Review

Cite This: Chem. Rev. 2018, 118, 4817−4833 pubs.acs.org/CR

Using Physical Organic Chemistry To Shape the Course of

Electrochemical Reactions
Kevin D. Moeller
Washington University in St. Louis, St. Louis, Missouri 63130, United States

ABSTRACT: While organic electrochemistry can look quite different to a chemist not
familiar with the technique, the reactions are at their core organic reactions. As such,
they are developed and optimized using the same physical organic chemistry principles
employed during the development of any other organic reaction. Certainly, the electron
transfer that triggers the reactions can require a consideration of new “wrinkles” to those
principles, but those considerations are typically minimal relative to the more traditional
approaches needed to manipulate the pathways available to the reactive intermediates
formed downstream of that electron transfer. In this review, three very different synthetic challengesthe generation and
trapping of radical cations, the development of site-selective reactions on microelectrode arrays, and the optimization of current
in a paired electrolysisare used to illustrate this point.

CONTENTS the attention those methods are garnering from the greater
synthetic community. Several nice reviews of these efforts
1. Introduction 4817
highlighting both direct1−6 and indirect7−11 electrolyses have
1.1. Physical Organic Chemistry, Electrochemis-
try, and Manuel M. Baizer 4818
been published including a very extensive summary by Baran
2. Intramolecular Anodic Olefin Coupling Reactions 4819 and co-workers.12 Many of the articles in this thematic issue of
2.1. Constant Current Electrolyses 4819 the journal expand upon the ideas presented therein and
2.2. Other Technical Considerations 4820 provide new insights into what is being accomplished and how
2.3. Radical Cation Polarity 4821 electrochemical methods can be employed. The presentation of
2.4. A Challenge, Curtin−Hammett Control, and these papers and the extensive literature review they provide
an Important Observation 4821 will serve to make the greater community aware of all that
2.5. An Oxidative Radical Pathway 4823 electrochemistry offers, and hopefully they will help provide
3. New Methods for the Synthesis of a Complex motivation for synthetic chemists to overcome the barrier that
Molecular Surface 4824 has long hindered the development of electroorganic synthesis.
3.1. An Array-Based Synthetic Strategy 4824 Yet as important as this effort is, the barrier to synthetic
3.2. Solving a Synthetic Challenge on an Array 4825 chemists adopting electrochemical methods is not simply a
3.3. New Chemistry Equals New Bioanalytical matter of knowing what reactions can be accomplished or
Capability 4826 having the equipment necessary to conduct them. It is also a
3.4. A Final Observation 4827 lack of familiarity with how to think about the reactions. How
4. Electrochemistry, Energy Economy, and the does one start utilizing the method, choose electrolytes, think
Valorization of Lignin 4827 about current density, and optimize a yield for a particular
4.1. Pairing Synthetic Transformations 4828
reaction?
4.2. Mechanism and the Optimization of Current
For this reason, this review will not focus on providing an
Flow 4829
exhaustive survey of electrochemical reactions that can be
5. Conclusions 4830
Author Information 4830 accomplished but rather will utilize a series of seemingly
ORCID 4830 unrelated transformations [(Scheme 1): (1) the development
Notes 4830 of radical-cation based oxidative cyclizations,13−26 (2) the use
Biography 4830 of chemical synthesis in the development of new micro-
Acknowledgments 4830 electrode array technology,27 and (3) the valorization of lignin
References 4830 derived building blocks28] to highlight how an organic chemist
can approach the development of electrochemical methods.

1. INTRODUCTION Special Issue: Electrochemistry: Technology, Synthesis, Energy, and

Materials
In recent years, there has been a tremendous resurgence in the
field of electroorganic synthesis that has seen both a dramatic Received: November 14, 2017
increase in the number of new methods being developed and Published: March 2, 2018

