Micro wet analysis system using multi-phase laminar flows in three-dimensional microchannel network

A three-dimensional microchannel network with two-level crossings of channels was constructed in a glass microchip by sandwiching an insulating glass plate between two glass plates with microchannels followed by thermal bonding. Pressure-driven stable multi-phase laminar flows inside the three-dimensional channel network were realized by balancing flow rates of syringe pumps. Micro unit operations for mixing, reaction, solvent extraction, and detection were properly arranged in the multi-phase laminar flows, so that four parallel analyses, comprising twenty unit operations in total, could be integrated onto a single chip. Two chelating reagents and two sample solutions containing heavy metal ions (Fe(ii) or Co(ii)) were mixed and reacted in four different combinations using the three-dimensional channel network. After chelating reactions were completed, post processing (solvent extraction or addition of acid) was applied to each solution stream to remove the interferences of coexisting metal ions. Finally, target metal complexes were detected using a thermal lens microscope (TLM). Integrity of the micro system was confirmed by qualitative analysis of Fe(ii) and Co(ii). This is the first example of continuous flow chemical processing utilizing multi-phase laminar flow realized in a three-dimensional channel network.     

Poly(dimethylsiloxane) microchip: microchannel with integrated open electrospray tip

A polymer microchip with an open tip for electrospray mass spectrometry is presented. The tip consists of a groove with parallel walls where a droplet can form at the end surface. A lid covers the whole chip except at the microchannel tip, which is left open. Poly(dimethylsiloxane) (PDMS) microchips were cast using a nickel mould which in turn was replicated from a dry etched silicon wafer. Tips with microchannel widths of around 50 microm could easily be replicated. Since the tip had no cover, the assembly of microchip and cover was simplified. A total ion current variation of 5% during 300 s was achieved for a 1 microM myoglobin solution. The non-complex design of the cover makes it suitable for versatile tests of chip prototypes. The nickel mould was found to be useful for PDMS microstructure fabrication. Also, such a robust mould allows casting electrospray tips in more rigid thermoset materials.     

Glass/SU‐8 microchip for electrokinetic applications

In this communication, we describe the fabrication and electric characterization of a hybrid glass/SU‐8 microchannels for high‐performance electrokinetic applications. The bonding process employed SU‐8 film as intermediate layer with reduced baking times; all the procedure took less than 50 min (only about 10 min disregarding the cleaning and dehydration steps). Additionally, further steps to improve the adhesion of the substrate to the SU‐8 were not needed. The developed configuration aggregates the advantages of both substrates, including (i) simple fabrication techniques; (ii) high compatibility for integration of microelectromechanical, optical, and electrochemical components (SU‐8); (iii) high and stable electroosmotic mobility (μ_EO); and (iv) satisfactory heat dissipation capacity (glass). Electroosmotic mobilities were measured as a function of the pH using the current monitoring method, whereas the heat dissipation capacity was investigated through Ohm's law plots for both glass and glass/SU‐8 microchips. The measured μ_EO values were similar for both microdevices, with mobilities of the order of 4.0–4.5 × 10^?4 cm² V^?1 cm^?1 at 4–12 pH range using phosphate buffer (10 and 20 mmol/L). The heat dissipation assays were carried out in microchannels filled with 20 mmol/L phosphate buffer. A considerable Joule heating was observed only at electric field strengths greater than 580 V cm^?1 in hybrid glass/SU‐8 microdevices, representing a substantial increase of 48% when compared to all SU‐8 microdevices.     

Poly (acrylic acid) microchannel modification for the enhanced resolution of catecholamines microchip electrophoresis with electrochemical detection

A new modification of glass electrophoresis microchips based on poly (acrylic) acid immobilization has been performed. It is based on the reaction of PAA with an amine functionalized surface, obtained through the bifunctional reagent 3-aminopropyl triethoxysilane. Parameters affecting all the three steps involved: surface activation, silanization and polymer immobilization were optimized employing soda-lime glass plates. Characterization by SEM and XPS was carried out. Application of the modified microchips to the separation of a model system: dopamine (D), epinephrine (E) and norepinephrine (NE), that on the other hand are of high clinical relevance was performed employing amperometric detection. Modification is necessary for obtaining partial resolution of all the three analytes in a microchip with an effective separation length of 30 mm. Situation changes from no resolution (Rs) at all (only one peak was achieved for the mixture) to a partial resolution (Rs D–NE and Rs NE–E are 0.25 and 0.24 respectively). Microchips with 60 mm of separation channel were also modified, implying this procedure a resolution enhancement (Rs of 0.49 and 0.28 for D–NE and NE–E respectively), even when methanol is employed as organic modifier (Rs values of 0.70 (D–NE) and 0.66 (NE–E) for a 3% MeOH).     

