
distillation, the mediator can be isolated in analytical purity by
dissolving the remaining solid in acetone and precipitation upon
cooling and addition of ether (recovery typically >95%).
a
Reaction conditions: Addition of 3 (and 10 equiv of arene in the case
of intermolecular coupling) to 10 mL of pre-electrolyzed solution of 1
(0.2 M) in HFIP (charge passed: 3 F per mol 3). Stirring of reaction
mixture at room temperature. Isolated yields. Yields based on
b
c
recovered starting material. Only 2 equiv of arene were employed.
d
Charge passed: 6 F per mol 3.
methyl-substituted arene compounds (see Scheme 3), a reaction
type that has been previously reported in the context of the
PhI(OAc)2 reagent.40 Thus, addition of 3e and 10 equiv of
mesitylene, o-xylene, or m-xylene to electrolyzed 1 in HFIP
render 4e, 4f, and 4g in 67−79% yield. We note that decreasing
the amount of arene to two equiv leads to significantly lower
yields of the C−N coupling product (see footnote c in Scheme
3). A limitation of the scope is represented by methoxy-
substituted arene components: Application of our protocol to 3e
in combination with anisole, 1,2-dimethoxybenzene, and 1,3,5-
trimethoxybenzene renders complex reaction mixtures in each
case, whereby the amide component remains mostly unaffected
Upon further exploration of the substrate scope, we found that
the procedure is also applicable to intermolecular oxidative C−N
coupling between 2H-benzo[b][1,4]oxazin-3(4H)-one (3e) and
C
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ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02979.
Experimental details, characterization of compounds,
optimization of reaction parameters, and conductivity
measurements (PDF)
(28) Sawamura, T.; Kuribayashi, S.; Inagi, S.; Fuchigami, T. Adv. Synth.
Catal. 2010, 352, 2757−2760.
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AUTHOR INFORMATION
Corresponding Author
■
(31) Francke, R.; Cericola, D.; Kotz, R.; Weingarth, D.; Waldvogel, S.
̈
R. Electrochim. Acta 2012, 62, 372−380.
*E-mail: robert.francke@uni-rostock.de.
Notes
́ ́
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(33) Kita, Y.; Tohma, H.; Inagaki, M.; Hatanaka, K.; Yakura, T. J. Am.
Chem. Soc. 1992, 114, 2175−2180.
The authors declare no competing financial interest.
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Ganesh, J.; Murai, K.; Kita, Y. Chem. Commun. 2010, 46, 4133.
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(36) Morimoto, K.; Sakamoto, K.; Ohshika, T.; Dohi, T.; Kita, Y.
Angew. Chem. 2016, 128, 3716−3720.
ACKNOWLEDGMENTS
■
R.F. is particularly grateful for a Liebig fellowship (Fonds der
Chemischen Industrie) and for a research stipend from the Max
Buchner Foundation (DECHEMA, grant number 3463).
Furthermore, financial support by the German Federal Ministry
of Education and Research (BMBF−Bundesministerium fur
Bildung und Forschung, project number 031A123) is highly
appreciated.
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