© 2018 American Chemical Society 4817 DOI: 10.1021/acs.chemrev.7b00656

Chem. Rev. 2018, 118, 4817−4833
Chemical Reviews Review

Scheme 1. Challenges

The reactions presented were each chosen for the specific
lesson that they have taught us.
1.1. Physical Organic Chemistry, Electrochemistry, and
Manuel M. Baizer
The development of new chemical reactions frequently benefits
from a consideration of physical organic chemistry. When a
reaction leads to a less than optimal yield, answers are found by
isolating the minor products generated, determining what
mechanistic steps led to their formation, and then adjusting
reaction conditions to maximize the rate of the desired
mechanism over the unwanted alternatives. The approach
takes advantage of conformational analysis, frontier molecular
orbital theory, stereoelectronic and steric factors, the Curtin−
Hammett Principle, the Hammond Postulate, linear free energy
relationships, etc.
While this approach is common in organic synthesis, the
development of electrochemical reactions has not always been
viewed in the same manner. Instead, problematic reactions
were discarded due to worries about “specialized equipment”
and concepts that appeared outside of the normal expertise of
an organic chemist. Fortunately, this attitude did not extend to
Manuel Baizer, Tatsuya Shono, Hennig Lund, Sigeru Torii,
Hans Schäfer, Jacques Simonet, James Utley, Jean-Michael
Savéant, Dennis Evans, Ikuzo Nishiguich, Al Fry, Dennis Peters,
Jean Lessard, and many others. Many of these efforts are
highlighted in refs 1−6. So, in the interest of space we will focus
here on one aspect of the many contributions made by Manuel
4818
Baizer, perhaps best known for the Monsanto adiponitrile
process.29−31 It was Manual Baizer that helped many of us see
that the mechanistically guided approach used for optimizing
organic reactions is just as relevant for electroorganic reactions.
In the adiponitrile process (Scheme 2), the reduction of an
Scheme 2. Adiponitrile Process
electron-poor olefin led to the production of a highly reactive
radical anion intermediate that was then channeled down a
productive dimerization pathway. This required the relative rate
of radical anion dimerization be optimized relative to either
protonation or polymerization of the radical anion. To this end,
the environment surrounding the cathode was controlled by
forming a double layer with a hydrophobic electrolyte in order
to limit the concentration of water near the electrode and slow
protonation of the reactive intermediate. At the same time, the
concentration of the radical anion was manipulated using
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current density in order to avoid polymerization. The use of the
double layer and current density to control reactions will be
discussed in more detail below. For now, it is most important to
note that the electrolysis reaction was optimized by examining
the same types of physical organic chemistry parameters one
needs to address for any highly reactive intermediate and then
using the reaction medium to manipulate the relative rates of
the relevant processes. While the electrochemical method was
new, the approach taken was not. It was this observation that
set the stage for development of complementary anodic
reactions that proceed through highly reactive radical cation
intermediates.
2. INTRAMOLECULAR ANODIC OLEFIN COUPLING
REACTIONS
Electrochemistry is by its very nature the chemistry of
umpolung reactions. In the adiponitrile process, a reduction
reaction is used to convert an electron-poor olefin into an
electron-rich radical anion. In a similar manner, the oxidation of
an electron-rich olefin leads to an electrophilic radical cation
intermediate.32,33 The result is an opportunity to develop new
modes of reactivity. Consider the generalized transformations
outlined in Scheme 3 (refs 34−46, for related nonelectrochem-
Scheme 3. Oxidative Coupling and an Umpolung
ical reactions please see refs 18−26 and 47−62). In the scheme,
the normal reactivity of an electron-rich olefin is compared to
that of the corresponding oxidation reaction. Note how the
oxidation changes the polarity of the olefin and the
regioselectivity of product formation. In addition, the oxidation
reaction increases the functionality of the molecule so that the
products from the transformation can be manipulated further in
synthetic efforts. Because of this synthetic potential, the
reactions have undergone extensive development. Our goal
here will be to use this chemistry to illustrate how mechanistic
considerations can be used to drive the development of an
electrochemical reaction.
2.1. Constant Current Electrolyses
For starters, it is important to understand the key role that
constant current electrochemistry63 can play in exploring the
chemistry of reactive intermediates.
There are two methods for conducting an electrolysis
reaction; controlled potential and constant current (galvano-
static). In a controlled potential electrolysis, the potential of the
working electrode is set relative to a reference electrode. The
potential selected corresponds to the potential needed for
either the oxidation or reduction of the desired substrate.
During the reaction, the potential of the working electrode is
held constant at this initial value. As the substrate for the
reaction is consumed, the current flow through the reaction
drops. Eventually, the reaction “turns itself off” when no
substrate remains. The reactions are advantageous in that they
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Review
are highly selective for the substrate. The disadvantage is that
the reactions slow down as substrate is consumed and the
current drops. Accordingly they can be hard to push to
completion.
In a constant current experiment, the current passed through
the reaction is set to a fixed value and the working potential of
the electrodes is allowed to float. As shown in Figure 1, at the
Figure 1. Relationship Between Anode Potential and Reaction
Progress.
start of such a reaction the potential at the electrodes (shown
for an anode) climbs to a point where it matches that of the
substrate in solution with the lowest oxidation potential. The
working potential of the anode then remains at that point until
the substrate is consumed. When insufficient substrate remains
at the electrode surface to consume the current needing to pass
through the reaction, the working potential of the electrode
climbs until it finds the substrate (potentially solvent) with the
next lowest oxidation potential. The reactions are advantageous
because they are simple to set up and require no reference
electrode. The disadvantage is that the reactions can lose
selectivity late. However, by keeping the current low in the
experiment, the climb in potential at the anode can be
prevented until the majority (greater than 90% conversion) of
the initial substrate is consumed.
The fact that the potential in a constant current electrolysis
automatically adjusts to match that of the substrate in the
reaction means that the same electrochemical reaction setup
and reaction conditions can be used to oxidize almost any
substrate. In each case, the potential at the working electrode
simply climbs to match that of the substrate. This basic
principle of a constant current electrolysis will play a key role in
solving all three of the challenges presented in Scheme 1. For
now, as an example consider the two reactions shown in
Scheme 4. In both cases, an oxidative cyclization reaction was
triggered by the oxidation of a dithioketene acetal substrate.
The first reaction generated a tetrahydrofuran product used in
the synthesis of nemorensic acid,19 and the second generated a
substituted proline derivative.64 The combination of these two
reactions nicely illustrates the power of this electrochemical
method. No single chemical oxidant could be employed to
oxidize both substrates successfully even though both reactions
originate from the loss of an electron from the same functional
group. In the first case, the oxidation potential of the substrate
matches that of the isolated dithioketene acetal at Ep/2 = +1.06
V relative to a Ag/AgCl reference electrode. For the second
