Alternating Current Electrolysis for the Electrocatalytic Synthesis of Mixed Disulfide via Sulfur–Sulfur Bond Metathesis towards Dynamic Disulfide Libraries

Article abstract of DOI:10.1002/chem.201904948

A novel approach of electrolysis using alternating current was applied in the sulfur–sulfur bond metathesis of symmetrical disulfides towards unsymmetrical disulfides. As initially expected, a statistical distribution in disulfides was obtained. Furthermore, the influence of electrode polarisation by alternating current was investigated on a two-disulfide matrix. The highly dynamic nature of this chemistry resulted in the creation of dynamic disulfide libraries by expansion of the matrices, consisting of up to six symmetrical disulfides. In addition, mixing of matrices and stepwise expanding of a matrix by using alternating current electrolysis were realised.

Full text of DOI:10.1002/chem.201904948

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Accepted Article
Title: Alternating Current Electrolysis for the Electrocatalytic Synthesis
of Mixed Disulfide via Sulfur-Sulfur Bond Metathesis towards
Dynamic Disulfide Libraries
Authors: Gerhard Hilt, Lars Erik Sattler, and Chris Josef Otten
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Alternating Current Electrolysis for the Electrocatalytic Synthesis
of Mixed Disulfide via Sulfur-Sulfur Bond Metathesis towards
Dynamic Disulfide Libraries
Lars Erik Sattler,[a, b] Chris Josef Otten,[b] and Gerhard Hilt*[b]
Dedicated to the late Jun-ichi Yoshida.
Abstract: A novel approach of electrolysis using alternating current
was applied in the sulfur-sulfur bond metathesis of symmetrical
disulfides towards unsymmetrical disulfides. As initially expected, a
statistical distribution in disulfides was obtained. Furthermore, the
influence of electrode polarisation by alternating current was
investigated on a two disulfide matrix. The highly dynamic nature of
this chemistry resulted in the creation of dynamic disulfide libraries by
expansion of the matrices, consisting of up to six symmetrical
disulfides. In addition, mixing of matrices and stepwise expanding of
a matrix by using alternating current electrolysis were realised.
reversible formation and cleavage of a sulfur-sulfur bond in
organic disulfides by redox chemistry could be of advantage as
these bonds can be cleaved and formed under relatively mild
chemical and electrochemical conditions.[5] In this respect, the
Otto group has performed seminal work in forming different
macrocyclic disulfides. Therefore, thiols were oxidised by air to
disulfides and the following disulfide metathesis reaction,
mediated by thiolate anions, led to the formation of these
macrocycles.[6]
A similar approach would be the oxidation of thiols to form
disulfides as shown in Scheme 1. To establish a dynamic system,
the reduction of the disulfides regenerates thiolates which can
then be reoxidised to form alternative structures.
Introduction
The modern approaches in systems chemistry are directed
towards the understanding of molecular interactions forming more
complex systems with new or altered characteristics. In the best
case, the new material has a function – in the broadest sense –
that the starting materials do not have.[1] Additionally, the system
should be able to react on changing reaction conditions. These
conditions will force the system to react in a dynamic fashion,
resulting in modes like self-replication or self-association. The
effect will be the generation of new species, in the best case with
new functions. Recent examples in this respect are described by
Otto for foldamers (self-folding molecules) formed from aromatic
dithioles by oxidation, the formation of new surfactants from
combinatorial libraries or new catalytic activities imposed upon
self-aggregation.[2] In order to generate a dynamic system that
can adjust to changing conditions as external pressure put onto
the system, a reversible process for the formation and cleavage
of covalent bonds will be necessary. In this respect the number of
covalent sigma-bond formation processes prone for such an
approach is limited[3] while coordinative bonds in transition metal
complexes would be more flexible but also less stable, unless the
complexes are kinetically inert.[4] Therefore, we envisaged the
Scheme 1. Example for the formation of aromatic thiols into a hexamer for the
self-aggregation and organization of peptide-side chains into stacked structures.
