Site-Selectively Functionalizing Microelectrode Arrays: The Use of Cu(I)

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Site-Selectively Functionalizing Microelectrode Arrays: The Use of Cu(I)-Catalysts Jennifer Bartels,† Peng Lu,‡ Karl Maurer,§,# Amy V. Walker,‡ and Kevin D. Moeller*,† †

Department of Chemistry, Washington University, St. Louis, Missouri 63130, United States Department of Materials Science and Engineering, University of Texas Dallas, Richardson, Texas 75080, United States § CombiMatrix Corporation, 6500 Harbor Heights Parkway, Suite 301, Mukilteo, Washington 98275, United States ‡

bS Supporting Information ABSTRACT: Site-selective Cu(I)-catalyzed reactions have been developed on microelectrode arrays. The reactions are confined to preselected electrodes on the arrays using oxygen as the confining agent. Conditions initially developed for the Cu(I)-catalyzed click reaction have proven general for the coupling of amine, alcohol, and sulfur nucleophiles to both vinyl and aryl iodides. Differences between reactions run on 1-K arrays and reactions run on 12-K arrays can be attributed to the 1-K array reactions being divided cell electrolyses and the 12-K array reactions being undivided cell electrolyses. Reactions on the 12-K arrays benefit from the use of a non-sugar-derived porous reaction layer for the attachment of substrates to the surface of the electrodes. The reactions are sensitive to the nature of the ligand used for the Cu catalyst.

’ INTRODUCTION Cu(I)-catalysts are powerful tools for effecting a wide variety of synthetically useful transformations.1 For this reason, we hope to harness their utility for site-selectively modifying microelectrode arrays.2 4 Our goal is to utilize the arrays for monitoring the binding of small molecule libraries with biological targets in “real-time”.5 To accomplish this goal, methods are needed for either building or placing molecules proximal to individual microelectrodes in the array, even when the array has a density of 12 544 electrodes 3 cm 2. This is done by first coating the arrays with a porous polymer that contains sites for chemical reactions.6 The microelectrodes in the array are then used to generate catalysts or reagents that initiate or mediate transformations on the polymer above the surface of the selected electrodes. In solution, a “confining-agent” is used to scavenge whatever catalyst or reagent is generated before it can migrate to remote, nonselected sites on the array. To date, a variety of reactions have been conducted in this manner.7 12 Efforts to utilize Cu(I)-catalyzed reactions in this context began with the development of [3 + 2] cycloaddition reactions (Scheme 1).13 In this work, the microelectrode array was first coated with an agarose polymer and then the polymer functionalized with an acetylene above each of the electrodes using a basecatalyzed esterification reaction.7 9 The cycloaddition was then conducted by adding an azide to the solution above the array along with copper sulfate, disodium bis(bathophenanthroline) disulfonate as a ligand for the Cu, tetrabutylammonium bromide electrolyte, and oxygen as an oxidant for Cu(I). Selected electrodes were than used as cathodes in order to reduce the Cu(II) in solution to the Cu(I)-catalyst by setting them at 2.4 V relative to a remote Pt-wire auxiliary electrode. Generation of the r 2011 American Chemical Society

Cu(I)-catalyst triggered the desired cycloaddition proximal to the selected electrodes. Since the solution above the array contained oxygen, the Cu(I) being generated was oxidized as it diffused away from the surface of the electrodes used. This prevented the Cu(I) catalyst from migrating to nonselected sites on the array. In the fluorescence image shown in Scheme 1, the success of this approach can be clearly seen since the azide used for the coupling reaction contained a pyrene ring. Hence, selected electrodes show fluorescence whereas unselected electrodes do not. New Site-Selective Cu(I) Reactions. Although the Cu(I)catalyzed cycloaddition reaction provides a nice method for placing molecules on the surface of an array, it does have limitations. It requires functionalization of both the polymer on the array surface and the molecule to be placed on the surface with appropriate groups. For example, we recently developed a new, stable porous reaction layer for the arrays.6 With this surface, the array is functionalized with aryl bromides. To conduct a cycloaddition on this surface requires changing the functional group on the surface of the array to either an acetylene or an azide, and then modifying the molecule to be placed on the surface in a complementary manner. A more efficient strategy would be to use the site-selectively generated Cu(I) catalyst to add a nucleophile already present in a molecule directly to the aryl bromide that is already on the surface. For example, a peptide could be coupled to the aryl bromide on the surface of an array using an alcohol, amine, or thiol nucleophile already present in the peptide.14 Received: May 19, 2011 Revised: July 19, 2011 Published: July 20, 2011 11199