substrate, the potential is lower due to a very fast cyclization
reaction that drains the radical cation away from the electrode
surface.65−67 This is a good thing because the lower potential
(Ep/2 = +0.60 V) is necessary to avoid overoxidation of the
cyclized product (Ep/2 = +0.89 V). The problem for a chemical
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Scheme 4. Two Sample Reactions Both Originating from the
Oxidation of a Dithioketene Acetal
oxidant is clear. If one were to choose an oxidant with an
oxidation potential high enough to oxidize the substrate in
equation 1 in Scheme 4, then its use for the reaction shown in
equation 2 would lead to an overoxidation product. If one were
to choose an oxidant with an oxidation potential suitable for the
selective oxidation required for the reaction shown in equation
2, then it would not be able to initiate the reaction shown in
equation 1. This problem was completely avoided with a
constant current electrolyses that allowed the oxidation
potential at the anode to automatically adjust to the oxidation
potential needed for both reactions while at the same time
enabling the selectivity needed throughout both processes.
2.2. Other Technical Considerations
In addition to the constant current conditions that will play
such a central role in the chemistry described below, there are a
number of other aspects concerning electrochemical reactions
that also deserve comment.
For the most part, the reactions to be discussed were all
conducted in an undivided cell. An “undivided cell” refers to an
electrochemical reaction that has both the anode and cathode
in the same reaction chamber. For the preparative scale
reactions discussed below, this amounts to a simple three neck
round-bottom flask. The electrodes are introduced into the
flask with a thermometer adapter that is sized to fit the ground
glass joints of the flask. This setup is used because it is simple
and takes advantage of glassware already available in any
synthetic lab.
The other option for an electrolysis reaction is the use of a
divided cell. Divided cells have two chambers that are separated
by either a glass frit or a membrane: one chamber for the anode
and another for the cathode. Such cells are commercially
available, and they can be very useful if one needs to protect a
substrate, product, or reagent in an electrolysis from the
counter electrode. For example, if an oxidation reaction
generates a molecule that can be reduced readily at a cathode,
then a divided cell may be necessary to separate the product
from the cathode. One such situation is the generation of an
enone at an anode. Enones can be reduced to radical anions at a
cathode. Hence, the reaction might require the use of a divided
cell to protect the desired enone product. For many reactions,
such as all of the anodic olefin coupling reactions shown in this
review, no such complication exists and the use of a simple
round-bottom flask, or a vial for smaller scale reactions, makes
for an ideal electrolysis cell.
Another common question that arises about electrochemical
reactions concerns the choice of electrodes used for a reaction.
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For our part, we mainly use carbon for the working electrode
(anode for an oxidation) because it is cheap and readily
available. For the reactions below, the counter electrode is
either a carbon rod or a simple Pt-wire. They can be used
interchangeably.
With that said, for many of the anodic olefin coupling
reactions shown you will note the use of a reticulated vitreous
carbon (RVC) anode. This is a high surface area carbon
electrode that is used for the anodic coupling reactions for two
reasons. The first is to help keep the current density used in the
reactions low. For an electrolysis reaction, current density
represents the “concentration of oxidant” used. The anodic
olefin coupling reactions proceed through a highly reactive
radical cation intermediate that can dimerize. For this reason,
the concentration of the radical cation is kept low by keeping
the effective concentration of oxidant (current density) low.
The second reason for the use of an RVC anode has a
historical basis (Scheme 5).36 When the first anodic coupling
Scheme 5. Initial Allylsilane Trapping Studies
reactions were conducted with allylsilane trapping groups, they
led to disappointingly low yields in spite of the fact that
allylsilanes are good nucleophiles. At the time, the reactions
were conducted at a Pt-anode. Efforts to optimize the reactions
led to the discovery of trace amounts of a vinylsilane product.
This product was surprising since the mechanism was supposed
to proceed through cationic intermediate 15, and its formation
suggested that the initial cyclization led to radical 14 that was
then slow to oxidize. A consideration of the literature11
indicated the Pt-anodes often favored one electron oxidations
since the surface of the anode is fouled during the electrolysis.
Higher surface area carbon electrodes did not have this
problem and led to faster two electron oxidations. Hence, a
shift was made to the RVC anode in an effort to accelerate loss
of the second electron from intermediate 14 and the problem
was solved. Since all of the olefin coupling reactions studied
require a net two electron oxidation, the RVC anodes that favor
such a process have been used ever since. They remain our
recommended electrode for any two electron process, especially
ones that proceed through a highly reactive intermediate.
The final electrochemical parameter that often raises
questions involves the choice of electrolyte used in the
reactions. In an electrochemical reaction, the electrolyte plays
a significant role in reducing resistance to the passage of
current. Simply put, an electrochemical reaction generates
cations by the anode and anions by a cathode. Since the two
electrodes are spatially remote from each other, there is a
buildup of charge at each. The more charge that is generated,
the harder it is to introduce more anions into solution. The
electrolyte serves to resolve this issue by providing counterions
for the charges being introduced.
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For the majority of electroorganic reactions, the choice of an based mechanistic studies. For example, because the potential
electrolyte is very simple. The best electrolyte is one that is of the reaction will float to match that of a substrate, the
soluble in an organic solvent but even more soluble in water. substrate for an oxidative cyclization reaction can be system-
That allows for the necessary ions during the organic reaction atically varied without any other change made to the reaction
while enabling easy removal of the electrolyte during workup. conditions. This allows for structure reactivity studies like the
Along these lines, the use of tetraethylammonium tosylate is one shown in Figure 2 relating the polarity of a radical cation to
nearly ideal. It is our first electrolyte of choice and used for the
majority of reactions presented here.
Of course, there are times when the choice of electrolyte can
have a direct impact on the course of a reaction. In those cases,
it is important to consider that a positively charged anode in an
electrolyte solution becomes coated with the negative ion from
the electrolyte. This leads to a negatively charged layer that is in
turn coated with the positive ion from the electrolyte. These Figure 2. Radical cation polarity vs chemoselectivity.
two charged layers make up the electrochemical “double layer”
(or outer Helmholtz layer for a physical chemist) that defines the propensity for carbon carbon bond formation. This data
the nature of the reaction medium at the anode surface.68,69 was then used to adjust the nature of the substrates used in a
Electron transfer reactions at the anode and any rapid chemical number of synthetic studies.71,72 For example, consider the two
reactions that follow occur in this double layer. Accordingly, the reactions shown in Scheme 7. In the first, an enol ether was
nature of the double layer can have a dramatic effect on a
reaction. Consider the chemistry illustrated in Scheme 6.70 Scheme 7. Synthetic Applications of a Mechanistic Finding

