Microelectrode Arrays: A General Strategy for Using Oxidation

Feb 5, 2014 - Microelectrode Arrays: A General Strategy for Using Oxidation Reactions To Site Selectively Modify Electrode Surfaces. Bichlien H. Nguye...
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Microelectrode Arrays: A General Strategy for Using Oxidation Reactions To Site Selectively Modify Electrode Surfaces Bichlien H. Nguyen, David Kesselring, Eden Tesfu, and Kevin D. Moeller* Department of Chemistry, Washington University, St. Louis, Missouri 63130, United States S Supporting Information *

ABSTRACT: Oxidation reactions are powerful tools for synthesis because they allow for the functionalization of molecules. Here, we present a general method for conducting these reactions on a microelectrode array in a site-selective fashion. The reactions are run as a competition between generation of a chemical oxidant at the electrodes in the array and reduction of the oxidant by a “confining agent” in the solution above the array. The “confining agent” does not need to be more reactive than the substrate fixed to the surface of the array. In many cases, the same substrate placed on the surface of the array can also be used in solution as the confining agent.

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INTRODUCTION

AN INITIAL EXPERIMENT AND A STRATEGY: THE WACKER OXIDATION All array-based reactions require two key components. First, the reagent to be employed must be located by the electrodes selected for the reaction. On an array with a high density of microelectrodes, this is best accomplished by using the electrodes themselves to make the reagent. Second, a strategy is needed to keep the reagent generated from migrating to remote sites on the array not selected for the reaction. This is accomplished by the addition of a “confining agent” to the solution above the array. The confining agent scavenges any reagent that diffuses away from the surface of the electrode where it was generated. With this in mind, the Wacker oxidation was selected for an initial attempt at a site-selective oxidation reaction.33 The Wacker oxidation converts an olefin into a carbonyl with the use of a Pd(II) oxidant and water. The reaction is stoichiometric in Pd(II) and produces a Pd(0) byproduct. The Wacker oxidation was selected for adaptation to a microelectrode array because the recycling of the Pd(0) byproduct to Pd(II) at an anode (with a triarylamine mediator) is a well-established preparative procedure.36,37 Since electrochemical reactions depend on current density and not the size of the electrode used, it seemed that the same method could be used to generate Pd(II) at the electrodes in an array. In addition, it was easy to identify a confining agent for the Wacker oxidation. Ethyl vinyl ether is an electron-rich olefin known to undergo a rapid Wacker oxidation with Pd(II) in water to form ethyl acetate and Pd(0). If placed in the solution

One intriguing possibility for monitoring binding events between small molecule libraries and biological receptors involves the use of a microelectrode array.1−14 Microelectrode arrays are collections of individually addressable electrodes that can be used to monitor the binding behavior of molecules affixed to their surface. This is accomplished with an electrochemical impedance experiment that does not require labeling of either the molecules on the array or the receptor being probed. In addition, impedance experiments can be used to monitor binding events that occur on the surface of an electrode in “real time”.15−29 While the use of a microelectrode array for monitoring a small molecule library has numerous advantages, it also presents its own set of challenges. The experiments described above require the surface of the microelectrode array to be carefully controlled so that each unique member of a molecular library to be studied is located exclusively by a unique, individually addressable electrode (or set of electrodes) in the array. For this reason, we have been working to develop a number of array-based reactions that can be site-selectively run at any electrode in the array.30−32 As part of this effort, the development of site-selective oxidation reactions has been particularly important.33−35 Oxidation reactions are powerful tools for synthesis because they increase the level of functionality in a molecule. The new functionality can be used as a handle to further develop the molecule. On an array, a similar strategy increases the level of functionality of the polymer coating the array next to the electrodes selected for the reaction. The new functionality then serves as a handle for developing the surface of the array next to those electrodes. © 2014 American Chemical Society

Received: December 24, 2013 Revised: February 4, 2014 Published: February 5, 2014 2280