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Langmuir Scheme 1. Site-Selective Cycloaddition Reaction

Scheme 2. N-Boc Amine and Vinyl Iodide Coupling

However, how general are site-selective Cu(I)-catalyzed reactions on a microelectrode array? Does the same synthesis and confinement of Cu(I) strategy developed for the cycloaddition reaction also work for other classes of Cu(I)-catalyzed reactions? The first reaction selected for study was the carbamate, vinyl iodide coupling illustrated in Scheme 2.15 The microelectrode array was coated with an agarose polymer (used because it can be easily removed from the array and the chip recycled) and then the polymer functionalized with a carbamate proximal to each microelectrode in the array. As is typical for agarose-coated arrays, the functionalization step utilized a base-catalyzed esterification reaction7 9 between an N-hydroxysuccinimide activated ester and the alcohols of the agarose polymer (Supporting Information). The base was generated by reducing vitamin B12 at all of the microelectrodes in the array. The newly functionalized array was submerged in an acetonitrile/DMF/water solution containing pyrene vinyl iodide, CuSO4, triphenylphosphine, and tetrabutylammonium bromide. Selected electrodes were then employed at cathodes by setting their potential to 2.4 V relative to a remote Pt-wire electrode for a period of 0.5 s and then turning them off for 0.1 s. The selected electrodes were cycled in this fashion 300 times. This was done to control the rate at which the Cu(I) catalyst was generated. As in the earlier cycloaddition, oxygen was used as the solution-phase “confining agent” in order to oxidize the Cu(I) catalyst before it could migrate to remote, nonselected sites on the array. The reaction was first conducted on an array having 1024 microelectrodes 3 cm 1 (a 1-K array). In this experiment, two rows of the microelectrodes were turned on followed by two that were left off. This pattern was repeated across the array in order to give

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Scheme 3. Phenylthiol and Vinyl Iodide Coupling

the “stripes” pattern observed in Scheme 2, image a. The image was taken after the reaction was stopped, and the microelectrode array carefully washed to remove any unreacted pyrene vinyl iodide. Similar reaction conditions could be applied toward the same reaction on an array containing 12 554 microelectrodes 3 cm 1 (a 12-K array). In this case, the microelectrodes were not cycled but rather held at a constant 2.0 V relative to the auxiliary electrode for 90 s. A checkerboard pattern, in groups of four microelectrodes at a time, was selected for the reduction. The result is shown in Scheme 2, image b. Clearly, oxygen also served as an effective confining agent for the reaction on the 12-K array. The reaction conditions developed for the “click-reaction” were directly compatible with the coupling of a carbamate and vinyl iodide. We next chose to examine the addition of a thiol nucleophile to a vinyl iodide.16 Thiol nucleophiles have been used to place peptides site-selectively on an array by taking advantage of a thiol-Michael reaction.5b Although the conjugate additions work well, they are reversible. Ideally, the same thiol nucleophiles could be added to a vinyl or aryl halide on the array to afford a more stable product. To this end, the reaction illustrated in Scheme 3 was studied. The reaction conditions employed were identical to those used for the carbamate addition in Scheme 2. The only change was the placement of a thiophenol derivative by each of the microelectrodes on the array prior to the Cu(I) reaction. Agarose was again used as the polymer coating for molecule attachment to the surface of the array and oxygen again served as the solution-phase confining agent. As in the previous case, the reaction worked nicely on both 1-K (Scheme 3, image a) and 12-K arrays (Scheme 3, image b). The addition of amine and alcohol nucleophiles to aryl iodide substrates on the array was also of interest because of the frequency with which they are found in biologically interesting molecules. Examination of these nucleophiles began with the chemistry illustrated in Scheme 4. The first reaction was conducted on a 1-K array that was coated with an agarose polymer and then functionalized proximal to every electrode in the array with 4-iodophenyl acetic acid. The same set of conditions used in the thiol vinyl iodide coupling were again employed when coupling a pyrene substituted methylamine to the phenyliodide, as illustrated in Scheme 3. A checkerboard pattern of microelectrodes was used for the reduction of Cu(II). As in the earlier reactions, oxygen was used as a confining agent and the reaction led to the expected site-selectivity (Scheme 4, image a). However, unlike the previous examples the reaction could not be transferred to a 12-K array. On the 12-K array, the reaction 11200