Scheme 6. Effect of Electrolyte on the Oxidation of a Sugar

Derivative

In this work, a hydrophilic sugar derivative was oxidized in

order to form a C-glycoside. With the use of the standard
tetraethylammonium tosylate electrolyte, the reaction was
plagued by poor current efficiencies and low yields. The
problem was solved by simply switching to the use of lithium
perchlorate as the electrolyte. This observation was the result of
the “greasy” double layer derived from the quaternary
ammonium salt excluding the very polar substrate from the
surface of the anode. This raised the effective concentration of
methanol and gave rise to a background solvent oxidation.
Switching to lithium perchlorate as the electrolyte led to a more
polar double layer that was better able to accommodate the
polar substrate solving the problem. The exact opposite effect
can be seen when the selective oxidation of a nonpolar
substrate is needed. This will be discussed in more detail below
(Section 2.4, Scheme 11).
In the end, the choice of the proper electrolyte relies on a
consideration of the nature of the solution surrounding the
anode and how it can be used to solubilize the substrate and
reactants for the reaction at the electrode surface. This choice is
no different than the choice of solvent for any organic reaction
where one needs to make sure the substrate and reagents are all
soluble.
2.3. Radical Cation Polarity
With that backdrop, it is time to turn our attention to the
development of the anodic olefin coupling reaction and our
understanding of radical cation intermediates. The flexibility of
the constant current electrolysis described above plays a key
role in this chemistry because it allows for structure activity-
4821
changed to a less polar vinyl sulfide in order to improve the
yield of an oxygen trapping reaction.70 In the second, the enol
ether was changed to a more polar ketene acetal in order to
improve the yield of a carbon−carbon bond forming reaction.25
2.4. A Challenge, Curtin−Hammett Control, and an
Important Observation
In both cases illustrated above, a physical organic chemistry
study led to observations that helped resolve synthetic
challenges that were being faced. This is a consistent pattern.
Take for example, the synthetically problematic case of
generating six-membered rings and quaternary carbons during
an oxidative cyclization (Scheme 8).73 In this example, the
cyclization reaction is slow. When a very reactive trapping
group such as an enol ether is used, the reaction proceeds fine.
However, when a less reactive trapping group such as an
allylsilane is used, the reaction fails, leading to the elimination
of a proton from the enol ether derived radical cation.
Synthetically, this is a significant problem because the use of an
allylsilane would lead to an olefin at the terminating end of the
cyclization. The presence of this olefin would be differentiated
from the acetal at the initiating end of the cyclization, thus
enabling the use of a wide variety of olefin based trans-
formations to carry the product forward in total synthesis
efforts. Unfortunately, variations in the reaction conditions and
nature of the radical cation all led to failure and it was
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Scheme 8. A Difficult Challenge and the “Need” for a
Reactive Terminating Group
concluded at the time that the allylsilane simply could not be
used for such reactions.66
It turns out that the problem encountered in Scheme 8 can
be solved. Allylsilanes can be used for the simultaneous
generation of six-membered rings and quaternary carbons if the
reactions are channeled down a proper pathway. The solution
arose from mechanistic observations that were made in what
initially appeared to be a completely unrelated set of
experiments, and it is instructive to follow the course of
those studies. Years after the chemistry highlighted in Scheme 8
was “complete”, reactions involving heteroatom trapping
groups and intramolecular electron transfer reactions were
being examined (Scheme 9).74 In these reactions, an initial
Scheme 9. Curtin−Hammett Control of a Reaction
oxidation reaction took place at a dithiane group leading to a
sulfur based radical cation. An intramolecular electron transfer
then occurred leading to an enol ether radical cation that was
subsequently trapped by an alcohol nucleophile leading to the
desired product. A side product was generated from methanol
trapping of the sulfur radical cation. The ratio of products
appeared to be controlled by the Curtin−Hammett Principle.
The observation that the reaction was controlled by the
Curtin−Hammett Principle was not an isolated one.75,76 For
example, consider the preparative amide oxidation shown in
Scheme 10.76 In this reaction, an amide was oxidized in the
presence of an electron-rich aromatic ring with an oxidation
potential that was approximately 300 mV lower than that of the
amide. Once again, the initial oxidation took place at the group
with the lowest oxidation potential in order to generate a
radical cation intermediate.30 In this case, the cationic character
of that radical cation was not located in a position that allowed
for the rapid elimination of a proton. Hence, the aryl radical
cation oxidized the neighboring amide. This electron transfer
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Review
Scheme 10. Curtin−Hammett Control of an Amide
Oxidation
was “uphill” in energy (the amide has a higher oxidation
potential), but it led to an amide radical cation that was
perfectly situated for a subsequent proton elimination. That
elimination drained the equilibrium of radical cations toward
the formation of the amide oxidation product.
This observation that intramolecular electron transfer
reactions occur and that the reactions can be controlled by
the Curtin−Hammett Principle can suggest changes to the
reaction conditions used for an electrolysis reaction. For an
example, let us return to a carbon−carbon bond forming
variation on the reactions shown in Scheme 9. In this case
(Scheme 11), the initial reaction conditions (LiClO4 electro-
Scheme 11. Synthetic Application of the Curtin−Hammett
Principle
lyte) for the cyclization were not particularly successful.74
Methanol trapping of the dithiane radical cation competed with
the cyclization reaction. This problem was largely circumvented
by the use of a hydrophobic electrolyte in higher concen-
trations; a change that led to a significant increase in the desired
product. This observation is consistent with the generation of a
less polar double layer by the anode as described above in
Section 2.2. In this case, the less polar electrolyte excludes more
of the polar methanol solvent from the region surrounding the
anode. The result was a decrease in the rate by which methanol
trapped the radical cation and more time for the desired
intramolecular cyclization.
This use of the electrolyte to protect a reactive intermediate
from solvent trapping is not simply a trick for a laboratory scale
reaction. As mentioned earlier, the same approach is used for
the industrial scale adiponitrile process developed by Baizer
(Scheme 2).29−31 As a reminder, in the adiponitrile process a
cathodic reduction is used to generate a radical anion from
acrylonitrile that is then dimerized. The reaction is conducted
in water solvent without the radical anion being protonated. It
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Chemical Reviews
works because the tetraethylammonium tosylate used as the
electrolyte for the reaction forms a “greasy” double layer at the
cathode surface. This double layer excludes the water solvent
and provides the time needed for the dimerization. So, in both
Scheme 11 and the adiponitrile process the electrolyte in the
reaction is used to provide a protective environment for the
reactive intermediates generated at an electrode surface. This
“trick” can enhance an electrochemical reaction relative to a
nonelectrochemical counterpart, and it is a common “hidden”
feature of many anodic coupling reactions. Note how in the
chemistry highlighted in Schemes 7 and 9 alcohols effectively
trapped olefin based radical cations. This occurs without the
methanol solvent trapping the intermediates first. This outcome
is a result of the double layer excluding the methanol solvent
from the region of the reaction close to the anode. The
cyclizations are fast and occur close to the anode surface.
Hence, the radical cation traps the internal alcohol in the
relative absence of the methanol solvent.
To continue the story about solving the challenge presented
in Scheme 8, it is important to note that the suggestion in
Schemes 9 and 10 that intramolecular electron transfer
reactions led to ongoing mechanistic investigations that
eventually afforded the alternative solution currently used.
Consider, for example, the chemistry shown in Scheme 12.77 In
Scheme 12. N-Based Systems
this case, the potential for an intramolecular electron transfer
led to questions about whether the cyclization between an
electron-rich olefin and a sulfonamide anion should be
considered an N-based radical cyclization or the trapping of a
radical cation intermediate by an activated nucleophile. It was
known that generation of the anion greatly improves the yield
of the cyclization and that from the oxidation potentials shown
the initial oxidation took place at the sulfonamide anion. So did
the reaction involve a radical cation at all?
The answer to this question was derived from a competition
study in which a second nucleophile was added to the substrate
(Scheme 13).77,78 The subsequent oxidation led to the N-based
radical 41. If the electron transfer did not happen, then only the
N-based cyclization would have occurred, leading to product
48. However, if the intramolecular electron transfer did happen,
then radical cation 42 would be generated. Alcohol trapping of
the radical cation would lead to product 45. In practice,
products 45 and 48 were both formed, confirming that the
intramolecular electron transfer did occur. In addition, it turned
out that the alcohol trapping product 45 was the kinetic
product and that the sulfonamide trapping product 48 was the
thermodynamic product derived from the reaction.78 This
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Scheme 13. Competition Study
observation could be used to select the product generated. The
oxygen trapping product was favored by low temperatures and
high current densities that accelerated oxidation of the second
electron from 43, leading to the generation of cation 44. Once
44 was generated, the cyclization was no longer reversible. The
thermodynamic N-trapping product was favored by elevated
temperatures and lower current densities that slowed removal
of a second electron from 43. This provided more time for the
reaction to be reversible, a change that led to the generation of
48.
2.5. An Oxidative Radical Pathway
It was the observation that the trapping of a radical cation by an
