Campus Box 1134
What are the "tools" that allow us to construct molecules, and are these "tools" capable of building what we need in a timely and efficient manner? These two questions provide the motivation for our group's exploration of electrochemistry, an exploration that has led us to pursue two broad areas of research.
New Synthetic Methodology/ Organic Synthesis:
Because electrochemistry enables the selective manipulation of molecular oxidation states, the generation of highly reactive intermediates, and the reversal of functional group polarity, it provides an ideal method for discovering and exploring new, synthetically useful reactions. For instance, consider the reactions highlighted in Scheme 1. In each of these reactions, an electron-rich, normally nucleophilic enolate equivalent is oxidized leading to the formation of an electrophilic radical cation. The radical cation traps a second nucleophile leading to the formation of a new bond and ring. The first two reactions illustrated highlight reactions that were used in the construction of the arteannuin M ring skeleton, the third shows a reaction used to construct new quaternary carbons, the fourth illustrates a route to new, constrained amino acid derivatives, and the fifth shows a rapid approach to the construction of glycopeptides. Each reaction reverses the polarity of an electron-rich olefin in order to accomplish a transformation that is otherwise not possible. All of the reactions shown can be performed in a three neck round bottom flask using solar-electrochemistry. In this way, the reactions consume only sunlight and generate only hydrogen gas as a byproduct.
The solar-electrochemical approach is not only important for direct oxidations like the ones illustrated in Scheme 1. It can also be used to recycle chemical oxidants. In this way, reactions can capitalize on the inherent “green”-aspects of electrochemistry while still taking advantage of the chemical selectivity of a chemical oxidant. To date, Pd(II), CAN, DDQ, TEMPO, Mn(V), Mn(III), and Os(VIII)-oxidants have all been utilized as catalytic reagents in solar-electrochemical reactions.
In addition our synthetic methods developments we are also using electrochemistry to probe the mechanism of electron-transfer reactions and to develop new routes for the total synthesis of complex targets. With respect to our total synthesis efforts, several molecules of current interest to the group are shown in Scheme 2. These molecules either represent synthetic challenges for specific electrochemical methods or molecules of interest in connection with biological studies (see below).
New Analytical Tools for Probing Molecular Interactions:
While the chemistry outlined above has proven very useful for solving a number of structural challenges in synthesis, not all synthetic challenges in organic chemistry are of a “structural-variety”. Instead some are of a logistical nature. For example, as part of a long standing effort to “map” the preferred three-dimensional binding motifs of biological receptors, we recently became engaged in an effort to develop methods for monitoring ligand – receptor binding events in “real-time”. To accomplish this goal, potential ligands (small molecules, peptidomimetics, glycoproteins, etc.) will be placed or synthesized on microelectrode arrays so that each unique molecular ligand is located proximal to a unique, individually addressable electrode in the array.
The electrodes in the array will then be used to monitor binding events between the potential ligands and various biological receptors. The monitoring experiments will be conducted using electrochemical impedance as outlined in Figure 1. In this experiment, the microelectrodes in the array are used as anodes in order to oxidize an iron species (typically ferrocene or ferricyanide) in the solution covering the array. The iron species is re-reduced at a remote Pt-wire cathode setting up a measurable current at each microelectrode. When a receptor (M1R) is added to the solution above the array and binds to ligands on the array (M1, M2, etc.) the iron species is impeded from reaching the neighboring microelectrodes. This causes the current measured at the microelectrode next to the ligand that binds to drop, an event that can be readily detected. In this way, each molecular ligand on the surface of the array can be monitored for its binding to a biological receptor at the same time and as the events occur.
While the plan seems straight forward, it leads to the logistical synthetic challenge mentioned earlier. With the microelectrode arrays used for the signaling experiments having a density of 12,544 electrodes cm-2, how does one place or build a molecular library so that each unique member of the library is located next to only one unique electrode? How can synthetic chemistry be accomplished in a site-selective fashion. One answer to these questions is to take advantage of the electrodes themselves to trigger chemical reactions. This can be done by capitalizing on what electrochemical reactions do best. They reverse the reactivity of groups by either adding or subtracting electrons. On an array, this ability can be used to setup a competition between an electrochemical reaction that synthesizes a chemical reagent and a solution phase reaction that destroys the reagent before it can migrate away from the site of its origin. The result is a net reaction that is highly selective for individual electrodes in an array. An example of one such reaction is illustrated in Scheme 3. In this example, a site-selective Diels-Alder reaction is accomplished by using selected electrodes in the array as anodes to generate a Sc(III) Lewis acid from Sc(I) in the solution above the array. The Lewis acid generated in this manner is then promptly destroyed again by the presence of a reducing agent in the solution. By increasing the rate of Sc(III) generation at any given microelectrode in the array, the formation of the Lewis acid can overwhelm the reducing agent in the region surrounding the electrode. The presence of the Lewis acid by the electrode triggers a Diels-Alder cycloaddition at that site. Of course, the concentration of the Lewis acid fall off as the distance from the electrode increases allowing the solution phase reducing agent to destroy the Sc(III) before it migrates to a non-selected electrode. The success of this approach is shown for arrays having both 1028 microelectrodes cm-2 and 12,544 microelectrodes cm-2.
