Miniaturization and Combinatorial Approach in Organic

Review Cite This: Chem. Rev. 2018, 118, 5985−5999

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Miniaturization and Combinatorial Approach in Organic Electrochemistry Koichi Mitsudo, Yuji Kurimoto, Kazuki Yoshioka, and Seiji Suga*

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Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan ABSTRACT: Recent advances in electro-organic chemistry involving miniaturization, integration, and combinatorial chemistry were reviewed. Microelectrode array technology for site-selective electro-organic reactions and addressable libraries provides a direct and unlabeled method for measuring small-molecule−protein interactions. Electrochemical systems using solid-supported bases and acids (“site separation”) can realize electrolysis without the addition of supporting electrolytes. Well-designed “bipolar electrodes” have enabled the production of patterned gradient polymer brushes and microfibers. For the display of combinatorial organic electrochemistry, batch and flow electrolysis systems for the optimization and screening of electro-organic reactions as well as the building of chemical libraries for organic compounds are described. peptide arrays was developed by Geysen.13−15 This method has been used to synthesize chemical libraries in combination with an automated parallel synthesizer.8 To construct a nonpeptide organic compound library, a very unique binary code tag was reported by Still, which records the reaction history of each bead as a solid support.16,17 In the field of electrochemistry, a microelectrode or ultramicroelectrode, which is a very small sized electrode that offers large diffusion layers and small overall currents, is widely used in the research on electrophysiology.18−33 Microelectrode arrays (or multielectrode arrays) with multiple plates work as neural interfaces connecting neurons to electronic circuitry.34,35 The combination of analytical chemistry and micronization has led to remarkable progress, and efforts have been made to apply micronization to the field of electro-organic chemistry. Over the past two decades, studies on very unique subjects, such as combinatorial electrosynthesis, site-selective synthesis, synthesis using a solid support acid/base, and device-assisted synthesis (microreactor, miniaturized bipolar electrode, and so on), have been reported. It can be time-consuming to find the best reaction conditions in electrode organic chemistry, since many parameters must be evaluated, such as the electrode material, the electrolyte, the solvent, the potential, and the current. If combinatorial screening of the reaction parameters is enabled, an optimal condition could be identified in a short time. Combinatorial synthesis can also be performed in a flow system because electricity (electrons) can act as a reagent (oxidant or reductant) and no chemical residues are produced. Thus, the combination of electrochemistry and a combinatorial approach should be advantageous. Unlike ordinary organic synthesis using a flask or other glassware, organic electrolysis is a synthetic method that strongly depends on the used equipment, and artifacts associated with the equipment inhibit the efficient production of the

CONTENTS 1. Introduction 2. Miniaturization in Organic Electrochemistry 2.1. Site-Selective Reaction and Addressable Libraries 2.2. Site Separation 2.3. Architecture Using Bipolar Electrodes 3. Combinatorial Organic Electrochemistry 3.1. Combinatorial Batch Synthesis 3.2. Combinatorial Flow Synthesis 4. Conclusion Associated Content Special Issue Paper Author Information Corresponding Author ORCID Notes Biographies Acknowledgments References

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1. INTRODUCTION In the 1990s, combinatorial chemistry, which enables the creation of libraries of various novel compounds, became a major trend in chemical research. This epoch-making technology was used for high-throughput screening in drug discovery1−8 and in the discovery of innovative materials.9−12 From a technological point of view, advances in combinatorial chemistry are related to miniaturization and automation (based on robotics), which have seen dramatic advances in the past several decades. The “split and mix synthesis” for preparing peptide libraries was developed on the basis of solid-phase synthesis, and “parallel synthesis”, which takes place on small plastic pins, the ends of which are coated with a solid support, for the preparation of © 2018 American Chemical Society

Received: September 3, 2017 Published: May 25, 2018 5985

DOI: 10.1021/acs.chemrev.7b00532 Chem. Rev. 2018, 118, 5985−5999

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Scheme 1. First Addressable Libraries Using Electrochemistry and Pd Catalysts on Microelectrode Arrays