alcohol moiety was fast that suggested a solution to the
challenge of simultaneously generating a six-membered ring
and a quaternary carbon with the use of an allylsilane trapping
group presented in Scheme 8. That solution called for a
substrate (49/ Scheme 14) that again had two trapping groups
Scheme 14. An Alternative Reaction Pathway
for the radical cation50.79 The first would be an alcohol that
would trap the radical cation and generate an intermediate
radical.51 Removal of the cation character of the reactive
intermediate in this manner reduces the possibility for
elimination reactions and provides more time for the desired
cyclization reaction. Based on the lessons learned during the
chemistry illustrated in Scheme 14, the temperature of the
reaction was kept cold in order to keep the alcohol cyclization
product closed. The result was a successful cyclization leading
to the quaternary carbon. At higher temperatures, some
elimination from radical cation 50 was observed, apparently
due to the reversibility of the alcohol cyclization reaction.
In summary, the chemistry highlighted in Scheme 14 shows
how our expanding understanding of radical cation mechanisms
can be used to resolve previous synthetic barriers. We had
concluded that anodic cyclizations leading to six-membered
rings and quaternary carbons could not be terminated with an
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allylsilane group. That conclusion was not correct. The reaction
just had to be channeled down a more productive pathway.
The use of physical organic chemistry to guide electro-
chemical reactions in this manner is not restricted to the
optimization of anodic olefin coupling reactions. It can be
utilized to develop and optimize electrochemical reactions on a
variety of platforms.
3. NEW METHODS FOR THE SYNTHESIS OF A
COMPLEX MOLECULAR SURFACE
One synthetic challenge that initially looks much different than
an oxidative cyclization is shown in Figure 3.
Figure 3. Signaling on a microelectrode array.
Depicted in the figure is an approach for monitoring the
binding of small molecules to biological receptors as the events
occur.80−98 This analytical method is conceptually simple. A
family of small molecules (represented by M1 and M2) is placed
or synthesized on an array such that each unique member of
the family is located by a unique, individually addressable
electrode or set of electrodes in the array. The array is then
immersed in a solution containing a redox mediator along with
a counter electrode. A current is passed through the solution by
oxidizing the redox mediator at the array and reducing it at the
remote electrode. This current can be measured at every
electrode in an array. A receptor is then added to the solution.
When it binds a molecule on the surface of the array, it impedes
the ability of the redox mediator to reach the surface of the
electrode below. This lead to a reduction in the current
measured at the electrode that can be used to monitor the
binding event as it occurs.
While the experiment is conceptually easy, it presents a
serious technological challenge. The arrays we use have over
12,000 electrodes per square centimeter of area.99,100 So how
does one selectively build or place each unique member of the
family of molecules to be studied by a unique, individually
addressable electrode or set of electrodes in the array? To put it
another way, how does one build a complex, addressable
molecular surface with control of spatial site-selectivity in
addition to all of the normal synthetic chemo-, regio-, and
stereoselectivities that one might need? The answer to this
question is derived by using the exact same approach applied
above for the development of anodic cyclization reactions.27
Once again, the success of an initial electron transfer is assured
by using a constant current electrolysis and allowing the
working potential of the electrode to float to match the needs
of whatever oxidation or reduction is required for a given
transformation. Once that electron transfer is complete, the
success of the reaction is dictated by understanding the physical
organic chemistry of the subsequent processes and channeling
the reactive intermediates generated down a productive
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pathway by controlling the relative rates of competing
reactions.
3.1. An Array-Based Synthetic Strategy
With that in mind, each array-based electrochemical reaction is
a competition reaction between two processes. The best way to
understand this is to initially focus on a single example (Scheme
15).101,102 In this example, a site-selective Suzuki reaction was
Scheme 15. Site-Selective Reactions on an Array
conducted on the array. The substrate for the reaction53 was
attached to a porous coating on the array that provides
attachment points for fixing molecules to the surface of the
electrodes. This surface must be permeable enough to reagents
so that the electrodes located below the coating can be used to
manipulate them. This reaction layer is an important part of the
system. But, since the focus of this review is on the use of
electroorganic synthesis, a more detailed discussion of the
surface will be left to elsewhere.103 With this backdrop, the
reaction itself was confined to selected electrodes in the array
by using those electrodes to generate the Pd(0)-catalyst needed
for the reaction. To this end, the array was treated with a
reaction medium that contained a Pd(II)-precursor for the
catalyst. The selected electrodes were used as cathodes to
reduce this precursor and generate the catalyst needed to form
product 54. The key for the site-selectivity of the reaction was
to make sure that the Pd(0) generated did not migrate to a
neighboring electrode that was not selected for the reaction.
This was accomplished by adding a “confining agent”55 to the
solution. A confining agent is a substrate for Pd(0) that will
oxidize the metal back to the inactive Pd(II) precursor. For the
reaction shown, this confining agent was allylacetate. The
allylacetate reacted with the Pd(0) in solution to form a π-allyl
palladium species that could no longer catalyze Suzuki
chemistry. The selectivity of the reaction on the array was
then optimized by controlling the relative rates of the two
transformations: one the generation of Pd(0) at the electrode
and two the destruction of Pd(0) in the solution above the
array. Changes in current could be used to adjust the rate of
Pd(0) generation. Changes in allylacetate concentration could
be used to adjust the rate of Pd(0) consumption. As an
alternative, air could be used as the confining agent.
With a mechanistic strategy in place, a large number of
synthetic reactions were developed for use on the arrays.27
These reactions have been reviewed, so a general discussion of
the chemistry will not be repeated here. Instead, a few examples
will be shown to highlight the types of opportunities the
chemistry can afford. First, the example above showed the use
of the array to conduct a reductive type coupling reaction. In
Scheme 16, two reactions are shown that highlight the use of
the array for oxidation reactions. Both were included to
emphasize the level of confinement that can be obtained. The
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Scheme 16. Array Based Oxidation Reactions
first reaction is an example of a site-selective Wacker
oxidation.104 It was included in order to illustrate how the
electrodes in an array can be used to manipulate a redox couple
in either direction. For the chemistry illustrated in Scheme 15,
the array was used to convert a Pd(II) precursor into a Pd(0)
catalyst. In this case, the array is used to convert a Pd(0)
precursor into a Pd(II) oxidant and then to convert the olefin
in substrate 56 into ketone 57 at selected electrodes in the
array. The reaction was confined by the addition of ethylvinyl
ether to the solution. The ethylvinyl ether underwent the
Wacker oxidation to generate ethyl acetate and prevent any
Pd(II) that escaped from the surface of the electrode from
reaching a neighboring electrode. In the image provided, the
electrodes are 43 μm across and are separated by only 35 μm.
In order to determine the site-selectivity of the reaction, the
ketone product was converted into a fluorescently labeled
amine.58 Clearly, either Pd(0) or Pd(II) can be confined nicely
on the array.
The second reaction shown is an example of a TEMPO
oxidation of an alcohol to an aldehyde on the array.105 The
reaction was confined to the selected electrodes with the use of
an electron rich benzylic alcohol that consumed any oxidant
that escaped from the surface of the electrode where it was
generated. The success of the reaction was determined by again
converting the product into a fluorescently labeled amine. This
reaction was important because the substrate for the reaction
was not a molecule placed on the surface of the electrodes but
rather an agarose coating that covered the entire surface of the
array. Hence, the substrate was not only located by the
electrodes but also located in between the electrodes.
Therefore, the image shows just how well the reaction can be
confined. Note how the fluorescence in the image is located
only over the electrodes and not in between the electrodes. The
confinement was perfect. This level of confinement was
obtained by manipulating the relative rates of TEMPO
generation (current flow) and TEMPO consumption (concen-
tration of the confining agent in solution).
The next reaction illustrated (Scheme 17) shows the cleavage
of a Diels−Alder product59 from the surface of the array.106
The Diels−Alder reaction was conducted on the array, and the
chemistry illustrated was used to remove it from the array so
that it could be fully characterized. In this example, the initial
dienophile for the Diels−Alder reaction was attached to the
array using a Kenner-type safety catch linker.107 After the
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Scheme 17. Acid Catalyzed Molecule Recovery
cycloaddition, acid was generated at every other electrode in
the array by using the electrodes as anodes to oxidize diphenyl
hydrazine. The acid generated catalyzed deprotection of the
Boc group in the linker which resulted in the formation of
lactam 60 and cleavage of the molecule from the surface. The
acid generated was confined to the selected electrodes with the
use of excess hydrazine. As in all such reactions, controlling the
relative rates of reagent generation at the electrode and reagent
consumption in the solution above the array allowed for
confinement of the reaction to the selected electrodes. The
approach shown in Scheme 17 is extremely useful because it
uses the electrodes in the array to conduct the cleavage
reaction. So, if in a subsequent binding study a drop in current
is recorded at a particular electrode in the array, then the same
electrode can be used to recover the molecule that gave rise to