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Scheme 4. Phenyliodide and Amine Coupling

Scheme 5. Site-Selective Pd(II) Oxonium Ion Trapping

completely lost confinement leading to fluorescence by every microelectrode in the array (not shown). This result was confusing since the method for generating and confining the Cu(I) catalyst was the same as that used for the earlier carbamate and thiol reactions. Why should confinement be lost only in this case, and why did this reaction behave so differently on a 12-K array relative to the identical reaction on a 1-K array? A potential answer to these questions was found by examining reactions that utilized Pd(0)-catalyzed Heck reactions to place amino acid derivatives on agarose-coated microelectrode arrays.8a The reactions used 4-iodobenzoic acid as the substrate on the surface of the array and an acrylate-functionalized amino acid as the solution-phase Heck-coupling partner. While previous site-selective Heck reactions had proceeded beautifully, the amino acid derived reactions did not. Instead of a reaction confined to sites where Pd(0) was generated, the amino acid wound up by every electrode in the array. After considerable confusion, we discovered that the Pd(II) precursor used for Pd(0) generation on the array served as a Lewis acid leading to oxonium ion formation from the agarose polymer. The oxonium ions were then trapped by the unprotected N-terminus of the peptide. Evidence for this mechanism was obtained using the chemistry illustrated in Scheme 5. In this experiment, Pd(II) was site-selectively generated on the array (the palladium acetate initially added to the reaction is reduced by ethyl vinyl ether. The microelectrodes are then used as anodes to oxidize the resulting Pd(0) reagent to Pd(II)).8d The array was functionalized at each electrode with an ester, so anywhere Pd(II) was generated an oxonium ion was formed and a solution-phase pyrene-labeled amine trapped. The reactions exclusively occurred at the microelectrodes used for Pd(II)-generation. A similar oxonium ion scenario seemed likely for the loss of confinement in the failed Cu(I) catalyzed reaction. However, there was a significant difference between the Cu(I) catalyzed reactions and the Pd(0) catalyzed Heck reaction. The peptidederived Heck reaction failed on both 1-K and 12-K arrays, an observation consistent with a solution-phase reagent decomposing the functionalized agarose. The Cu(I) catalyzed amine addition worked well on 1-K arrays. It only failed on 12-K arrays. For the reaction to work on a 1-K array, the functionalized agarose surface had to be stable to Cu(II). So, unlike the Heck reaction, for the Cu-chemistry it was not the Lewis acid precursor to the catalyst that generated the oxonium ion. Instead, a different mechanism for oxonium ion formation had to be operating, a mechanism that only occurred on a 12-K array.