Scheme 4. Addressable Libraries for an Electrochemical Mizoroki−Heck Reaction on a Chip

Scheme 2. Addressable Molecular Libraries: Chip-Based Reductive Amination Reactions

Scheme 5. Addressable Libraries Based on the Site-Selective Suzuki−Miyaura Cross-Couplings on Microelectrode Arrays

Scheme 3. Site-Selective Synthesis of Coumarin Derivatives

reaction system. As mentioned above, a microelectrode has large diffusion layers and small overall currents, which should help to reduce the ohmic resistance. Thus, miniaturization of the electrochemical apparatus should make electrochemical optimization much more enhanced compared to that with traditional equipment. In this review, we present unique methods for electro-organic synthesis, mainly grounded in combinatorial and device-assisted approaches, as well as miniaturization.

molecular library can be attached to its surface. In addition, the microelectrode array system offers an unlabeled and direct methodology for measuring molecule−protein interactions. For the functionalization of a microelectrode array system, tools for the site-selective attachment of molecules to the surface of the electrode are needed. A solution of this issue is the use of eletrolysis to trigger chemical reactions.36 In 2004, Moeller reported addressable libraries to control the reaction sites using electrochemistry to generate active Pd(II) species.37 A small chip with an array of individually addressable platinum electrodes was coated with a porous membrane polymer and reacted with the N-hydroxysuccinimide ester (Scheme 1). The substrate was concentrated on the chip close to the electrodes by a reaction catalyzed by a base, which was generated from vitamin B12 by electroreduction.38 Selected electrodes were held at a potential

2. MINIATURIZATION IN ORGANIC ELECTROCHEMISTRY 2.1. Site-Selective Reaction and Addressable Libraries

Advances in the development of microelectrode arrays promote their application in various biological assays. One advantage of a microelectrode array system is that the electrodes in the array are individually addressable, which means that a member of a 5986


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Scheme 6. Addressable Libraries Using an N-Acyliminium Ion Intermediate

Scheme 9. Addressable Libraries Using the Click Reaction Strategy

Scheme 7. Addressable Libraries for the Site-Selective HeteroMichael Reaction

Scheme 10. Diblock Copolymer for the Porous Layer of a Microarray System

Scheme 11. Addressable Molecular Libraries Using the Diblock Copolymer as a Porous Reaction Layer

Scheme 8. Addressable Libraries Using Lewis Acid-Catalyzed Reactions

counter electrode were placed into 0.5 M Et4NOTs and CH3CN/H2O (7/1) solution including catalytic amounts of Pd(OAc)2 and (4-BrC6H4)3N. A pulse electrolysis was carried out for the oxidation. After electrolysis, the generated ketones were treated with 2,4-dinitrophenol (2,4-DNP), and then the chip was incubated with bovine serum albumin (BSA) in phosphate-buffered saline (PBS) including a rabbit antibody bearing a fluorescent probe. Subsequently, the chip was washed with PBS buffer and analyzed by an epifluorescence microscope. The resulting image shows site-selective formation of the desired compound at the selective electrodes. As another approach, Moeller used the site-selective electrooxidation of alcohols to afford aldehydes followed by an

difference versus the Pt counter electrode, and then the potential difference was turned off for several cycles. After the reaction, remaining free hydroxyls on the chip were capped by the reaction with acetic anhydride using a similar electrogenerated base. A Wacker-type oxidation was then conducted by reversing the electrode polarity at selected electrodes.39−41 The chip and 5987


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With the use of these arrays for probing 3D binding preferences of biological receptors, the stereochemistry of the molecules on the arrays is important. Therefore, an approach that enables the examination and characterization of molecules on the array is required. A solution of this issue is the development of linkers that recover molecules site-selectively. For that, a linker is required that can be cleaved electrochemically (Scheme 12).57−59 Moeller also developed a “safety-catch” linker to cleave molecules siteselectively from microelectrodes in an array. Moeller and co-workers recently extended their microelectrode array strategy to a variety of reactions,60−68 in particular to the attachment of peptides. Once a peptide is attached to an electrode, it can be detected in real time (Scheme 13).