the signal. In this way, the fidelity between a signal on the array
and characterization of the molecule that led to it is perfect.
3.2. Solving a Synthetic Challenge on an Array
Of course, not every reaction run using a synthetic method
works perfectly every time. This statement is just as true for a
reaction run on a microelectrode array as it is for a reaction run
in solution. When a reaction does not work as planned, the key
is to identify the parameters that control the reaction and think
about possible mechanisms. For an array-based example, let us
consider the Cu(I)-catalyzed “click reaction” between an
acetylene and an azide that was developed for use on either a
1K- or 12K-array (Scheme 18).108 For these reactions, the
Scheme 18. A Site-Selective Click Reaction on Agarose
Cu(I) catalyst was generated by the reduction of Cu(II) at the
selected electrodes and confined to those electrodes with the
use of oxygen. In the initial experiments, the arrays were coated
with an agarose polymer. The reactions were successful with
either the azide or the acetylene substrate fixed to the surface of
the array.
To our surprise, the closely related Cu(I) catalyzed addition
of an alcohol nucleophile to an aryl bromide on the array
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(Scheme 19) could only be confined on a 1K array. No
confinement of any kind was observed on a 12K array.109 So
Scheme 19. An Alcohol−Arylbromide Coupling Reaction
why did the confinement strategy for Cu(I) that worked so well
for the click reaction on both 1K and 12K arrays only work for
a 1K array for this reaction? In the past, questions of this nature
have frequently led synthetic chemists to conclude that
electrochemical reactions are not general. However, such
failures rarely have anything to do with the electrochemical
part of the reaction. As mentioned above in connection with
the olefin coupling reactions, the electron transfer at the
electrode almost always happens. The key is to look for the
difference between the reactions and to consider chemical
possibilities that might occur downstream of that electron
transfer. The same is true for an array-based synthetic method.
With this in mind, the differences between how reactions are
run on a 1K array and a 12K array was considered in
connection with how those differences might alter the course of
a mechanistic pathway. To this end, it was noted that 1K array
reactions are run by simply inserting the array into a beaker
along with a remote Pt-wire counter electrode. The reactions
are essentially divided cells since the remote counter electrode
is remote from the array. In contrast, 12K array reactions are
run in a thin film flow cell format. The reaction solution is
flowed in between the array and a Pt-electrode that is separated
from the array by 0.95 mm. The cell is for all practical purposes
an undivided cell. So the difference between the two formats
has to do with the counter electrode and its relationship to the
array. This is important because for a reduction reaction on the
array (the generation of Cu(I) from Cu(II)) the counter
electrode is an anode that generates acid. The closeness of the
anode and the cathode in the 12K array flow cell means that the
surface of the 12K array is much more likely to become acidic
when compared to a 1K array. Once that observation was made,
the rest was easy. For these initial experiments, the surface of
the array was coated with agarose. If that surface becomes
acidic, then oxonium ion formation and nucleophilic addition
to the anomeric carbon of the sugar can occur. For a click
reaction, this was not a problem because there was no
nucleophile in solution for the oxonium ion. This was not the
case for the alcohol addition chemistry. Under acidic
conditions, the nucleophile could be added to the agarose
polymer. This would afford the observed “loss of confinement”.
This background reaction only happened on the 12K array
because the 1K array is essentially a divided cell with little
communication between the two electrodes. The surface of the
array was not exposed to the acid generated at the counter
electrode.
With the problem identified, finding a solution was
straightforward. While the reaction could be run under more
basic conditions, the best solution was to change the polymer
surface from agarose to a nonsugar diblock copolymer that had
no anomeric carbons (Scheme 20).109 Once again, the key to
solving the challenge encountered was the identification of an
organic chemistry solution to the problem.
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Scheme 20. A Successful Reaction with an Alcohol
Nucleophile on a 12K Array
3.3. New Chemistry Equals New Bioanalytical Capability
For the sake of completion, it is important to note that the
development of new synthetic chemistry on the arrays is not
being done simply because it can be. New synthetic chemistry
on an array leads to new biology. As an illustration, consider the
Cu(II)-type Chan Lam coupling reaction shown in Scheme
21.83,110 In this example, Cu(II) generated at the selected
Scheme 21. Placement of an Acetylene on an Array
electrodes was used to trigger a reaction between a borate ester
based coating on an array and an acetylene. The reaction was
confined with the use of excess acetylene in solution (Cu(II)
effects an oxidative dimerization of the acetylenes that
consumes the oxidant). This reaction was developed so that
peptides already functionalized with acetylenes for use in click-
based bioconjugate studies could be placed directly on an array
without further modification. This enabled evaluation of their
binding properties to a selected target. Consider the experiment
shown in Figure 4.83 In this case, a v107 peptide developed for
PET-imaging studies was placed onto an array using the
acetylene initially added to the peptide so that it could be
coupled to a radiolabeling group. The binding of the peptide to
both human and murine VEGF protein (its intended biological
target) was then evaluated with the array. Because of the
synthetic focus of this review, the analytical study will not be
detailed here. However, the raw CV data for a block of 12
electrodes functionalized with the peptide is shown. The image
shows the CV data for a ferrocene carboxylic acid redox
mediator as the concentration of human VEGF receptor is
increased. The decrease in the total current measured (red
arrow) for each sweep directly coincided to the increase in
receptor. Note how the change in current was slow, then steep,
and then slow again, a change consistent with a normal binding
event.
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Figure 4. A v107-peptide on an array. The red arrow indicates the
drop in current as the VEGF receptor concentration is increased.
3.4. A Final Observation
One of the most important things to recognize about site-
selective reactions conducted on a microelectrode array is that
they are not electrochemical reactions. They are standard
synthetic reactions. Electrochemistry is simply used to generate
the reagent employed in the reaction so that it can be spatially
located on the array. In this way, the chemistry fits within the
general family of mediated or indirect electroorganic
reactions.111−113 This is particularly important to note since
electrochemical reactions can be scaled. In fact, the first
reaction run site-selectively on an array was the Wacker
oxidation reaction. This reaction was an exact duplicate of the
known preparative electrochemical reaction.114,115 It was simply
scaled down to the size needed on the array. Reactions
developed for the arrays can also be scaled in the opposite
direction. Take for example the two reactions shown in Scheme
22.
Scheme 22. Scalable Array Reactions
In both of these reactions, selected electrodes in an array
were used to generate a reagent that could be confined to the
surface of those electrodes. The method used was identical to
that described above. For the first reaction,105 CAN was
generated at the electrodes in order to trigger an oxidative
condensation reaction between a surface bound aryldiamine
and an aldehyde and then confined there with the use of an
electron-rich amide73 which reduced the CAN in the solution
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above the electrodes. This reaction can be scaled, and it was
selected for illustration here because it will be employed as a
preparative reaction in Part 4 of this review.
For the second reaction shown in Scheme 22, selected
electrodes in the array were used as cathodes to reduce
methanol and generate hydrogen gas. The hydrogen gas was
then employed for a site-selective hydrogenolysis reaction. This
was done because the Pd(0) catalyst needed for the reaction
could not be confined in the presence of hydrogen. Remember
that the use of Pd(0) on an array requires that the array be
treated with Pd(II) and then the Pd(II) reduced at the
electrodes. The presence of hydrogen gas interferes with this
cycle by reducing the Pd(II) in solution. Hence, the approach
taken. Once again, this example was selected because of the
preparative scale production of hydrogen gas to be discussed in
Part 4 of this review.
4. ELECTROCHEMISTRY, ENERGY ECONOMY, AND
THE VALORIZATION OF LIGNIN
The final challenge that will be addressed here, the valorization
of lignin, initially is much different than the others. At its core is
the disassembly of the lignin biopolymer into two building
blocks that can then be converted into a series of value added
synthetic building blocks (Scheme 23). The effort started with a
Scheme 23. Converting Lignin to Synthetic Building Blocks
solvolysis reaction that depending on conditions allowed either
of the two building blocks to be selectively extracted from
sawdust.116 While this work does not lie within the scope of this
review, the conversion of those building blocks into value
added materials does. That is because those transformations
frequently involve the use of a redox reaction. In fact, every one
of the synthetic building blocks shown in Scheme 23 that is
marked with an asterisk required a redox reaction for its
formation from lignin. It is as this point that electroorganic
synthesis can play a significant role in upgrading lignin building
blocks because it allows for those redox reactions to be
conducted in a more sustainable manner. As an example, in
Scheme 24 a scaled version of the mediated electrochemical
oxidative condensation initially developed for use on an array
(Scheme 22a)105 is illustrated.
The reaction allows for the generation of benzimidazole 75
in just two steps from raw pine-sawdust (the source of 74).116
Reactions of this type offer an opportunity for sustainability
because they channel the stoichiometric reduction reaction
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Scheme 24. A Preparative Oxidative Condensation To test this approach, the anodic oxidation of an alcohol was
used to generate hydrogen gas at the cathode (Scheme 25).116