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Pd(II) chemistry made the identification of a fast-acting confining agent for Pd(II) straightforward. Would the same strategy work with a chemical oxidant that was not so well understood? In such a case, how can an appropriate confining agent be identified? For the site-selective Wacker oxidation, ethyl vinyl ether was selected because it was known to undergo the reaction much faster than the olefin on the surface of the array. Was this faster rate necessary? To answer these questions before attempting an oxidation with a less well-understood oxidant, a second Wacker oxidation was conducted. In this case, a monosubstituted olefin (1octene) directly analogous to the substrate from the surface of the array was used as the confining agent (Scheme 2). In this

above the array, ethyl vinyl ether would quickly scavenge any Pd(II) that migrated away from the electrodes where it was generated. In this way, only olefins bound to the surface of the electrodes used to generate Pd(II) would undergo oxidation. In practice, the reaction worked beautifully (Scheme 1). For the experiment, an array was first coated with agarose. The Scheme 1. Wacker Oxidation in a “Checkerboard Pattern”

Scheme 2. Wacker Oxidation in a “W Pattern”

agarose provides attachment points for fixing molecules to the surface of the electrodes. A monosubstituted olefin was then attached to the agarose proximal to every electrode in the array by coupling an activated ester to the alcohols in agarose with the use of an electrogenerated base.38 The Wacker oxidation was then conducted by treatment of the array with an electrolyte solution that contained a catalytic amount of Pd(OAc)2, a triarylamine, and an excess of ethyl vinyl ether. The excess ethyl vinyl ether ensured that at the start of the experiment only Pd(0) existed in the solution above the array. A “checkerboard pattern” of electrodes in the array was then set to a positive potential relative to a remote Pt wire counter electrode. This oxidized the triarylamine to a radical cation, which in turn oxidized the Pd(0) close to the electrode surface to Pd(II). The newly generated Pd(II) triggered a Wacker oxidation with the olefin substrate attached to the surface of the electrodes. Any Pd(II) that was not consumed by the surface Wacker oxidation was scavenged by the ethyl vinyl ether in solution. During the reaction, the electrodes selected for the oxidation were turned on for a period of 0.5 s and then turned off again for a period of 0.1 s. Cycling of the electrodes in this manner slowed the buildup of Pd(II) so that the solution-phase reduction of the reagent with ethyl vinyl ether could effectively compete with Pd(II) generation. The success of the site-selective Wacker oxidation was demonstrated by converting the ketones generated on the surface of the array into 2,4-dinitrophenylhydrazine (2,4-DNP) derivatives and then incubating the array with a fluorescently tagged anti-2,4-DNP antibody. When examined with a fluorescence microscope, the array clearly showed fluorescence at only electrodes that were used as anodes for the oxidation. The overall strategy proved to be general for Pd(II) oxidations, and we were able to show how identical reaction conditions could also be used to confine the Pd(II) oxidation of an alcohol to an aldehyde or ketone.34 However, the use of Pd(II) as an oxidant on the array really was an ideal test case. The oxidation states of Pd are easily manipulated using electrochemistry, and our extensive knowledge of Pd(0) and

way, there would be no difference in rate between the reaction on the surface and the reaction with the confining agent. If such an approach was possible, then the design of a new array-based oxidation reaction would be trivial. One could simply run a solution-phase oxidation reaction with a catalytic amount of oxidant. The reaction would stop when the oxidant was consumed, leaving the remaining starting material in solution to serve as a confining agent for a subsequent array reaction. Insertion of an array functionalized with the substrate into the solution and then regeneration of the oxidant at selected electrodes would lead to the desired site-selective reaction. In this case, the presence of the ketone was detected by conducting a reductive amination reaction on the ketone with sodium cyanoborohydride and Texas Red hydrazide. As shown in the image provided in Scheme 2, this simplified confinement strategy worked perfectly to keep the Pd(II) from migrating away from a “W pattern” of electrodes used for the oxidation. Clearly, the confining agent used in solution does not need to be more reactive than the substrate on the surface of the array.