Reactions on 1-K and 12-K arrays are different. 1-K arrays are employed by taking the array and placing it in a vial along with a remote Pt wire that serves as the auxiliary electrode (Supporting Information) For all practical purposes, the systems are divided cells. The reaction that occurs at the counter electrode has no influence on the chemistry happening on the array. Reactions on 12-K arrays use a slide format. The array is imbedded in the slide, and then the slide fit with a cap that is separated from the array with a Kalrez spacer. The reaction solution is then flowed into the space between the array and the cap. The counter electrode for the experiment is platinum metal that has been sputtered onto the cap. Its distance from the array is ca. 0.95 mm, making the 12-K array setup an undivided cell. In an undivided cell, the product generated at the counter electrode can influence reactions at the working electrode. For reduction reactions, the oxidation at the counter electrode generates acid. The result is that the pH for a reduction on a 12-K array is lower than the pH for the same reaction on a 1-K array. Could oxonium ion formation on a 12-K array simply be a matter of acid catalysis? To test this idea, the reaction on the 12-K array was repeated at a pH of 9 (Scheme 4, image b). A checkerboard in a box pattern of microelectrodes was used as a cathode. The use of the more basic conditions improved the reaction. While fluorescence again appeared at many nonselected sites on the array, in places on the array the expected pattern was observed. We were moving in the right direction, but more basic conditions were needed. Of course, discovering that the loss of confinement was due to acidic decomposition of the functionalized agarose polymer coating the array suggested a second solution; the use of a more stable polymer. To this end, a 12-K array was coated with a nonsugar-based diblock copolymer (Scheme 6).6 The polymer has one block built from a methacrylate monomer and one block built from a 4-bromostyrene monomer. The methacrylate block is functionalized with a cinnamate group that can be photochemically cross-linked to add stability to the polymer once it is placed on the array. The 4-bromostyrene block can be used to add functional groups to the surface of the array. The polymer contains no acetal groups and hence provides no opportunity for acid-catalyzed oxonium ion formation. Accordingly, the reaction to place an amine on the surface of a 12-K array proceeded well (Scheme 6). The reaction worked best when a potential of 1.7 V relative to the auxiliary electrode was used, a value slightly lower than that used with the agarose polymer. The reaction was again run for 90 s. In order to optimize the conversion at the selected microelectrodes, the reaction was repeated 4 times with the intensity of the fluorescence monitored 11201

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Langmuir Scheme 6. Aryl Bromide and Amine Coupling on the 12 K Array

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Scheme 8. Aryl Bromide and Alcohol Coupling on the 12 K Array

Scheme 9. Aryl Bromide and Alkyl Thiol Coupling Scheme 7. Phenyl Iodide and Alcohol Coupling on the 1 K Array

after each run. The use of the lower potential and multiple runs was preferable to the previous conditions shown in Scheme 4 because higher potentials led to delamination of the diblock copolymer from the array. This was not a problem at lower potentials. The same observations were made when alcohol nucleophiles were employed (Scheme 7). Initially, the reaction was studied on a 1-K array coated with agarose and used the same reaction conditions developed for the carbamate nucleophile. A pyrenyl alcohol was used as the nucleophile in solution. A checkerboard pattern of microelectrodes was used as cathodes. The reaction was nicely confined to the selected microelectrodes. As with the amine nucleophile, the use of an agarose coated 12-K array met with failure. Again, the reaction appeared to lose confinement, and once again the problem resulted from the instability of the surface. When reactions that used an alcohol nucleophile, were repeated on the 12-K array coated with the diblock copolymer, they proceeded well (Scheme 8). The reaction conditions were identical to those used for the amine addition. An alternating pattern of squares, each comprising four microelectrodes, was used as cathodes, and confinement of the reaction was observed over the whole array. Surprisingly, the reaction to place molecules on the diblock copolymer coated 12-K array did not work as well with a sulfur nucleophile (Scheme 9). In this experiment, the selected microelectrodes were set at 1.7 V, again in an alternating squares

pattern. The reaction proceeded, but it only did so slowly. With reaction times equivalent to the amine and alcohol nucleophiles, very little fluorescence was seen proximal to the electrodes selected for the reduction (Scheme 9).

’ LIGAND EFFECTS Fortunately, Buchwald and co-workers have shown that Cu(I)-coupling reactions can be dramatically influenced by the ligand used for the Cu catalyst.17 This observation is true for siteselective reactions on arrays as well. Consider the thiol-based addition reaction illustrated in Scheme 10. In this experiment, the triphenylphosphine ligand in the original reaction was replaced with isobutyl 2-carboxycyclohexanone.18 The effect on the reaction was dramatic with significantly more fluorescence being observed by each of the selected microelectrodes using one-half of the reaction time (two periods of 90 s). The faster reaction was still confined nicely by the oxygen in solution. Interestingly, reactions that used alcohol and amine nucleophiles with ketoester based ligands did not go as well as the same reactions which used the triphenylphosphine ligand. However, repeating the amine and alcohol-based reactions with the new ligand showed that the amine proceeded better than the alcoholderived coupling, a result that is consistent with the rate differences for the reactions in solution reported by the Buchwald group. Such observations suggest that in the future the ligand effects and ligand control of chemoselectivity observed for solution-phase Cu(I) reactions may also shape the chemistry of microarray-based transformations. 11202