Scheme 12. Microelectrode Array System with Site-Selective Cleavable Linkers

2.2. Site Separation

While electro-organic synthesis should be a green sustainable process, electrochemical reactions usually require the addition of supporting electrolytes to ensure that the solvents have sufficient electrical conductivity. To solve this problem, Tajima and Fuchigami developed an electrochemical reaction using solid-supported bases and methanol (Scheme 14).69,70 In this system, the protons derived from methanol carry an electric charge, and methanol acts as not only a solvent but also a supporting electrolyte generated in situ. Methoxylation of the Scheme 13. Site-Selective Introduction of Peptides to a Microelectrode Array

electro-reductive amination reaction using fluorophore-labeled amines (Scheme 2).42 By repeated electrolysis using different amines, a site-selective fluorescent pattern of different colors was obtained. These results indicate that effecting reductive aminations is available by a site-selective strategy, which represents a novel method for locating molecules on the surface of a chip. Moeller also reported the synthesis of coumarin derivatives using a microelectrode array system (Scheme 3).43 A binding assay of the anticoumarin antibody was conducted by monitoring the current. Several other reactions have also been shown to be suitable for constructing libraries, such as the Mizoroki−Heck reaction (Scheme 4),44 Suzuki−Miyaura coupling (Scheme 5),45 removal of a tert-butoxycarbonyl (Boc) group,46 the generation of active N-acyliminium ion intermediates (Scheme 6),47 a heteroMichael reaction (Scheme 7),48 Lewis acid-catalyzed reactions (Scheme 8),49 and Cu(I)-catalyzed Huisgen cycloadditions (click reactions) (Scheme 9).50,51 The progress of these reactions on the microelectrodes was determined by fluorescence techniques. For optimization of the reaction conditions, and to obtain more information about the reactions, Moeller used the time-of-flight secondary ion mass spectrometry (TOF-SIMS) technique. The important point of this method is the use of a mass spectrometry cleavable linker.52,53 In their microelectrode arrays, they coated the electrodes with a porous layer such as agarose or sucrose,54,55 but such sugar layers have drawbacks. The agarose polymer is unstable, and the sucrose polymer is easily polyhydroxylated. As a solution to this problem, Moeller developed a diblock copolymer as a porous layer (Scheme 10).56 The surface of the coating was dry, and the porous cross-linked polymer on the microelectrode was easily obtained by irradiation using a Hg lamp. Several site-selective reactions were carried out on the microelectrode array (Scheme 11). 5988


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Scheme 13. continued

Scheme 15. Anodic Acetoxylation with a Solid-Supported Base

Scheme 16. Mixed-Kolbe Electrolysis Using a Silica GelSupported Base

Scheme 17. Kolbe Carbon−Carbon Coupling Electrolysis Using a Silica Gel-Supported Base

Scheme 18. Non-Kolbe Electrolysis with a Site-Separation System

Scheme 19. Anodic Fluorination Using a Silica Gel-Supported Acid

Scheme 14. Anodic Methoxylation with a Solid-Supported Base

Figure 2. Site-separation strategy using a solid-supported acid.

addition of supporting electrolytes and (ii) facile isolation of the product by simple filtration. The solid-supported bases could be used repeatedly in subsequent reactions. Tajima and Fuchigami also applied this strategy to various anodic reactions,71−86 such as the anodic acetoxylation reaction (Scheme 15),71,72 mixedKolbe electrolysis (Scheme 16),73 Kolbe C−C bond coupling (Scheme 17),74 and non-Kolbe-type electrolysis (Scheme 18).75 Tajima and Fuchigami used a solid-supported base to promote these reactions. In all cases, the solid-supported base could be recovered by filtration and it could be reused again. Tajima and

Figure 1. Site-separation strategy using a solid-supported base.

substrate proceeded smoothly with solid-supported bases (Figure 1). The advantages of this “site-separation” system are that it involves (i) an electrolytic system that does not require the 5989


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Figure 3. Bipolar electrode system using a poly(3-methylthiophene) film. Reprinted with permission from ref 92. Copyright 2010 WileyVCH Verlag GmbH & Co. KGaA, Weinheim.