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EXTENDING THE SCOPE OF OXIDANTS TO CERIC AMMONIUM NITRATE With a simple method for identifying a confining agent in place, attention was turned to establishing the generality of the method with other oxidants. Ceric ammonium nitrate (CAN) was chosen for this effort because it is an effective oxidant for triggering a wide variety of synthetic transformations,39 including reactions that transform silylated amino acids into functionalized peptide derivatives.40 The preparative recycling of a Ce(IV) oxidant at an electrode has been reported,41 but information about the electrochemical manipulation of cerium oxidation states and chemical reactions leading to the reduction 2281

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and co-workers.42 They demonstrated that the Sharpless asymmetric dihydroxylation can be run without the need for a stoichiometric chemical oxidant by recycling ferricyanide at an anode. Hence, the only thing necessary for developing an arraybased Sharpless dihydroxylation was a plan for confinement of the osmium tetroxide reagent to the region of the array surrounding the electrodes where it was generated. The simple strategy developed above suggested that any olefin in solution would serve in this capacity. Along these lines, the site-selective dihydroxylation reaction illustrated in Scheme 4 was conducted. The reaction conditions

and oxidation of cerium are far less available than in the case of palladium. In this way, Ce(IV) provided an ideal test case for expanding the overall strategy developed for the Wacker oxidation. Could we rapidly develop a site-selective oxidation reaction knowing only that a solution-phase reaction worked? The answer is highlighted in Scheme 3.35 Scheme 3. CAN Oxidation in a “Checkerboard in a Box Pattern”

Scheme 4. Dihydroxylation Reaction in an “Os Pattern”

In this example, a silylated amide was placed proximal to each microelectrode on an agarose coated array having 12 544 microelectrodes/cm2. This was again accomplished by coupling an activated ester to the alcohols in agarose with the use of an electrogenerated base.38 The dimethoxyaryl-substituted silyl group was selected for the substrate because of its proven compatibility with ceric ammonium nitrate oxidations in solution-phase reactions.40 In these reactions, oxidation of the silylated amide gives rise to an N-acyliminium ion that is then trapped by nucleophiles. For the reaction highlighted in Scheme 3, the functionalized array was treated with a premixed electrolyte solution, containing tetrabutylammonium hexafluorophosphate in acetonitrile/DMF (9:1), a catalytic amount of ceric ammonium nitrate, an excess of the activated ester 5, and 1-pyrenebutanol as a nucleophile to trap any N-acyliminium ion that formed. Activated ester 5 was added to the mixture to serve as the confining agent for Ce(IV) generated at the electrodes in the array. In this way, the same activated ester used to place the substrate onto the surface of the array was used as the confining agent. The oxidation was run with the use of a “checkerboard in a box pattern” of electrodes. The image provided shows that the oxidation and confinement strategy worked well. Generation of Ce(IV) at electrodes in the array led to formation of the N-acyliminium ion and subsequent trapping by the pyrene butanol. While some fluorescence is apparent between the electrodes that were used, no reaction occurred at electrodes not selected for the oxidation.

employed were nearly identical to those used in the preparative experiment by Torii and co-workers. The only differences were the use of an “Os pattern” of electrodes on the microelectrode array to recycle the oxidant and the presence of styrene as a confining agent in solution. As in the Wacker and CAN oxidations, the reaction solution contained an excess of the confining agent and a catalytic amount of the oxidant. The solution was allowed to stand prior to the electrolysis in order to ensure that all of the oxidant in solution was consumed prior to starting the array reaction. The reaction solution was then placed over the surface of the array, and then the electrodes in the array were used to generate the Os(VIII) oxidant where it was desired. The success of the reaction was determined with a second transformation that treated the array with pyreneboronic acid in the presence of an electrogenerated acid and a water scavenger.43 This was done in order to convert any vicinal diols formed on the array into pyrene-labeled borate esters. Following this second transformation, the array was examined with a fluorescence microscope to give the image shown in Scheme 4. Clearly, a vicinal diol was formed at the anodes used for the dihydroxylation reaction. No evidence for dihydroxylation at electrodes not selected for the oxidation was observed. Two aspects of the image deserve further comment. First, the rather faint image is due to the use of agarose as the polymer coating on the array. Agarose is not entirely stable to the reaction conditions. Thus, when the reaction was run for longer times, the fluorescent image became brighter but the agarose began to delaminate from the surface of the array. Further optimization of the reaction would require a more stable surface.44 Second, note that the method for imaging a vicinal diol does not afford background fluorescence from the agarose polymer. This is a result of the esterification reaction used to place the substrate above every electrode in the array being very

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OSMIUM TETRAOXIDE AND TEMPO The strategy is very general. For example, asymmetric dihydroxylation reactions are powerful tools for synthesis because they allow for the construction of building blocks with asymmetric centers. For this reason, we hoped to make the reactions available for array-based syntheses. As a starting point for such an effort, we took note of the beautiful work by Torii 2282