Such a suggested reduction/oxidation cycle will be associated
with the formation of side products derived from a spent redox
reagent. Therefore, we became interested in the formation of
mixed disulfides by a metathesis reaction of two symmetrical
disulfides by an electrochemical reduction/oxidation process,
highlighting the advantage of organic electrochemistry in reducing
the amount of generated waste due to redox reagents.[7] The
simple principle of this reduction/oxidation reaction for the
metathesis of sulfur-sulfur bonds is shown in Scheme 2. Further,
the control of the current passing through the solution or the exact
[a]
[b]
M. Sc. L. E. Sattler
Fachbereich Chemie
Philipps-Universität Marburg
Hans-Meerwein-Str. 4, 35032 Marburg (Germany)
M.Sc. L. E. Sattler, C. J. Otten, Prof. Dr. G. Hilt
Institut für Chemie
Carl von Ossietzky Universität Oldenburg
Carl-von-Ossietzky-Str. 9-11, 26129 Oldenburg (Germany)
E-mail: gerhard.hilt@uol.de
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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control of the redox potential could be another advantage
associated with electrochemical methods.[8] In the seminal work
by Le Guillanton symmetrical disulfides were applied in a cation-
pool strategy using a divided cell. The disulfides were oxidised to
the thiyl cations (R-S+) at low temperature in a stabilising
solvent.[9] Subsequent addition of a thiol (R´-SH) then led to the
formation of mixed disulfide (R-S-S-R´) in good to excellent yields.
Furthermore, the synthesis of mixed disulfides from two thiols in
good to excellent yields has been described recently by Lei under
constant current electrochemical conditions.[10]
other starting materials. Nevertheless, electrochemical
conversions of disulfides under galvanostatic conditions (constant
current controlled electrolysis) often led to the formation of a
polymeric film on the electrodes (electrode fouling) and reduced
yields.[15] With respect to the realisation of a reversible process of
a sulfur-sulfur bond metathesis reaction under electrochemical
conditions, we selected several symmetrical disulfides (1-6) as
model compounds (Figure 1).
Figure 1. Structures of the symmetrical disulfides 1-6 utilized in this
investigation.
From these six symmetrical disulfides several mixed
unsymmetrical disulfides (7-21) might be generated when the
metathesis of the sulfide residues does not follow steric or
electronic restrictions but proceed statistically (Figure 2). In the
first step, we investigated transformations under which two
symmetrical disulfides (1 and 2) can be converted to a (statistical)
mixture of the possible disulfides including the new and desired
mixed disulfide 7.
Scheme 2. Proposed reduction/oxidation cycle for the metathesis of Sulfur-
Sulfur bonds leading to a mixed disulfide.
We intended to apply two disulfides at ambient temperatures in
undivided cells to generate the desired mixed unsymmetrical
disulfides to realise a dynamic library of symmetrical and mixed
disulfides in a statistical fashion and eventually lay the basis for
an approach to investigate self-assembled systems. In other
words, the focus of this investigation was not the synthesis of a
single mixed unsymmetrical disulfide in high yields but the in-situ
formation of all possible combinations of disulfides by
electrochemical methods avoiding classical redox reagents and
undesired side-products. The results of the initial investigation are
presented herein.
Results and Discussion
Disulfides have been investigated intensively in the past under
electrochemical conditions and depending on the substituents on
the sulfur different species can be generated under
electrochemical conditions.[11] For once, the oxidation of disulfides
can result in the formation of radical cations as well as thiyl cations
(R-S+) which can associate with another disulfide molecule to
+ [12]
generate thiiranium species of the general constitution (RS)3 .
Latter species are believed to undergo a series of RS+-transfer
reactions in organic chemistry.[13] On the other hand, under
reductive conditions, radical anions can be generated which
dissociate to form thiyl radicals (R-S·) and a thiolate anion.[14] Also,
two electron-transfer process are described so that the disulfides
are converted to the corresponding thiyl radicals R-S·, cations RS+
or anions RS-. Accordingly, under both electrochemical conditions,
reactive species are formed which undergo various reactions with
Figure 2. Structures of the desired unsymmetrical disulfides 7-21 in this
investigation.
Two Disulfide Matrix
When the electrolysis of 1 and 2 was performed in an undivided
cell, the yield of mixed disulfide 7 was 50% (determined by
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GC-FID analysis) and could be isolated in 42% yield (corrected
yield due to some contamination with 2) by column
chromatography.
setup one or two electron transfer processes to or from the
disulfides occur that led to the formation of the product 7 by
associative/dissociative processes (probably via the species
+
In the next step, the electrolysis of the two disulfides 1 and 2 were
performed in a divided cell and the formation of the desired mixed
unsymmetrical disulfide 7 was observed (identified by GCMS
analysis; Figure 3) in both cell compartments (Scheme 3).