Electrochemical detector for microchip electrophoresis of poly(dimethylsiloxane) with a three-dimensional adjustor

This paper presents an electrochemical detector for poly(dimethylsiloxane) (PDMS) microchip CE with a three-dimensional adjustor which makes it possible to accurately align a separate working electrode that can be easily fabricated in laboratory to the uncertain PDMS microchannel outlet. The substantial influence of the electrode-PDMS microchannel distance was investigated. The optimal electrode-outlet distance was found to be 10 microm for the PDMS microchannel with the width of 50 microm due to its relatively slow electroosmotic flow. Adrenaline and catechol were well separated, with a linear response range from 20 microM to 1 mM, and a detection limit of 2 microM for catechol, using carbon disk electrode (diameter of 300 microm). Furthermore, arginine and histidine can be well separated and detected directly in the PDMS microchannel using a Cu disk electrode (diameter of 150 microm).     

Hydrothermal synthesis and characterization of a novel polyoxometallate-templated three-dimensional supramolecular network

The well-known polyoxomolybdate anion [Mo₈O₂₆]^4? has been used as a noncoordinating anionic template for the construction of a novel three-dimensional (3D) supramolecular network, [Co(phen)₃]₂[Mo₈O₂₆]·?2.5H₂O (1) (phen?=?o-phenanthroline). Compound 1 has been characterized by elemental analyses, IR spectrum, X-ray photoelectron spectroscopy (XPS), TG analysis and single-crystal X-ray diffraction. Single-crystal X-ray diffraction analysis reveals that [Co(phen)₃]²⁺ coordination complexes are packed together via aromatic?π–π?stacking and hydrogen-bonding interactions, and exhibit an interesting 3D supramolecular network with one-dimensional (1D) box-like channels in which the octamolybdate anions reside.     

Expedient parallel synthesis of 2-amino-4-heteroarylpyrimidines

[reaction: see text] An expedient synthesis of diverse 2-amino-4-heteroarylpyrimidines via a 2-chloropyrimidine intermediate is described. A series of potentially biologically active analogues have been synthesized in two parallel steps to afford focused arrays.     

Solution-phase parallel synthesis of 3,5,6-substituted indolin-2-ones

A practical and efficient new parallel method has been developed for the synthesis of 3-substituted indolin-2-ones with a large variety of substituents at the 5- and 6-positions using 1,5-difluoro-2,4-dinitrobenzene. This 3,5,6-substituted indolin-2-one skeleton possesses three points of diversification and, thus, affords new opportunities for identification and optimization of leads in drug discovery.     

Solid-phase parallel synthesis of drug-like artificial 2H-benzopyran libraries

This review covers the construction of drug-like 2H-benzopyrans and related libraries using solid-phase parallel synthesis. In this context, the preparation of substituted benzopyrans such as mono-, di- and trisubstituted benzopyran derivatives and additional ring-fused benzopyrans such as benzopyranoisoxazoles, benzopyranopyrazoles, six-membered ring-fused benzopyrans, and polycyclic benzopyrans are highlighted.     

Solution-phase parallel synthesis of diverse 1,5-benzodiazepin-2-ones

A practical and efficient parallel method has been developed for the synthesis of 1,5-benzodiazepin-2-ones with a large variety of substituents at the 3-, 4-, 5-, 7-, and 8-positions using 1,5-difluoro-2,4-dinitrobenzene as the starting material. All the reactions involved here are highly effective in giving the desired products under mild conditions.     

Fluorous electrophilic scavengers for solution-phase parallel synthesis

A fluorous isatoic anhydride and isocyanate are synthesized and used as scavengers for amines in solution-phase parallel synthesis of urea, thiourea, and β-hydroxyamine analogs. The resulting fluorous derivatives are readily separated from the reaction mixture by solid-phase extractions (SPE) over FluoroFlash™ cartridges to give products with good purity. The SPE cartridges can be reused.     

An efficient method for solution-phase parallel synthesis of 2-quinoxalinol salen Schiff-base ligands

A solution-phase parallel method for the synthesis of 2-quinoxalinol salen ligands was designed and optimized. The synthesis begins with commercially available 1,5-difluoro-2, 4-dinitrobenzene (DFDNB) and employs a sequence of five straightforward and high-yielding reaction steps. Simple laboratory techniques with low sensitivity to water or air for solution-phase parallel reactions were coupled with convenient workup and purification procedures to give high-purity and yield a small ligand library of 20 compounds. The final step, a Schiff-base condensation of an aldehyde with the diaminoquinoxaline results in a new category of ligands for metal coordination or of potential bioactivity, based on the skeleton 2,2'-(1E,1'E)-(quinoxaline-6,7-diylbis(azan-1-yl-1-ylidene))bis(methan-1-yl-1-ylidene)diphenol. The approach described here is easily adaptable for parallel synthesis of a larger library.     