Figure 5. ac−bipolar electropolymerization of EDOT. Reprinted with permission from ref 99. Copyright 2016 Nature Publishing Group.

Figure 4. Photographs of the polythiophene film produced by bipolar patterning. Reprinted with permission from ref 92. Copyright 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Fuchigami also reported electro-oxidative reactions using solidsupported acids. They developed an electrochemical system for oxidative fluorination based on the site-separation strategy using the solid-supported acids (Scheme 19).76 This exchange promotes the generation of 2,6-lutidine hydrofluoride, which works as not only a fluorinating reagent but also a supporting electrolyte of the reaction (Figure 2).

Figure 6. Experimental setup for SAEP: (a) before assembly; (b) after assembly. (c) Experimental setup for SAEP. Reprinted from ref 102. Copyright 2010 American Chemical Society.

Inagi and Fuchigami also demonstrated an application of the bipolar electrode as a patterning method for conducting polymer films.95 The local application of an anodic potential to polythiophenes on a bipolar electrode realized local electrochemical doping, which resulted in drawing of complex patterns in a sitecontrolled manner on the polymer “canvas”. Recently, Inagi reported several other applications of the bipolar strategy for organic synthesis.96−101 For instance, they reported a click-type reaction using a bipolar electrode,96 and they also developed an electrochemically mediated atom transfer radical polymerization (ATRP) using bipolar electrolysis to realize the fabrication of patterned and gradient polymer brushes.97 They also synthesized microfiber networks of poly[3,4-(ethylenedioxy)thiophene] (PEDOT) by electrolysis using a bipolar strategy and ac (Figure 5).99

2.3. Architecture Using Bipolar Electrodes

A bipolar electrode, which is an electrode that works as both an anode and a cathode is an isolated conducting material in a solution placed in an electric field. Bipolar electrodes make it possible to study chemical reactions on the isolated electrode.87−90 In 2010, Inagi and Fuchigami used a U-type cell system containing a bipolar electrode to pattern conducting polymers (Figure 3).91−94 They demonstrated patterning by the use of electrochemical doping and electrochemical chlorination of polythiophene films. This method can provide conducting polymer films with gradient functionality (Figure 4). In this bipolar system, the polymer does not need to be attached to a circuit. 5990


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Scheme 20. Parallel Electrosynthesis Using the Spatially Addressable Electrolysis Platform (SAEP)

Scheme 21. Anodic Methoxylation of Carbamates Using Si−Piperidine

Figure 8. (a) Setup of a parallel system for electrochemical synthesis developed by Waldvogel. (b) Cross-section of undivided and divided cells. (c) Cross-sections of the carousels. Reprinted from ref 112. Copyright 2015 American Chemical Society.

Figure 7. Fuchigami and Tajima’s experimental setup for parallel anodic methoxylation.

3. COMBINATORIAL ORGANIC ELECTROCHEMISTRY

methoxylated products were obtained only by filtration and following concentration. A highly evolved system for parallel electrochemical synthesis was reported by Waldvogel and co-workers.112 They used eight undivided cells (5 mL) with two electrode holders for each, which were placed on a steel block having eight cavities (Figure 8). All of the electrodes were connected to a dc power source with multichannels. They also developed a similar system with six divided cells (6 mL) . The temperature of the stainless block can be controlled. The galvanostat (dc power source) had a coulomb meter, and the current and voltage were adjustable for each channel. They applied this system to a wide variety of electrochemical transformations (e.g., electrochemical oxidative crosscoupling,113−115 dehalogenation reactions,116 deoxygenations,117−119 and domino-type oxidation−reduction reactions) (Scheme 22).120 Yudin, Tajima, and Waldvogel generated cationic or anionic intermediates in situ in each cell simultaneously and reacted them with coexisting reagents. These methods require as many electrochemical cells as the number of reactions. Another approach was reported by Yoshida and Suga. They generated and accumulated cationic species as a “cation pool” using low-temperature