Furthermore, the rate for the formation and the yield of 7 were
nearly identical in both compartments (see SI chapter 2.3, Tables
S6 and S7). It must be mentioned that extended electrolysis led
to side-products in the anodic compartment and oxidation of the
disulfide to oxo-species which could be observed by GCMS
analysis. In the cathodic compartment the complete consumption
of the disulfides was observed associated with the formation of a
R3S3 or RS·) as mentioned above. The observed difference to
the theoretical ratio in disulfide distribution of 1 : 1 : 2 can be a
result of generating ionic species, which are removed during
sample preparation for GC-FID analysis. Furthermore, it is also
possible that there is a slightly thermodynamic preference
towards the unsymmetrical disulfide 7, which can explain this
deviation.
The formation of 7 could be further improved when one of the
disulfide components (e.g. compound 2) was applied in excess.
The GC ratio increased to 89% of 7 (with respect to the minor
component 1) in the presence of 3.0 equiv. of 2 and reached 98%
black precipitate at the platinum cathode in this divided cell design. when 5.0 equiv. of 2 were used (see SI chapter 2.9, Table S14).
As these results show, the stoichiometric reduction/oxidation of
the disulfides is probably not needed and is even counter-
productive. This aspect was confirmed when a “catalytic” amount
of electricity was applied. After passing 0.1 F·mol-1 (5 mol% of the
theoretical amount of electricity for the reduction and oxidation)
through the electrochemical cell, the statistical mixture of 1 : 1 : 2
was already established after only 8 min reaction time. Although
these results were already encouraging, we also investigated an
alternating current approach in (un)divided cells at ambient
temperature to form product 7. For this purpose the polarisation
of the electrolysis was held at a constant current (e.g. 10 mA) for
a specified period of time (t1; pulse time), followed by a quiet time
Scheme 3. Results of constant current electrolysis in a divided cell. Conditions:
(t2) and then the polarisation of the electrodes was altered for
divided cell; Pt / Pt (1.0 cm2 each); 10 mA; 1/2 (0.5 mmol each), CH3CN (10 mL),
another fixed time interval (t1); and the total time of the electrolysis
TBABF4 (0.3 M), rt.
is represented by t3.
The effect (for the solution near the electrode) is an oxidation
pulse, then a quiet time followed by a reduction pulse. The current
profile for one electrode – as this methodology makes no
difference which electrode serves as anode or cathode – is shown
in Figure 4.[16] The rationale for applying this type of pulse
electrolysis was the idea that the reduction of the disulfides 1 and
2 proceeds at the electrode when a reduction pulse is applied and
the change of polarisation would oxidise the thiolates back to the
disulfides. The quiet time t2 was introduced to allow diffusion of
the electrogenerated active species into the solution before the
reversed pulse would quench these species.
Figure 3. GCMS analysis of the electrolysis with the two disulfides 1 and 2 by
anodic oxidation. ISTD = n-dodecane as internal standard. The numbers in
parenthesis express the [M]+ ion masses.
These electrochemical sulfur-sulfur bond metathesis reactions
were tested in acetonitrile, dimethylformamide and methanol as
solvent and the best results were obtained in acetonitrile (see SI
chapter 2.7, Table S12). Also, among several supporting
electrolytes, tetrabutylammonium tetrafluoroborate (TBABF4)
Figure 4. Schematic alternating current profile for one electrode over time.
proved to be most efficient. The formation of the product 7 in the
anode compartment as well as in the cathode compartment was
determined in an averaged statistical ratio of 1 : 2 : 7 = 1.0 : 1.0 :
2.7 from the GC-FID trace. Therefore, we assume that in this
electrode to the other electrode over a relatively large distance
In addition, the diffusion of the electrogenerated species from one
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would not be needed. More importantly, if e.g. the reductively
electrogenerated species would be absorbed on the cathode
surface diffusion to the anode would be impossible, but the
application of an oxidation pulse would recombine the reduced
sulfide species to form sulfur-sulfur bonds again and eventually
this should lead to the formation of the mixed disulfide 7.