The overall plan for conducting site-selective reactions on the arrays has proven to be general. The strategy has been used to site-selectively run acid and base catalyzed reactions, transition metal reactions using Pd(0), Pd(II), and Cu(I), and oxidation reactions using both Pd(II) and ceric ammonium nitrate. These reactions can be very useful. The use of a base on the arrays has allowed us to place peptide substrates proximal to the microelectrodes using Michael reaction chemistry.
The ability to place peptides on the arrays allows us to explore the electrochemical impedance approach to monitoring binding events as outlined in Figure 1. For example, consider the study highlighted in Figure 2. In this experiment, two RGD peptides were placed onto a microelectrode array having 12,544 microelectrodes cm-2 (a 12K-array). Both peptides were located proximal to a block of ten microelectrodes. The first peptide (sequence = KGGRGDSPC) is known to bind tightly to the integrin receptor αIIbβIII (GPIIb/IIIa). The second peptide (sequence = KGGRADSPC) is known to bind weakly to the integrin receptor. The microelectrode array was then inserted into a solution containing potassium ferricyanide and a Pt-counter electrode. A cyclic voltammogram was run using the microelectrodes located next to both the tight binding peptide (the CV on the left) and the weak binding peptide (the CV on the right) giving rise to the red line in both cases. This line represents the background current associated with ferricyanide in the absence of the receptor. The integrin receptor was then added to the solution and the CV experiments repeated giving rise to the blue line in both cases. Clearly, a difference in binding was observed with the current measured at the microelectrodes proximal to the tight binding peptide dropping off significantly more than the current measured at the microelectrodes proximal to the weak binding peptide.
Work on this project is continuing along several paths. New site-selective synthetic methods are being explored, site-selectively cleavable linkers are being developed for characterizing molecules on the surface of an array, strategies for determining in “real-time” the relative binding of molecular ligands to various biological receptors are being studied, new custom polymers for coating the arrays and controlling the surface used for the subsequent synthetic and analytical experiments are being synthesized, and studies aimed at expanding the utility of the microelectrode arrays as bioanalytical tools are being pursued.
“Cyclization Reactions of Anode-Generated Amidyl Radicals.” Hai-Chao Xu, John M. Campbell, and Kevin D. Moeller. J. Org. Chem. 2014, ASAP.
“Sunlight, Electrochemistry, and Sustainable Oxidation Reactions.” Bichlien Nguyen and Kevin D. Moeller. Green Chemistry 2014, 16, 69.
“Oxidative Cyclizations, the Synthesis of Aryl Substituted C-Glycosides, and the Role of the Second Electron Transfer Step.” Jake A. Smith and Kevin D. Moeller. Org. Lett. 2013, 15, 5818.
“Oxidative Cyclization Reactions: Controlling the Course of a Radical Cation-Derived Reaction with the Use of a Second Nucleophile.” Alison Redden, Robert J. Perkins, and Kevin D. Moeller. Angew. Chem. Int. Ed. 2013, 52, 12865.
“The Use of UV-Cross-Linkable Diblock Copolymers as Functional Reaction Surfaces for Microelectrode Arrays.” Hu, L.; Graff, M. D.; Moeller, K. D. J. Electrochem. Soc. 2013, 160, G3020.
“The Anodic coupling of Carboxylic Acids to Electron-Rich Double Bonds: A Surprising Non-Kolbe Pathway to Lactones.” Robert J. Perkins, Hai-Chao Xu, John M. Campbell, and Kevin D. Moeller. Beilstein J. Org. Chem. 2013, 9, 1630..
“Investigating the Reactivity of Radical Cations: Experimental and Computational Insights into the Reactions of Radical Cations with Alcohol and p-Toluene Sulfonamide Nucleophiles.” John M. Campbell, Hai-Chao Xu, and Kevin D. Moeller. J. Am. Chem. Soc. 2012, 134, 18338.
“Site-Selective Chemistry and the Attachment of Peptides to the Surface of a Microelectrode Array.” Melissae Stuart Fellet, Jennifer L. Bartels, Bo Bi, and Kevin D. Moeller. J. Am. Chem. Soc. 2012, 134, 16891.
“Building Addressable Libraries: Amino-Acid Derived Fluorescent Linkers.” Takamasa Tanabe, Bo Bi, Libo Hu, Karl Maurer, and Kevin D. Moeller. Langmuir 2012, 28, 1689-1693.
2006-present, Member of the Executive Committee for the Organic and Biological Electrochemistry Division of The Electrochemical Society
2001, Washington University Student Union--College of Arts and Sciences Professor of the Year
1999, State of Texas, Robert A. Welch Lecturer
1997, American Chemical Society's "St. Louis Award"
Chemistry 252, Organic Chemistry
Chemistry 358, Quantitative Analysis Lab
Chemistry 451, Organic Chemistry III
Chemistry 5522, Modern Synthetic Methods