Scheme 25. Oxidations and the On-Site Generation of

Hydrogen Gas at the Cathode

required for any oxidation to the formation of hydrogen gas at

the cathode, and they can be driven with sunlight and the use of
a simple photovoltaic (or any other sustainable source of
electricity).117 The same argument can be made for any of the
oxidation reactions needed to form the new synthetic building
blocks shown in Scheme 23.
4.1. Pairing Synthetic Transformations
Yet while the reaction is optimal in terms of atom economy, it
is not so in terms of energy economy. This is also true for any
of the oxidation reactions conducted above. That is because
while the reaction at the counter electrode generated a benign
product in hydrogen gas, it requires energy to do so. Consider
the energy diagram shown in Figure 5 that shows the total
energy needed to run an electrolysis cell.

Rather than let the hydrogen gas escape as a benign byproduct,

Figure 5. Energy requirements of an electrolysis.
For the reaction shown in Scheme 24, only the energy
highlighted in green was used for a productive transformation.
The energy for the reduction was thrown away.
This observation has been made numerous times in the past,
and it has led to the development of paired electrochemical
reactions.4,118−121 In a paired electrochemical reaction, both the
oxidation at the anode and the reduction at the cathode are
used for productive reactions. The best known example of this
is the chloro-alkali process that converts seawater into chlorine
gas and sodium hydroxide.122 Numerous other examples have
been forwarded and reviewed. Most of these reactions take
advantage of two reactions that are ideally paired and target
particular products. However, the array chemistry described
above suggested something else. For the reaction highlighted in
Scheme 22b, the electrolysis was not used to make a particular
product but rather to conduct the site-selective synthesis of a
reaction substrate. In fact, all of the reduction reactions on the
arrays are used to make substrates, chemical reagents, or
catalysts. So, in principle an oxidation does not need to be
paired with a specifically matched reaction generating a
particular product. Instead, it can be paired with the synthesis
of a whole range of chemical reagents, substrates, and products.
4828
it was trapped and then used to conduct either a hydrogenation
reaction to form 79 or a hydrogenolysis reaction to form 81.
The reaction setup for these transformations was very simple.
The electrolysis reaction was run in a three neck round-bottom
flask, one end of a cannula was inserted into the head space
above the reaction in this flask, and then the other end of the
cannula was inserted into a second flask so that the hydrogen
gas generated from the electrolysis could bubble through the
desired hydrogenation or hydrogenolysis reaction. A balloon
was added to the flask used for the reduction in order to avoid a
buildup of pressure in the system. The electrolysis reaction was
conducted as normal. The hydrogen gas generated at the
cathode diffused over to the second flask where the reduction
reaction occurred. All of the reactions proceeded in high yield.
It is important to note that a paired electrolysis of this nature
is not restricted to a specialized, matched pairing of reactions.
As always, in a constant current electrolysis the working
potential at the electrodes (both anode and cathode) floats to
match the potential of the substrates in solution. Hence, any
two reactions can be paired. As an illustration, consider the
paired reactions shown in Scheme 26. In this case, an oxidative
condensation reaction to form 75 was paired with the
production of carbon monoxide from carbon dioxide.123 The
oxidation reaction proceeded in a fashion consistent with the
Scheme 26. A Second Paired Electrolysis
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earlier reactions, and the reduction of carbon dioxide proceeded oxidation of groups in solution (like the aromatic product) with
with high efficiency. a higher oxidation potential than the thioaminal. The key then
4.2. Mechanism and the Optimization of Current Flow is to make sure that the reaction has enough of the thioaminal
present.
While the reactions are easy to demonstrate, how does one
In principle, this should not have been a problem. Even the
optimize a paired electrolysis when the initial reaction is less
higher currents used for the reaction were not so high as to
that ideal? It was for this reason that the reaction shown in
cause a problem with the amount of aldehyde and thioamine
Scheme 26 was included here. As a proof-of-principle, the
used for the transformation. However, the higher current might
reaction worked well. However, it was fundamentally flawed if
be a problem if the amount of aldehyde and thioamine use led
the goal of the process was to produce useful amounts of
to only a small amount of the thioaminal. After all, there was no
carbon monoxide at the cathode.124 A more careful look at the
guarantee that the equilibrium that formed thioaminal
conditions needed for the oxidative condensation highlights the
intermediate 82 favored the formation of that intermediate.
problem. Consider again the reaction shown in Scheme 24 and
In the original reaction there was no driving force provided for
not that the current used for the reaction is highlighted in red.
this equilibrium. This omission was addressed (Scheme 28) by
This was done to call attention to the fact that the optimized
reaction conditions employed only 4 mA of current. Higher
current levels led to overoxidation of the product. Thus, the Scheme 28. A Plan To Drive the Initial Equilibrium
paired electrolysis shown in Scheme 28 was also run at a
current of 4 mA. This allowed for the production of the desired
product in a high yield, but it also meant that the rate of carbon
monoxide generated at the cathode was very low. So how can a
paired electrolysis of this type be optimized so that more
current can be passed through the cell and in so doing carbon
monoxide can be generated at the cathode at a faster rate? As in
the earlier reactions, the key to optimizing this electrochemical
reaction did not rest with the electron transfer processes but
rather with understanding the organic chemistry that governed
the transformation downstream of that event. For this
understanding, it was critical to note that the reaction did
afford good yields of the product without overoxidation at
lower current values. Consider the proposed mechanism for the
reaction highlighted in Scheme 27. The reaction begins with
stirring the reaction mixture over MgSO4 for 24 h. This
Scheme 27. Proposed Reaction Mechanism removed water, driving the initial equilibrium to form the
thioaminal before conducting the oxidation. The change in the
reaction worked well, and even at higher currents the reaction
afforded none of the overoxidation product. However, while the
reaction was clean and formed only the desired product and
recovered starting material (Scheme 29), the current efficiency