3.1. Combinatorial Batch Synthesis

The first combinatorial approach in electro-organic synthesis was reported by Yudin in 2000.102,103 Yudin reported parallel electrochemical synthesis with a spatially addressable electrolysis platform (SAEP). He designed a parallel electrolysis platform with 16 cells that were equipped with a graphite rod anode and a stainless steel cathode, which were connected with a dc supply (Figure 6). All cells could be subjected to constant-current electrolysis simultaneously. Yudin carried out the electrochemical α-alkoxylation of carbamates and sulfonamides (Scheme 20). These synthetically useful transformations are well-known as the Shono oxidation.104−109 SAEP could be used for screening both the conditions and the scope of the reactions. In 2001, Yudin also applied this method to the electroreductive dimerization of imines for the synthesis of 1,2-diamines (Scheme 20).110 Tajima also reported a parallel anodic memoxylation of carbamates with silica-supported piperidine (Scheme 21).111 The electrolysis was carried out under a constant current in the five connected undivided cells (Figure 7). Five different substrates were methoxylated in a single electrolysis. The 5991


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Scheme 22. Electrochemical Transformations by the Parallel System Developed by Waldvogel

Figure 9. Concept of the cation pool method for the formation of a carbon−carbon bond.

Scheme 23. Generation of Iminium Cation Pools and Their Reactions with Nucleophiles Figure 11. Example of a cation flow system.

easily oxidized under oxidative conditions can also be used for these reactions (Scheme 23).121 Yoshida and Suga applied the cation pool method to both conventional organic syntheses and combinatorial parallel syntheses in the solution phase with a robotic synthesizing system.121 The substrate was oxidized electrochemically at lowtemperature for the generation of a cation pool, and then it was divided into several portions (Figure 10). The portions were reacted with different nucleophiles (B1−B5) to afford the desired compounds in each vessel of the synthesizer. Various products could be obtained by the use of different nucleophiles. 3.2. Combinatorial Flow Synthesis

Microflow systems have been the focus in the field of organic synthesis since they can realize precise temperature control and efficient mass transport.157−179 The marriage of flow chemistry and electrochemistry is certainly attractive because handling of a highly reactive intermediate

Figure 10. Parallel combinatorial synthesis based on the cation pool method.

electrolysis (Figure 9).121−156 After electrolysis, the cation pool can be reacted with several nucleophiles. Nucleophiles that are 5992


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Scheme 24. Electro-Oxidative Bond Formation of Carbamates Using Cation Flow

Scheme 26. Electro-Oxidative Allylation Using a Thin-Layer Flow Cell

Figure 12. Cation flow system for sequential and continuous combinatorial synthesis.

Figure 15. Chemoselective reduction using a parallel laminar flow electrochemical system. Reprinted with permission from ref 190. Copyright 2010 The Royal Society of Chemistry.

examples that noticeably demonstrated the advantage of the microflow system are shown below. In 2001, the “cation flow method” by the use of a new electrochemical microflow system was developed by Yoshida and Suga. Flow cells were constructed by diflone and stainless steel with an anode (carbon felt) and a cathode (Pt) (Figure 11). The two compartments of the electrochemical reactor were divided by a Poly(tetrafluoroethylene) (PTFE) membrane filter. The electro-oxidation at low temperature gave a cationic intermediate, which was immediately allowed to react with a nucleophile to give rise to the formation of the final coupling product (Scheme 24). The “cation flow” system readily realizes both sequential and continuous combinatorial approaches for the syntheses of several products by simply changing the flow pathway (Figure 12) Atobe developed a thin-layer microflow cell for electrosynthesis (Figure 13).184−195 In 2005, Atobe presented the use of the electrochemical thin-layer microflow cell for the synthesis of 2,5-dihydrofuran (Scheme 25). The striking feature of the reaction system is that it can be conducted without any electrolyte.184 In 2007, Atobe designed a laminar flow system using an ionic liquid as a reaction medium (Figure 14), and he also used the strategy for an electrochemical allylation (Scheme 26).187 The injection of two different solutions from the two inlets forms a liquid−liquid phase, and mass transfer between the two phasees occurs only by diffusion. Therefore, the substrate is oxidized predominantly, and the procedure prevents the nucleophile from being oxidized. Thus, the generated carbocation diffuses into the ionic liquid solution, and the reaction with the nucleophile occurs. It is worth noting that the system realizes the reactions of electrochemically generated carbocations with carbon nucleophiles bearing lower oxidation potential. In 2010, Atobe developed an electroreductive allylation reaction of carbonyl compounds with a thin-layer flow reactor