Therefore, we expected a statistical mixture of the disulfides 1, 2
and 7 to be formed over time when applying alternating current.
This setup led to the formation of the desired mixed
unsymmetrical disulfide 7 again in a short period of time whereas
the formation of the black precipitate could be avoided, no side
products were encountered and the disulfides were not consumed
or decomposed as was the case under constant current
electrolysis (see SI appendix, Figure S13). Even the application
of 10.0 F·mol-1 in this alternating current setup led to the statistical
ratio and the peaks in GCMS in reference to the internal standard
remained constant. This type of reaction was tested in a divided
cell utilising two different electrode materials and all other
components were held identical. Accordingly, the effect of the
electrode material upon the formation of the mixed disulfides
could be investigated. The best results were observed when the
reactions were performed at a platinum electrode or glassy
carbon electrode whereas inferior results were obtained when
copper, stainless steel and carbon fiber electrodes were used
(see SI chapter 2.7, Table S11).[17] Based on these positive
effects all other disulfide metathesis reactions were conducted
with the alternating current electrolysis setup.
became of interest when matrices with a higher number of
disulfides were applied (see below).
Three and Six Disulfide Matrix
With these conditions in hand, the next step in this investigation,
utilising three disulfides in one setup, was undertaken in order to
illustrate that a more complex mixture of symmetrical and
unsymmetrical disulfides could be formed and analysed.
Therefore, a small library of disulfide compounds was envisaged.
When a matrix consisting out of three different aromatic and
aliphatic disulfides (1, 2 and 4) were electrolyzed under the
alternating current conditions (t1 = 4 s; t2 = 1 s; I = 10 mA,
t3 = 80 min, 0.8 F·mol-1) three additional mixed disulfides should
be formed (Scheme 4).
The GCMS analysis of the reaction mixture shown in Figure 5
illustrates the formation of all possible products, identified by their
molecular masses and fragmentation patterns. In this case a
baseline separation of the individual species could be realised
(see SI chapter 2.11.1).
In addition, the equilibration of the disulfide distribution was
investigated by comparison of the alternating current approach in
reference to a thiolate mediated metathesis. Therefore, a
catalytical amount of sodium thiophenolate (25 mol%) was used
to achieve the metathesis (see SI chapter 2.4). In contrast to the
alternating current approach, the thiolate mediated metathesis
proved to be a slow process and even after 1520 min reaction
time only 15% yield of the mixed disulfide 7 was obtained (for the
comparison see SI chapter 2.4, Figure S4).
Next, the pulse times t1 were altered in a range from 40 seconds
to 4 milliseconds to determine the formation of 7 even under fast
alternating current conditions (see SI chapter 2.8, Table S13).
Even at these short pulse times (t1 = 4 ms; t2 = 1 ms) the
formation of the mixed product 7 could be observed, but
prolonged electrolysis time was needed. Furthermore, the
formation of product 7 only occurred at the platinum electrode
while at the glassy carbon electrode the product formation was
less than 10%. These observations indicated that the charging of
the electrodes in terms of a capacitor is on the one hand a
relatively fast process on platinum; on the other hand, it cannot
be neglected in terms of unproductive current consumption when
short pulse times t1 are applied. For relatively long pulse times
(e.g. t1 > 1 s) the capacitor energy consumption can be neglected.
In summary, these results showed that the formation of reactive
species is a fast process and that these reactive species are
unlikely to be adsorbed on the electrode surface but diffuse into
solution to initiate the metathesis of the sulfur-sulfur bond of
disulfide molecules. In a control experiment in the absence of
electricity no mixed disulfide was observed, but this aspect
Scheme 4. Sulfur-sulfur bond metathesis matrix consisting of three symmetrical
disulfides leading to six disulfides.
It should be noted that the peak height and the integral of the
peaks do not directly correlate with the mass balance. Though, a
static mixture of all six compounds was obtained, although no
detailed quantification of the GCMS spectra was undertaken.
Nevertheless, with increasing numbers of matrix members, the
possible combinations increase significantly, and problems might
arise.
Figure 5. GCMS analysis (total ion spectrum mode) of the electrolysis of the
matrix with three disulfides 1, 2 and 4.