ROMPgel-supported triphenylphosphine with potential application in parallel synthesis

[reaction: see text] ROMPgel-supported triphenylphosphine was synthesized in three steps (67%) from norbornadiene, 4-bromoiodobenzene, and chlorodiphenylphosphine. The supported reagent has a high loading (2.5 mmol/g) and favorable swelling properties in organic solvents. It has been utilized for the conversion of alcohols to halides, the reduction of ozonides, and the isomerization of alpha,beta-acetylenic esters and in the Staudinger reaction. In general, filtration of the resin from the reaction mixtures and evaporation gave the corresponding products in high yield and purity.     

Automation of fluorous solid-phase extraction for parallel synthesis

An automatic fluorous solid-phase extraction (F-SPE) technique is developed by using FluoroFlash SPE cartridges on the RapidTrace workstation. A 10-module workstation has the capability to complete a maximum of 100 SPEs each round in 1-2 h. Another important feature of the RapidTrace system is that it has the capability to load slurry samples onto the F-SPE cartridges. The F-SPE cartridge charged with 2 g of fluorous silica gel is used to purify up to 200 mg of crude sample. Sample loading, elution solvent, cartridge reuse, and SPE reproducibility are evaluated. The automatic SPE system is used for purification of a small urea library generated from amine-scavenging reactions using fluorous dichlorotriazine, a 96-membered amide library generated using 2-chloro-4,6-bis[(perfluorohexyl)propyloxy]-1,3,5-triazine as the coupling agent, and another 96-membered library generated from fluorous Mitsunobu reactions. Approximately 90% of the products have > 90% purity after F-SPE.     

Plate-to-plate fluorous solid-phase extraction for solution-phase parallel synthesis

A commercially available Argonaut VacMaster-96 plate-to-plate solid-phase extraction (SPE) station equipped with 24 FluoroFlash cartridges is employed for parallel purification of fluorous reaction mixtures. Each cartridge charged with 3 g of fluorous silica gel has the capability to produce up to 100 mg of purified small molecules. The 24-well receiving plate has a standard footprint that can be directly concentrated in a Genevac vacuum centrifuge. Important issues such as sample loading, product cross-contamination, cartridge reuse, and reproducibility are investigated. The SPE system has been demonstrated in the purification of three small libraries that were produced involving amine scavenging reactions with fluorous isatoic anhydride, amide coupling reactions with 2-chloro-4,6-bis[(perfluorohexyl)propyloxy]-1,3,5-triazine (fluorous CDMT), and amide coupling reactions with a newly developed fluorous Mukaiyama condensation reagent.     

A three-dimensional, noninterpenetrating metal--organic framework with the moganite topology: a simple (4(2)x6(2)x8(2))(4x6(4)x8)(2) net containing two kinds of topologically nonequivalent points

Self assembly of Cu(2+) with the multifunctional ligand 2-(4-pyridyl)thiazole-4-carboxylic acid (Pytac) affords the neutral 3D coordination polymer [Cu(3)(Pytac)(6)](H(2)O)(14) (hereafter, SZL-1), which has the rare moganite topology. The mineral moganite has a topology that is closely related to the well-known quartz topology, but the two topologies are differentiated by the number of topologically inequivalent nodes. Whereas only one kind of node is present in quartz, two types of topologically inequivalent nodes are present in moganite. The title compound, which has three vertices in its repeat unit, has two types of topologically inequivalent nodes with the overall vertex symbol (4(2)x6(2)x8(2))(4x6(4)x8)(2) corresponding to the moganite net. Prior to this report, few metal-organic framework materials (MOFs) have been found to contain more than one type of node, and SZL-1 is the first MOF with the moganite topology.     

A traceless approach for the parallel solid-phase synthesis of 2-(arylamino)quinazolinones

A traceless approach for the parallel solid-phase synthesis of 2-arylamino-substituted quinazolinones is described. Acylation of MBHA resin with o-nitrobenzoic acid derivatives, followed by reduction of the nitro group with tin chloride, generated a resin-bound o-anilino derivative. Reaction of resin-bound o-anilino derivative with arylisothiocyanates yielded resin-bound thioureas, which reacted with amines in the present of Mukaiyama's reagent (2-chloro-1-methylpyridinium iodide) to afford resin-bound guanidines. Following intramolecular cyclization of the resin-bound guanidines during cleavage from the resin by HF/anisole (95/5) for 1.5 h at 0 degrees C, the desired products were obtained in good yield and purity.