Figure 13. Thin-layer flow cell system designed by Atobe. Reprinted with permission from ref 184. Copyright 2005 Elsevier.

Scheme 25. Cation Flow System for the Electro-Oxidative Bond Formation

Figure 14. Concept of a parallel laminar flow reactor.

generated in an electrochemical reaction is much easier with a microflow system than with a batch system.180−183 Characteristic 5993


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in a chemoselective manner (Figure 15).190 The key points of this reaction are selection of the corresponding cathode material and the use of a suitable flow mode. Chemoselective reduction was thus performed to give the desired products regioselectively.

Associate Professor, he was appointed Professor of Okayama University in 2008. Since 2017, he has been Executive Vice President at the same university. He is conducting research on the transformation of organic compounds based on electron transfer chemistry, flow chemistry, and organocatalysts.

4. CONCLUSION In this review, recent advances in electro-organic chemistry involving miniaturization, integration, and combinatorial chemistry are described. The miniaturization of electrochemistry can provide addressable libraries, which may become powerful bioassay tools in the field of peptide and protein chemistry. Combinatorial chemistry based on electro-organic chemistry is also important. Several approaches were described for both batch and flow systems. These systems enable high-throughput screening in electrolytic synthesis and afford organic compound libraries. Since continued advancements in electrolytic methods highly depend on the accessibility of devices, both availability and further improvement of the equipment for electro-organic reactions and synthesis should be significant. It is expected that the present research area will further develop by fusion of various fields such as mechanical and electronic engineering. We hope that the attractive technologies will be applied even more in the variety of research fields of life and material science.