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Eventually, a matrix consisting out of six different disulfides were
applied in an alternating current approach (Scheme 5, see also SI
chapter 2.11.2) and up to 21 possible disulfides could be formed
(t1 = 4 s; t2 = 1 s; I = 10 mA, t3 = 160 min, 1.6 F·mol-1). In this case,
we selected the symmetrical disulfides with respect to their
molecular masses and this aspect proved to be very useful for the
analysis of the reaction mixture. The GCMS analysis seemed to
reach its limits as not all peaks could be separated on a regular
GCMS column (Macherey-Nagel Optima 5 HT). This can best be
seen at the peak at 6.25 min of the chromatogram (Figure 6)
which consists of three different disulfides overlapping in one
broad peak (Figure 7, left). But, the chosen starting materials have
different molecular masses so that each combination of
symmetrical or unsymmetrical disulfides resulted in product
disulfides with different molecular masses. Accordingly, when the
GCMS analysis was switched from total ion current measurement
to selected ion monitoring, the three different components could
be differentiated and the peaks resolved (Figure 7, right).
Figure 6. GCMS analysis of the electrolysis of the matrix with six disulfides (total
ion spectrum mode).
Also in this case, we tested the stability of the disulfide mixture in
the electrolyte for 1 hour without applying electricity (see SI
chapter 2.10). Interestingly, in the case of the matrix consisting of
six disulfides (1-6) we observed mixed unsymmetrical disulfides;
but remarkably only from the aromatic disulfides in significant
amounts (Scheme 6).
Figure 7. Exemplary comparison of a total ion spectrum (left) versus a selected
ion monitoring mode GCMS analysis (right) for the chromatogram from 6.15-
6.30 min for the GCMS peak consisting of compounds 1, 3 and 8.
In addition, traces of unsymmetrical disulfides 19 and 20, resulting
from metathesis reaction of 4 and 6, were observed. The
remaining aliphatic disulfides did not undergo the metathesis
reaction in the absence of electricity (Figure 8). Also, addition of
NaSPh as a possible initiator for the sulfur-sulfur bond metathesis
did not result in the formation of any other mixed disulfides.
Scheme 5. Sulfur-sulfur bond metathesis matrix consisting of six symmetrical
disulfides.
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Scheme 6. Control experiment of the sulfur-sulfur bond metathesis matrix
consisting of six symmetrical disulfides in the absence of electricity.
species and after mixing of the two matrix solutions no further
metathesis reaction was observed.
Figure 8. GCMS analysis (total ion spectrum mode) of the control experiment
above in absence of electricity with borosilicate glass ware.
Further investigations on the aromatic disulfide metathesis were
carried out with a two-disulfide matrix consisting of 1 and 5 (see
SI chapter 2.10.3). When this matrix was stirred under inert
atmosphere, the mixed disulfide 11 was also formed. Only stirring
in the dark let to the suppression in disulfide formation. However,
when the matrix was stirred in a plastic container (PTFE vessel)
instead in a glass flask (borosilicate or soda-lime glass) the
formation of the aromatic mixed disulfides could be suppressed to
a large extent.[18] Furthermore, the addition of crushed glass into
the PTFE reaction vessel did not initiated the sulfur-sulfur bond
metathesis reaction of the aromatic disulfides to form the product
11 to a similar extent as in the glass flask. We suggest that the
formation of the unsymmetrical disulfide 11 benefits from the
higher alkali and alkaline earth metal ion content in soda-lime
glass in contrast to borosilicate glass in combination with visible
light. Further studies are going on to prove this hypothesis.
Scheme 7. Split and combine of matrices to establish the dynamic nature of the
formation of disulfides under alternating current conditions (t1 = 4 s; t2 = 1 s;
I = 10 mA, t3 = 15 min, 0.15 F·mol-1).
Figure 9. GCMS analysis of the sulfur-sulfur bond metathesis matrix consisting
of disulfides 3, 5 and 6.
Mixing and Expanding Matrices
The dynamic nature of this type of disulfide chemistry was next
investigated when the six-membered disulfide matrix was split
into two matrices consisting of three disulfides each (Scheme 7,
see also SI chapter 2.11.2.1.2). These two matrices were
electrolysed under alternating current conditions (t1 = 4 s; t2 = 1 s;
I = 10 mA, t3 = 15 min, 0.15 F·mol-1) and the individual mixtures
were analysed by GCMS (see Figures 5 and 9). As before, each
possible combination of disulfides was detectable by GCMS
analysis (by selected ion monitoring).