Scheme 29. Solution

the formation of thioaminal 82 that is then oxidized to form a

radical cation intermediate.83 The loss of a proton followed by a
second oxidation and loss of a second proton leads to the new
aromatic ring. For this reaction to form the product in high
yield at low current densities, thioaminal 82 must have a lower
oxidation potential than the product. Otherwise, the reaction
would always lead to the overoxidation product. With the low
current, there is enough of the thioaminal to consume the
current and hence the working potential of the anode remains
consistent with that of the thioaminal. With higher currents
there is more of a demand for substrate at the surface of the
anode. If this demand is not met, then the working potential of
the electrode will climb, leading to a loss of selectivity and the
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of the process was very poor. Only 38% conversion of the
starting material was realized when the theoretical amount of
current was passed through the reaction.
Fortunately, this was a mechanistic paradigm we had seen
before. When dealing with the formation of C-glycosides125 and
the generation of lactones from carboxylic acid derivatives,126 it
became evident that when a radical or radical cation
intermediate generated at the anode in an undivided cell was
very stable it would survive long enough to be rereduced at the
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cathode. This led to poor current efficiencies. The potentially
stable amine radical cation generated in the current reaction83
fits nicely into this picture.
There are two possible solutions to this problem. One is to
accelerate decomposition of the radical cation, and the second
is to divide the cell so that the radical cation cannot reach the
cathode. In this case, dividing the cell worked perfectly. The
reduction in the cathode chamber again generated carbon
methoxide from carbon dioxide in an efficient manner while in
the anodic chamber complete conversion of the starting
materials into the benzthiazole product could be accomplished
in a 71% isolated yield with a current of 40 mA and no
overoxidation.
So even with a more complicated paired electrochemical
reaction, the “secret” to its optimization was a consideration of
the types of physical organic chemistry questions that are
common for the optimization of any synthetically useful
organic reaction. Once again, the working potential at both
electrodes automatically adjusted to the potentials needed for
the electron transfer reactions. The key was optimizing the
substrate concentration available for the reaction and then
protecting the reactive intermediate generated from reduction.
5. CONCLUSIONS
There are two main themes concerning the use of organic
electrochemistry in synthesis that have arisen during the studies
outlined above and our 30 years of exploring electroorganic
synthesis. The first is that for the optimization of electroorganic
reactions, fixing the problems encountered is most often about
the organic chemistry involved. One of the true ironies of the
development of organic electrochemistry through the years is
that organic chemists (including our group) initially struggled
because we were so focused on the electrochemistry that we did
not always do the organic chemistry part of things well. An
electroorganic reaction is an organic reaction. The “rules of the
game” needed to optimize such a transformation are not new
but rather the same rules we have used for years.
The second important lesson is just how versatile a constant
current electrolysis is as a synthetic tool. If we just consider the
anodic side of the electrolysis, through the years we have
oxidized substrates that range in potential from +0.6 V to +2.3
V (relative to Ag/AgCl), recycled chemical oxidants such as
TEMPO, Pd(II), Cu(II), Ru(VII), Mn(VII), Os(VIII), Ce(IV),
Sc(III), and amine radical cations, and paired a number of those
reactions with the hydrogenation of double bonds, the
hydrogenolysis of aryl ethers, and the reduction of carbon
dioxide. In each case, we have simply let the potential of the
anode float to where it was needed. The exact same approach
can be used to conduct reactions with everything ranging from
a battery or simply photovoltaic to preparative electrolysis
setups to a microelectrode array. Reactions run on a
microelectrode array have been scaled over 12 order of
magnitude and vice versa. It is difficult to imagine any other
single method that would have allowed us to explore the range
of chemistry examined during these studies.
AUTHOR INFORMATION
ORCID
Kevin D. Moeller: 0000-0002-3893-5923
Notes
The author declares no competing financial interest.
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Biography
Kevin D. Moeller joined the chemistry faculty at Washington
University in St. Louis in 1987 and has been Professor of Chemistry
since 1999. He was born in Scranton, Pennsylvania, on November 25,
1958, earned a BA degree in Chemistry from the University of
CaliforniaSanta Barbara in 1980 and then his Ph.D. degree in
Organic Chemistry (Professor R. Daniel Little) from the same
institution in 1985. He was an NIH Postdoctoral Fellow at the
University of WisconsinMadison (Professor Barry M. Trost) from
1985 to 1987. His long-standing research interests center on the
interplay between electrochemistry and organic synthesis. These
efforts have used electrochemical methods to study reactive radical
cations, synthesize complex molecules, construct complex, addressable
molecular surfaces, and develop more atom and energy economical
approaches to redox chemistry. In 2016, he received the Manuel M.
Baizer Award in Organic and Bioorganic Electrochemistry from the
Electrochemical Society. He can be reached at moeller@wustl.edu.
ACKNOWLEDGMENTS
We thank the National Science Foundation (CBET-1262176,
CHE-1240194, and CHE-1463913) for their generous support
of the work outlined above.
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(76) For an earlier example involving the anodic oxidation of an
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Reactivity of Radical Cations: Experimental and Computational
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K. D. New Methods for the Site-Selective Placement of Peptides on a
Microelectrode Array: Probing VEGF − v107 Binding as Proof of
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electrodes (rectangular cells) = 245.3 and 337.3 μm; 12K slide:
diameter = 44 μm; Distance between the Pt-electrodes (square cells) =
33 μm..
(100) Microelectrode arrays and the power supply for addressing
them can be purchased from CustomArray, Inc., 18916 North Creek
Parkway, Suite 115, Bothell, WA 98011 (www.CustomArrayInc.com).
For a detailed discussion of how the array reactions are run see the
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(106) Bi, B.; Maurer, K.; Moeller, K. D. Building Addressable
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Angew. Chem., Int. Ed. 2009, 48, 5872−5874.
(107) Bi, B.; Huang, R. Y. − C.; Maurer, K.; Chen, C.; Moeller, K. D.
Site-Selective, Cleavable Linkers: Quality Control and the Character-
ization of Small Molecules on Microelectrode Arrays. J. Org. Chem.
2011, 76, 9053−9059.
(108) Bartels, J. L.; Lu, P.; Walker, A.; Maurer, K.; Moeller, K. D.
Building Addressable Libraries: A Site-Selective Click-Reaction
Strategy for Rapidly Assembling Mass Spec Cleavable Linkers. Chem.
Commun. 2009, 37, 5573−5575.
(109) Bartels, J. L.; Lu, P.; Maurer, K.; Walker, A. V.; Moeller, K. D.
Site-selectively Functionalizing Microelectrode Arrays: The Use of
Cu(I)-Catalysts. Langmuir 2011, 27, 11199−11205.
(110) For array based Chan-Lam coupling reactions see: Graaf, M.
D.; Moeller, K. D. Chemoselectivity and the Chan-Lam Coupling
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(111) Ogibin, Y. N.; Elinson, M. N.; Nikishin, G. I. Mediator
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(113) For a review of electrochemistry as a “green”-method see:
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System Consisting of Palladium Complex and Tri(4-bromophenyl)-
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(116) Nguyen, B. H.; Perkins, R. J.; Smith, J. A.; Moeller, K. D.
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Building Blocks from Sawdust. J. Org. Chem. 2015, 80, 11953−11962.
(117) Nguyen, B. H.; Perkins, R. J.; Smith, J. A.; Moeller, K. D.
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(118) “Toward paired and coupled electrode reactions for clean
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DOI: 10.1021/acs.chemrev.7b00656
Chem. Rev. 2018, 118, 4817−4833