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reactions that can be conducted on the arrays, the approach does have limitations. Consider the oxidative condensation reaction illustrated in Scheme 6. The reaction forms either

efficient and affording a high level of surface coverage. In addition, the reaction with the boronic acid was done in a siteselective fashion that confines it to each electrode in the array. Hence, no reaction between the boric acid and the agarose polymer between the electrodes is possible. In a fashion directly analogous to the development of the dihydroxylation, the oxidative “tool kit” for array-based synthesis was expanded to include nitroxyl radicals. Nitroxyl radicals are useful, selective oxidation reagents for the conversion of primary and secondary alcohols to aldehydes and ketones.45 The compatibility of the transformations with the array platform was demonstrated with a 2,2,6,6-tetramethyl1-piperidinyloxy (TEMPO) oxidation of the agarose coating on an array (Scheme 5). The confining agent for the reaction was

Scheme 6

benzimidazole or benzthioimidazole ring skeletons.47,48 Both ring systems are potential core scaffolds for building libraries on the array. Using the synthesis of the benzimidazole as an example, the plan for an array-based variant of this reaction would call for the placement of aryldiamine 12 on the surface of the array. The functionalized array would then be treated with an aldehyde (13), a catalytic oxidant (either ceric ammonium nitrate (CAN) or 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ)), and a confining agent. The catalytic oxidant would be recycled at selected electrodes in the array, while the confining agent prevented migration of the oxidant to remote sites on the array. But what confining agent could be used to keep the oxidative condensation reaction located by the selected electrodes in the array? According to the general strategy forwarded above, the confining agent for the reaction would simply be an aryldiamine related to one used as a substrate on the surface of the array. However, in this reaction the oxidation step follows an initial condensation reaction between the diamine 12 and aldehyde 13. If excess diamine were to be used as the confining agent in solution, then the initial condensation reaction would occur in solution. This would remove the aldehyde from the reaction and stop any possibility for the surface reaction. In practice, this turned out to be the case. All attempts to use a diamine in solution as a confining agent led to no reaction on the surface of the array. Clearly, a different confinement strategy was needed. One of the main things learned from our early studies on site-selective oxidations was that the confining agent for the reactions did not need to be especially reactive. Any molecule that was oxidized by the chemical oxidant generated on the array could be used as the confining agent in solution as long as it was sufficiently soluble in the reaction medium. Hence, for the oxidative condensation reaction, we simply needed to find a substrate for oxidation by either CAN or DDQ that did not undergo a reaction with the aldehyde needed for the condensation. Since methoxylated aromatic rings undergo oxidation with both CAN and DDQ, methoxyphenylamide 15 was selected (Scheme 7).49 The array reaction was then run in a fashion nearly identical to the earlier reactions. The reaction solution was prepared by adding a catalytic amount of the oxidant (either CAN or DDQ) to an excess of 15 and tetrabutylammonium tetrafluoroborate in 2:7:1 mixture of DMF, CH3CN, and H2O. After allowing the reaction to consume all of the oxidant, the solution was placed over an array that was functionalized with the diamine. In this case, the surface of the array was coated with a more stable diblock copolymer that contained an arylborate functional group.44 The diamine was placed on the array by each of the electrodes with the use of a Suzuki reaction.50 The oxidative condensation reaction was run by using selected electrodes in the array as anodes to regenerate either the CAN or DDQ oxidant. For the

Scheme 5. TEMPO Oxidation in a “T Pattern”

4-methoxybenzyl alcohol, a solution-phase substrate for TEMPO that would consume any oxidant that migrated away from the site of its origin. As in each of the earlier experiments, a catalytic amount of the oxidant was incubated with an excess of the confining agent prior to introduction of the array. This ensured complete consumption of the oxidant before the electrolysis was conducted. The solution was then placed over an agarose-coated array, and a “T pattern” of electrodes was used to generate the TEMPO. The electrochemical conditions used were the same as those used previously for recycling TEMPO in preparative electrolyses.46 The success of the reaction was determined by treating the oxidized array with sodium cyanoborohydride and Texas Red hydrazide. The ensuing reductive amination showed where on the array a carbonyl had been generated. As can be seen in the image provided, carbonyl formation occurred only at the “T pattern” of electrodes used for the oxidation. Again, no evidence for oxidation at sites remote from the selected electrodes was observed. With the use of the agarose surface as the substrate for the oxidation, the strict confinement of the reaction to just the electrodes and not even the area of the array surrounding the electrodes indicated just how well the confinement strategy worked.