However, when the two solutions were mixed directly after
electrolysis (<1 min) no further electrolysis was needed to form
the identical result obtained from the electrolysis of the original
undivided six disulfide matrix whose GCMS analysis is identical
to this shown in Figure 6. We reasoned that active species for the
disulfide metathesis were still present in solution and initiated the
metathesis reactions. Control experiments revealed that the
filtration through a small plug of silica gel removed the active
Only when a further catalytic amount of electricity (7.5 mol%) was
applied (t1 = 4 s; t2 = 1 s; I = 10 mA, t3 = 15 min, 0.15 F·mol-1), the
complete number of product possibilities of the matrix (1-21) was
formed.
Inspired by the initial observation that the active species for the
metathesis reaction are still present in the reaction mixture, we
decided to investigate an expanding-type approach to realise a
dynamic library (see SI chapter 2.11.2.1.1). Accordingly, when the
two disulfide matrix containing disulfide 1 and 2 was electrolyzed
under the standard conditions (t1 = 4 s; t2 = 1 s; I = 10 mA,
t3 = 15 min, 0.15 F·mol-1) utilising a catalytic amount of current
(7.5 mol%) and the electrolysis was stopped the matrix could be
expanded by addition of another disulfide 4 towards a three
disulfide matrix. After another electrolysis cycle of 15 min utilising
the above-mentioned condition the expected number of disulfides
could be identified by GCMS analysis. Thereafter, the addition of
the fourth disulfide 3 was undertaken and this procedure was
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of the ratio in disulfide distribution was accomplished by GC-FID or GCMS
analysis. Furthermore, for the resolution of overlaid components in the gas
chromatogram measurements in selected ion monitoring (SIM) mode were
performed.
extended until all six components 1-6 were present. At the end
the undivided six-membered matrix was obtained in the same
manner (see Figure 6).
Keywords: alternating current • mixed disulfides •
electrochemistry • dynamic libraries • sulfur-sulfur bond
metathesis
Conclusions
In this investigation we were able to show that the sulfur-sulfur
bond metathesis can be realised by catalytic amounts of electricity
and we applied an alternating current approach to ensure the
formation of all combinations of symmetrical und unsymmetrical
disulfides. Furthermore, alternating current avoided the formation
of undesired side products, the consumption of the starting
materials in unproductive reaction pathways and the formation of
insulating precipitates on the electrode surface in contrast to
direct current. In addition, alternating current electrolysis allows
the formation of the desired disulfides whether in catalytic or over-
stoichiometric amounts of current without decomposition. The
analysis of the products was realised by GCMS and GC-FID
analysis and the choice of starting materials with differing
molecular masses helped to analyse overlapping peaks when
selected ion monitoring was utilised in the GCMS analysis.
Therefore, all disulfides 1-21 could be identified by GCMS and in
one example, the presence of three disulfides in a broad peak
could be proven. The dynamic nature of the matrices could be
shown by split and mix approaches. When the mixing of the
matrices were performed shortly after electrolysis the presence of
active species in the solution allowed the further formation of the
complete matrix without any further electrolysis needed. However,
when the active species were removed by filtration, renewed
electrolysis started the process of the sulfur-sulfur metathesis
right away. Therefore, we are convinced that these results
represent a much needed tool which will be of great interest for
those scientists conducting systems chemistry in the future where
fast responses to changing conditions rely on reversible
processes that can be easily initiated. The sulfur-sulfur bond
metathesis seems to be an excellent example for this type of
chemistry and the alternating current electrolysis is a key element
to achieve this goal.
[1]
a) R. F. Ludlow, S. Otto, Chem. Soc. Rev. 2008, 37, 101; b) G. von
Kiedrowski, S. Otto, P. Herdewijn, J. Sys. Chem. 2010, 1, 1; c) G.
Ashkenasy, T. H. Hermans S. Otto, A. F. Taylor, Chem. Soc. Rev. 2017,
46, 2543.
[2]
a) B. Bartolec, G. Leonetti, J. Li, W. Smit, M. Altay, G. M. Santiago, Y.