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Scheme 10. Improved Aryl Bromide and Alkyl Thiol Coupling

Scheme 11. Multistep Synthesis on a 1 K Array

’ MULTISTEP PROCEDURES With a method for site-selectively generating Cu(I) catalysts in place, attention was turned toward a multiple-step synthetic sequence that would build molecules of potential biological interest. Our goal was to demonstrate that we could both synthesize and characterize molecules at specific locations on an array. For this purpose, a plan to synthesize substituted benzotriazepines on the arrays was developed (Scheme 11). The chemistry aimed to take advantage of two Cu(I) catalyzed reactions. In the first, a Cu(I) catalyzed “click-reaction” would be used to place a benzotriazepine ring skeleton onto the array.13,19 The resulting triazole ring would be used as a “mass-spectrometry cleavable” linker for characterizing the products from subsequent reactions.13 In the second, a Cu(I) catalyzed arylation reaction would be used to functionalize the building block on the array.20 The synthesis started by placing an azide substrate by each of the microelectrodes in an agarose-coated array (Scheme 11). As in the earlier experiments, this was accomplished by base

Figure 1. High-resolution positive-ion mass spectra of the array in Scheme 11.

catalyzing an esterification reaction between an N-hydroxysuccinimide ester and the alcohols on the agarose surface (Supporting Information).7 11, The Cu(I)-“click-reaction” was then run at every microelectrode utilizing the reaction conditions highlighted in Scheme 1. The “click-reaction” was immediately followed with a second Cu(I)-catalyzed reaction that coupled a vinyl iodide to the imine of the benzotriazepine. The reaction was again run by treating the array with an acetonitrile/DMF/water solution containing copper sulfate, triphenylphosphine ligand, tetrabutylammonium bromide electrolyte, and air as a confining agent. The needed Cu(I) catalyst was then generated at selected microelectrodes in the array (a checkerboard pattern) by setting the potential at the electrodes to 2.4 V relative to the remote Pt-wire anode. The electrodes were turned on for a period of 0.5 s and then turned off again for a period of 0.1 s. This was repeated for 600 cycles. At the end of the reaction, the microelectrode array was washed and then examined with a fluorescence microscope to give the picture illustrated in Scheme 11. The reaction clearly led to confinement of the fluorescence to the desired microelectrodes, but was the product from the sequence really what we thought it was? In order to answer this question, we took advantage of time-offlight mass spectrometry (TOF-SIMS). Previously, we demonstrated that triazoles fragmented nicely in TOF-SIMS experiments to either cleave alpha to the ring or cleave by a retro [3 + 2]-cycloaddition.13 In addition, we have seen McLafferty-type fragmentations and cleavages around pyrene groups on the surface of a microelectrode array in TOF-SIMS experiments.21 When the array used in Scheme 11 was subjected to the TOFSIMS experiment using a bismuth particle beam, a series of fragments were observed (Figure 1). The first fragment of note was a retro [3 + 2]-product at 242 m/z. This fragment was consistent with unreacted benzotriazepine and indicated that the Cu(I) reaction had not gone to completion. However, it did indicate that the reaction placing the substrate for the first Cu(I)coupling reaction on the surface of the array was successful. Other fragments obtained indicated that the vinyl iodide coupling reaction on the surface of the array had worked. Fragments at m/z 439 and m/z 550 (not shown) were both consistent with the coupled product. They differed only in how they were cleaved from the array in the TOF-SIMS. The m/z 439 fragment cleaved next to the triazole ring, a cleavage consistent with earlier observations.13 The fragment at m/z 550 resulted 11203

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Langmuir from a McLafferty fragmentation involving the ester group that attached the molecule to the surface of the array (a fragmentation directly analogous to the one leading to the m/z 350 fragment). The MS obtained for the fragment at m/z 550 was consistent with the charge on this fragment being a radical cation of the pyrene. For example, the fragment at m/z 350 is a cleavage product of the fragment at m/z 550 that is consistent with earlier TOF-SIMS cleavage products from substituted pyrenes. From the TOF-SIMS experiment, it was clear that the multistep synthesis led to the desired substituted benzotriazepine. Once again, a new Cu(I) catalyzed reaction was performed using the same catalyst generation and confinement strategy used in the initial site-selective “click-reaction”.