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OXIDATIVE CONDENSATION REACTIONS: CAN AND DDQ While the use of the surface substrate as a confining agent in solution led to a rapid expansion in the types of oxidation 2283

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Scheme 7. Oxidative Condensation Reactions in “CAN and DDQ Patterns”

site-selective oxidation reactions the solution-phase substrate can be the same substrate used on the surface of the array. In such cases, the design of the site-selective reaction is trivial. After placing the substrate by the electrodes in the array, a solution is made with the same substrate and a catalytic amount of the oxidant to be used. The solution is allowed to stand until all of the oxidant is consumed. The array is then inserted into the solution, and electrodes in the array are used as anodes in order to regenerate the oxidant at the specific sites where it is desired. The excess solution-phase substrate then serves as the confining agent for the reaction. The plan works for any oxidation where the surface-bound substrate is directly oxidized. It does not work in cases where the surface-bound reaction undergoes a transformation prior to the oxidation reaction. In such cases, the initial transformation happens in solution so that no surface reaction occurs on the array. A different confining strategy is needed. Fortunately, any substrate for the oxidant that is chemically inert toward the other reagents in solution can be used. The availability of a general strategy for confining electrochemically generated oxidants to the region immediately surrounding the electrodes in a microelectrode array makes the use of oxidation reactions powerful tools for building microelectrode array-based molecular libraries. These reactions can be used to add molecules to the surface of the arrays or to build core scaffolds on the arrays.

reaction with CAN, this was done by setting the selected electrodes at a potential of +2.4 V relative to the counter electrode. As in the earlier experiments, the electrodes in the array were cycled, this time by turning them on for 30 s and then off again for 10 s. This was done for a total of 10 cycles. The DDQ reaction was run by setting the electrodes at a potential of +1.7 V relative to the counter electrode. In this case, the electrodes were cycled in the same manner 20 times. When the DDQ reaction was run at +2.4 V, a slight loss of confinement was observed, evidence that the production of oxidant was too fast for the solution phase confinement agent to keep up. This suggests that either the oxidative condensation reaction is faster with CAN than with DDQ so that less of the CAN escaped from the surface of the electrode where it is generated or that the reduction of DDQ by the confining agent is slow relative to the reduction of CAN. In either event, the reaction was easy to optimize by controlling the rate of oxidant generation. Evidence for the success of both reactions is shown in Scheme 7. In the images shown, the anodes selected either spelled “CAN” or “DDQ” in order to indicate which oxidant was used. In both cases, the reaction occurred at only the selected electrodes. The lack of fluorescence at the nonselected electrodes served as an effective control experiment for the reaction by showing that no reaction occurs in the absence of the oxidant. In these experiments, fluorescence at an electrode could in principle be derived by the generation of an aminal on the surface of the array without the subsequent oxidation step. However, this should occur at every electrode in the array since every electrode was functionalized with the diamine. The lack of fluorescence in the absence of the oxidant indicates that the aminal intermediate is not stable and falls apart when the array is washed following the reaction.

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ASSOCIATED CONTENT

S Supporting Information *

An experimental description for all new array reactions along with information about how the arrays are coated with the polymer surfaces. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail [email protected] (K.D.M.). Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Science Foundation (CBET 1262176) for their generous support of our work. We also gratefully acknowledge the Washington University High Resolution NMR facility, partially supported by NIH grants RR02004, RR05018, and RR07155, and the Washington University Mass Spectrometry Resource Center, partially supported by NIHRR00954, for their assistance.

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CONCLUSIONS A general strategy for conducting site-selective oxidation reactions on microelectrode arrays has been developed. Key to this strategy is a need to confine oxidants generated at the electrodes in an array to the region immediately surrounding those electrodes. This is accomplished by the placement of a substrate (the “confining agent”) for the electrochemically generated oxidant in the solution above the array. The solutionphase substrate reduces the oxidant before it can migrate to remote sites on the array. The solution-phase substrate used for this effort does not have to be more reactive toward the oxidant than the substrate on the surface of the array. In fact, for many

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