Yan, S. Otto, Langmuir 2019, 35, 5787; b) B. Liu, C. G. Pappas, E.
Zangrando, N. Demitri, P. J. Chmielewski, S. Otto, J. Am. Chem. Soc.
2019, 141, 1685; c) M. Malakoutikhah, G. Schaeffer, G. M. Santiago, S.
Yang, I. Marić, S. Otto, J. Sys. Chem. 2019, 7, 9.
[3]
[4]
[5]
S. J. Rowan, S. J. Cantrill, G. R. L. Cousins, J. K. M. Sanders, J. F.
Stoddart, Angew. Chem. 2002, 114, 938; Angew. Chem. Int. Ed. 2002,
41, 898.
a) J. N. H. Reek, P. F. Dydio, Eur. Pat. Appl. 2013, EP 2559484; b) V.
Patroniak, Wiadomosci Chemiczne 2010, 64, 285; c) U. C. Agrawal, H.
L. Nigam, J. Ind. Chem. Soc. 2008, 85, 677.
For the electrochemistry of thioles and disulfides, see: a) S. Torii,
Electroorganic Reduction Synthesis, Vol. 1, Chpt. 6, 2006, Wiley-VCH,
Tokyo; see also: b) M. Yan, Y. Kawamata, P. S. Baran, Chem. Rev. 2017,
117, 13230; c) M. D. Kärkäs, Chem. Soc. Rev. 2018, 47, 5786; d) A.
Wiebe, T. Gieshoff, S. Möhle, E. Rodrigo, M. Zirbes, S. R. Waldvogel,
Angew. Chem. 2018, 130, 5694; Angew. Chem. Int. Ed. 2018, 57, 5594;
e) P.-G. Echeverria, D. Delbrayelle, A. Letort, F. Nomertin, M. Perez, L.
Petit, Aldrichim. Acta 2018, 51, 3; f) S. Kitada, M. Takahashi, Y.
Yamaguchi, Y. Okada, K. Chiba, Org. Lett. 2012, 14, 5960-5963;.g) K.
Matsumoto, H. Shimazaki, T. Sanada, K. Shimada, S. Hagiwara, S. Suga,
S. Kashimura, J.-i. Yoshida, Chem. Lett. 2013, 42, 843-845; h) P. Wang,
S. Tang, P. Huang, A. Lei, Angew. Chem. 2017, 129, 3055-3059; Angew.
Chem. Int. Ed. 2017, 56, 3009-3013.
[6]
[7]
For recent examples, see: a) B. M. Matysiak, P. Nowak, I. Cvtila, C. G.
Pappas, B. Liu, D. Komáromy, S. Otto, J. Am. Chem. Soc. 2017, 139,
6744; b) B. Bartolec, M. Altay, S. Otto, Chem. Commun. 2018, 54, 13096;
c) M. Altay, Y. Altay and S. Otto, Angew. Chem. 2018, 130, 10724;
Angew. Chem. Int. Ed. 2018, 57, 10564, d) S. Otto, R. L. E. Furlan, J. K.
M. Sanders, Science 2002, 297, 590-593.
a) R. H. Verschueren, W. M. De Borggraeve, Molecules 2019, 24, 2122;
b) J. B. Sperry, D. L. Wright, Chem. Soc. Rev. 2006, 35, 605; c) H. A.
Lund J. Electrochem. Soc. 2002, 149, S21.
Experimental Section
[8]
[9]
O. Hammerich and B. Speiser, Organic Electrochemistry, 5th Ed. 2016,
Taylor&Francis, Boca Ratton.
General Procedure for an Alternating Current Electrolysis: Both
compartments of an H-type divided cell were equipped with a magnetic
stirring bar and charged with 988 mg (3.00 mmol) TBABF4. The supporting
electrolyte was dissolved in 10 mL CH3CN in each compartment.
Afterwards, 109 mg (0.500 mmol, 1.0 equiv.) diphenyl disulfide (1),
95.1 µL (0.500 mmol, 1.0 equiv.) di-n-butyl disulfide (2), 115 mg
(0.500 mmol, 1.0 equiv.) dicyclohexyl disulfide (3), 201 mg (0.499 mmol,
1.0 equiv.) di-n-dodecyl disulfide (4), 123 mg (0.500 mmol, 1.0 equiv.) di-
p-tolyl disulfide (5), 143 mg (0.500 mmol, 1.0 equiv) Bis(p-methoxyphenyl)
disulfide (6) and 0.5 mL (0.500 mmol, 1.0 equiv.) n-dodecane solution
(1.0 M in CHCl3) as internal standard were added in both compartments.