’ CONCLUSIONS The conditions developed for site-selectively conducting Cu(I) catalyzed cycloaddition reactions on a microelectrode array have been extended to seven new site-selective reactions. In each case, the previously developed method for generating and confining the Cu(I) catalyst proved general. For the first time, reactions using 12-K arrays did not directly mimic reactions using the 1-K arrays. The difference turned out to be the nature of the electrolysis cell used. The 12-K array reactions are undivided cells, and the 1-K array reactions are divided cells. The 12-K array being an undivided cell led to problems with acid generated at the counter electrode interfering with the 12-K array reactions. This problem can be solved by either using more basic reaction conditions on the array or even better the use of a more stable diblock copolymer surface for attaching substrates to the arrays. Finally, the Cu(I) catalyzed reactions described here represent the third family of reactions developed on the arrays. Earlier, we demonstrated the generality of both Pd(0) catalyzed coupling reactions and Pd(II) based oxidations on the arrays. It appears that, with transition metals, once a method for confining a reagent to specific sites on a microelectrode array is found, it can be adopted with relatively few changes to a variety of reactions. ’ ASSOCIATED CONTENT

bS

Supporting Information. Full experimental and characterization data are provided for all substrates and products. Copies of proton and carbon NMR spectra are included. This material is available free of charge via the Internet at http://pubs.acs.org.

’ AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Present Addresses #

Customarray Inc., 6500 Harbour Heights Parkway, Suite 202, Mukilteo, WA 98290.

’ ACKNOWLEDGMENT We thank the National Science Foundation (CHE-0909723 and CHE-0847937) for their generous support of our work. We also gratefully acknowledge the Washington University High Resolution NMR facility, partially supported by NIH grants

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RR02004, RR05018, and RR07155, and the Washington University Mass Spectrometry Resource Center, partially supported by NIHRR00954, for their assistance.