ACKNOWLEDGMENTS This work was supported in part by JSPS KAKENHI (Grant Nos. 16H01155 and 16K05777) and by JST, ACT-C, Japan. REFERENCES (1) Lowe, D. B. Drug Discovery Combichem All over Again. Nat. Chem. 2014, 6, 851−852. (2) Barot, K. P.; Nikolova, S.; Ivanov, I.; Ghate, M. D. Liquid-Phase Combinatorial Library Synthesis: Recent Advances and Future Perspectives. Comb. Chem. High Throughput Screening 2014, 17, 417− 438. (3) Guido, R. V. C.; Oliva, G.; Andricopulo, A. D. Modern Drug Discovery Technologies: Opportunities and Challenges in Lead Discovery. Comb. Chem. High Throughput Screening 2011, 14, 830−839. (4) Edwards, P. J. The Use of Combinatorial Chemistry Methodologies to Discover Novel Chemotherapeutic Agents. Drug Discovery Today 2009, 14, 108−110. (5) Melkko, S.; Dumelin, C. E.; Scheuermann, J.; Neri, D. Lead Discovery by DNA-Encoded Chemical Libraries. Drug Discovery Today 2007, 12, 465−471. (6) Dey, R.; Khan, S.; Saha, B. A Novel Functional Approach toward Identifying Definitive Drug Targets. Curr. Med. Chem. 2007, 14, 2380− 2392. (7) Koppitz, M.; Eis, K. Automated Medicinal Chemistry. Drug Discovery Today 2006, 11, 561−568. (8) Geysen, H. M.; Schoenen, F.; Wagner, D.; Wagner, R. Combinatorial Compound Libraries for Drug Discovery: an Ongoing Challenge. Nat. Rev. Drug Discovery 2003, 2, 222−230. (9) Ji, Q.; Lirag, R. C.; Miljanic, O. S. Kinetically Controlled Phenomena in Dynamic Combinatorial Libraries. Chem. Soc. Rev. 2014, 43, 1873−1884. (10) Moulin, E.; Cormos, G.; Giuseppone, N. Dynamic Combinatorial Chemistry as a Tool for the Design of Functional Materials and Devices. Chem. Soc. Rev. 2012, 41, 1031−1049. (11) Potyrailo, R.; Rajan, K.; Stoewe, K.; Takeuchi, I.; Chisholm, B.; Lam, H. Combinatorial and High-Throughput Screening of Materials Libraries: Review of State of the Art. ACS Comb. Sci. 2011, 13, 579−633. (12) Maier, W. F.; Stoewe, K.; Sieg, S. Combinatorial and HighThroughput Materials Science. Angew. Chem., Int. Ed. 2007, 46, 6016− 6067. (13) Geysen, H. M.; Meloen, R. H.; Barteling, S. J. Use of Peptide Synthesis to Probe Viral Antigens for Epitopes to a Resolution of a Single Amino Acid. Proc. Natl. Acad. Sci. U. S. A. 1984, 81, 3998−4002. (14) Devlin, J. J.; Panganiban, L. C.; Devlin, P. E. Random Peptide Libraries: A Source of Specific Protein Binding Molecules. Science 1990, 249, 404−406. (15) Cwirla, S. E.; Peters, E. A.; Barrett, R. W.; Dower, W. J. Peptides on Phage: a Vast Library of Peptides for Identifying Ligands. Proc. Natl. Acad. Sci. U. S. A. 1990, 87, 6378−6382. (16) Ohlmeyer, M. H.; Swanson, R. N.; Dillard, L. W.; Reader, J. C.; Asouline, G.; Kobayashi, R.; Wigler, M.; Still, W. C. Complex Synthetic Chemical Libraries Indexed with Molecular Tags. Proc. Natl. Acad. Sci. U. S. A. 1993, 90, 10922−10926. (17) Nestler, H. P.; Bartlett, P. A.; Still, W. C. A General Method for Molecular Tagging of Encoded Combinatorial Chemistry Libraries. J. Org. Chem. 1994, 59, 4723−4724. (18) Kozai, T. D. Y.; Jaquins-Gerstl, A. S.; Vazquez, A. L.; Michael, A. C.; Cui, X. T. Brain Tissue Responses to Neural Implants Impact Signal Sensitivity and Intervention Strategies. ACS Chem. Neurosci. 2015, 6, 48−67.

ASSOCIATED CONTENT Special Issue Paper

This paper is an additional review for Chem. Rev. 2018, volume 118, issue 9, “Electrochemistry: Technology, Synthesis, Energy, and Materials”.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. ORCID

Koichi Mitsudo: 0000-0002-6744-7136 Seiji Suga: 0000-0003-0635-2077 Notes

The authors declare no competing financial interest. Biographies Koichi Mitsudo received his Ph.D. degree from Kyoto University under the direction of Prof. Jun-ichi Yoshida in 2003. He then worked as a postdoctoral fellow in the research group of Prof. Mark Lautens at the University of Toronto from 2003 to 2004. In 2004, he joined the group of Prof. Hideo Tanaka at Okayama University as an assistant professor. In 2009, he moved to the group of Prof. Seiji Suga as an assistant professor and was promoted to an associate professor in 2013. Yuji Kurimoto was born in Osaka, Japan (1992). He obtained a bachelor’s degree in engineering from Okayama University in 2016. He is now a postgraduate student at Okayama University (Prof. Suga’s group). Kazuki Yoshioka was born in Tokushima, Japan (1994). He received a bachelor’s degree in engineering in 2017. He is currently a postgraduate student in the group of Prof. Suga. Seiji Suga graduated from Nagoya University under the guidance of Professor Ryoji Noyori and received his Ph.D. in 1995. After working as a postdoctoral researcher at the University of Oxford (JSPS Postdoctoral Fellowship for Research Abroad, Prof. Sir Jack E. Baldwin), he moved to Kyoto University as an assistant professor (Prof. Jun-ichi Yoshida’s research group) in 1996. After being promoted to Lecturer and 5994


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