At last, the electrodes (first compartment platinum, second compartment
glassy carbon) were immerged into the solution (surface area: 1.0 cm²)
and a constant current (10 mA) with an alternation in electrode polarisation
of 5 s (t1 = 4 s pulse time, t2 = 1 s quiet time) was applied. After 15 min
(0.15 F·mol-1) a sample for GCMS analysis was taken. The determination
a) Q. T. Do, D. Elothmani, G. Le Guillanton, J. Simonet, Tetrahedron Lett.
1997, 38, 3383; For recent reviews on electrochemical cation-pool
chemistry, see b) J.-i. Yoshida, A. Shimizu, R. Hayashi, Chem. Rev. 2018,
118, 4702; c) K. Matsumoto, S. Suga, J.-i. Yoshida, Org. Biomol. Chem.
2011, 9, 2586.
[10] P. Huang, P. Wang, S. Tang, Z. Fu and A. Lei, Angew. Chem. 2018, 130,
8247; Angew. Chem. Int. Ed. 2018, 57, 8115.
[11] a) S. Boryczka, D. Elothmani, Q. T. Do, J. Simonet, G. Le Guillanton, J.
Electrochem. Soc. 1996, 143, 4027; b) Q. T. Do, D. Elothmani, G. Le
Guillanton, Electrochim. Acta 2005, 50, 4792.
[12] a) C. Grogger, S. G. Fattakhov, V. V. Jouikov, M. M. Shulaeva, V. S.
Reznik, Russ. J. Gen. Chem. 2005, 75, 386; b) S. Antonello, R. Benassi,
G. Gavioli, F. Taddei, F. Maran, J. Am. Chem. Soc. 2002, 124, 7529.
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[13] For some selected examples, see: a) K. Matsumoto, S. Fujie, S. Suga,
T. Nokami, J.-i. Yoshida, Chem. Commun. 2009, 5448; b) K. Matsumoto,
S. Fujie, S. Suga, T. Nokami, J.-i. Yoshida, Chem. Commun. 2009, 5448.
[14] S. Antonella and F. Maran, Chem. Soc. Rev. 2005, 34, 418.
[15] M. Borsari, M. Cannio and G. Gavioli, Electroanalysis 2003, 15, 1192.
[16] Alternating current has rarely been used in organic synthesis. For some
examples, see: a) B. Lee, H. Naito, M. Nagao, T. Hibino, Angew. Chem.
2012, 124, 7067; Angew. Chem. Int. Ed. 2012, 51, 6961; b) S. M. Lee, J.
M. Roseman, C. B. Zartman, E. P. Morrison, S. J. Harrison, C. A.
Stankiewicz, W. J. Middleton, J. Fluorine Chem. 1996, 77, 65; c) S. C.
Savett, S. M. Lee, A. Z. Bradley, S. P. Kneizys, J. M. LoBue, M. J.
Middleton, Microchem. J. 1993, 48, 192; d) A. Kraj, H-J. Brouwer, N.
Reinhoud, J.-P. Chervet, Anal. Bioanal. Chem. 2013, 405, 9311-9320.
[17] The carbon fiber electrodes were manufactured from material was
purchased from R&G Faserverbundwerkstoffe GmbH, Germany (item
description: Carbon roving PyrofilTM TR50S 6k/400 tex); for a recent
application, see: P. Röse, S. Emge, C. A. König, G. Hilt, Adv. Synth. Catal.
2017, 359, 1359.
[18] For the analysis of the reaction mixture, a sample was taken from the
reaction vessel by a PTFE pipette and put in a PTFE vial for GCMS
analysis.
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L. E. Sattler, C. J. Otten, G. Hilt
Page No. – Page No.
Alternating Current Electrolysis for
the Electrocatalytic Synthesis of
Mixed Disulfide via Sulfur-Sulfur
Bond Metathesis towards Dynamic
Disulfide Libraries
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