’ REFERENCES (1) Patai Series: The Chemistry of Organocopper Compounds, Rappaport, Z. Z.; Marek, I., Eds; Wiley: New York, 2010. (2) For a description of the chips used here, seeDill, K.; Montgomery, D. D.; Wang, W.; Tsai, J. C. Anal. Chim. Acta 2001, 444, 691K chips: electrode diameter = 92 μm; Distance between the Pt-electrodes (rectangular cells) = 245.3 and 337.3 μm; 12K slide: diameter = 44 μm; Distance between the Pt-electrodes (square cells) = 33 μm. (3) Microelectrode arrays can be purchased from CustomArray, Inc. (4) For alternative approaches, see (a) Sullivan, M. G.; Utomo, H.; Fagan, P. J.; Ward, M. D. Anal. Chem. 1999, 71, 4369. (b) Zhang, S.; Zhao, H.; John, R. Anal. Chim. Acta 2000, 421, 175. (c) Hintsche, R.; Albers, J.; Bernt, H.; Eder, A. Electroanalysis 2000, 12, 660. (d) Gardner, R. D.; Zhou, A.; Zufelt, N. A. Sens. Actuators, B 2009, 136, 177. (e) Beyer, M.; Nesterov, A.; Block, I.; K€onig, K.; Felgenhauer, T.; Fernandez, S.; Leibe, K.; Torralba, G.; Hausmann, M.; Trunk, U.; Lindenstruth, V.; Bischoff, F. R.; Stadler, V.; Breitling, F. Science 2007, 318, 1888. (f) Devaraj, N. K.; Dinolfo, P. H.; Chidsey, C. E. D.; Collman, J. P. J. Am. Chem. Soc. 2006, 128, 1794. (g) Wassum, K. M.; Tolosa, V. M.; Wang, J.; Walker, E.; Monbouquette, H. G.; Maidment, N. T. Sensors 2008, 8, 5023. (h) Kerkoff, H. G.; Zhang, X.; Mailly, F.; Nouet, P.; Liu, H.; Richardson, A. VLSI Design 2008, Article ID 437879 (doi:10.1155/ 2008/437879). (i) Zhang, Y.; Wnag, H.; Nie, J.; Zhang, Y.; Shen, G.; Yu, R. Biosens. Bioelectron. 2009, 25, 34. (j) Maurer, K.; Yazvenko, N.; Wilmoth, J.; Cooper, J.; Lyon, W.; Danley, D. Sensors 2010, 10, 7371. (k) Li, X.; Tian, Y.; Xia, P.; Luo, Y.; Rui, Q. Anal. Chem. 2009, 81, 8249. (l) Chan, E. W. L.; Yousaf, M. N. ChemPhysChem 2007, 8, 1469. (5) For real time signaling on an array, see:(a) Tesfu, E.; Roth, K.; Maurer, K.; Moeller, K. D. Org. Lett. 2006, 8, 709. (b) Stuart, M.; Maurer, K.; Moeller, K. D. Bioconjugate Chem. 2008, 19, 1514. (6) For an example, see:Hu, L.; Bartels, J. L.; Bartels, J. W.; Maurer, K.; Moeller, K. D. J. Am. Chem. Soc. 2009, 131, 16638. (7) For Pd(II) reactions:(a) Tesfu, E.; Roth, K.; Maurer, K.; Moeller, K. D. Org. Lett. 2006, 8, 709. (b) Tesfu, E.; Maurer, K.; Ragsdale, S. R.; Moeller, K. D. J. Am. Chem. Soc. 2004, 126, 6212. (c) Tesfu, E.; Maurer, K.; McShae, A.; Moeller, K. D. J. Am. Chem. Soc. 2006, 128, 70. (8) For Pd(0) reactions:(a) Tian, J.; Maurer, K.; Tesfu, E.; Moeller, K. D. J. Am. Chem. Soc. 2005, 127, 1392. (b) Tian, J.; Maurer, K.; Moeller, K. D. Tetrahedron Lett. 2008, 49, 5664. (c) Hu, L.; Maurer, K.; Moeller, K. S. Org. Lett. 2009, 11, 1273. (d) Hu, L.; Stuart, M.; Tian, J.; Maurer, K.; Moeller, K. D. J. Am. Chem. Soc. 2010, 132, 16610. (9) For examples of the site-selective generation of base, see ref 5b andMaurer, K.; McShea, A.; Strathmann, M.; Dill, K. J. Comb. Chem. 2005, 7, 637. (10) For the site-selective generation of acid:Kesselring, D.; Maurer, K.; Moeller, K. D. Org. Lett. 2008, 10, 2501. (11) For the use of CAN in a site-selective fashion:Kesselring, D.; Maurer, K.; Moeller, K. D. J. Am. Chem. Soc. 2008, 130, 11290. (12) For the site-selective use of Sc(III), see Bi, B.; Maurer, K.; Moeller, K. D. Angew. Chem., Int. Ed. Engl. 2009, 48, 5872. (13) Bartels, J. L.; Lu, P.; Walker, A.; Maurer, K.; Moeller, K. D. Chem. Commun. 2009, 5573. (14) For reviews of N, O, and S coupling reactions, see(a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400. (b) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428. For reactions with amine nucleophiles, see(c) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4, 581. (d) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793. (e) Jones, G. O.; Liu, P.; Houk, K. N.; Buchwald, S. L. J. Am. Chem. Soc. 2010, 132, 6205. For reactions with alcohol nucleophiles, see (f) Wolter, M.; Nordmann, G.; Job, G. F.; Buchwald, S. L. Org. Lett. 2002, 4, 973. (g) A., R.; Shafir, A.; Choi, A.; Lichtor, P. A.; Buchwald, S. L. J. Org. Chem. 2008, 73, 284. For couplings of both alcohols and amines, see(h) Rao, H.; Jin, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Chem.—Eur. J. 2006, 12, 3636. 11204

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