Integration of Impedimetric Sensors for In Situ Electrochemical Impedance Spectroscopy in Free-Flow Electrophoresis Applications in Lab-on-Chip Systems.

Miniaturization and integration of chemical reactions into fluidic systems in combination with product purification or buffer exchange can reduce the amount of solvents and reactants required while increasing synthesis efficiency. A critical step is the regulation of flow rates to realize optimal synthesis conditions and high purification rates, so real-time, label-free monitoring is required in methods such as free-flow electrophoresis. Optical detection methods are widely used, but they often have complex excitation and detection setups that are disadvantageous for point-of-care applications. The method we have chosen is electrochemical impedance spectroscopy for detecting charged compounds in aqueous buffers with low ionic strength. Propranolol was selected for proof of concept and was separated from the organic solvent and the precursor oxirane by free-flow electrophoresis. For this purpose, electrode structures were fabricated in microfluidic channels by photolithographic lift-off technique and optimized in terms of positioning, electrode size and distance for sensitive detection, and quantification of propranolol in the nanomolar range. It is also noteworthy that the organic solvent dimethyl sulfoxide (DMSO) could be detected and quantified by an increased impedance magnitude. Subsequently, the optimized interdigital electrode structures were integrated into the outlet channels of the electrophoretic separation chamber to monitor the various outgoing fluidic streams and provide in-line control of the fluidic flows for the purification step. In conclusion, we can provide a microfluidic chip to monitor the separation efficiency of a substance mixture during free-flow electrophoresis without the need of complex analytical techniques using electrochemical impedance spectroscopy.

Photocatalytic Arylation of P4 and PH3 : Reaction Development Through Mechanistic Insight.

Detailed 31 P{1 H} NMR spectroscopic investigations provide deeper insight into the complex, multi-step mechanisms involved in the recently reported photocatalytic arylation of white phosphorus (P4 ). Specifically, these studies have identified a number of previously unrecognized side products, which arise from an unexpected non-innocent behavior of the commonly employed terminal reductant Et3 N. The different rate of formation of these products explains discrepancies in the performance of the two most effective catalysts, [Ir(dtbbpy)(ppy)2 ][PF6 ] (dtbbpy=4,4'-di-tert-butyl-2,2'-bipyridine) and 3DPAFIPN. Inspired by the observation of PH3 as a minor intermediate, we have developed the first catalytic procedure for the arylation of this key industrial compound. Similar to P4 arylation, this method affords valuable triarylphosphines or tetraarylphosphonium salts depending on the steric profile of the aryl substituents.

On-chip mass spectrometric analysis in non-polar solvents by liquid beam infrared matrix-assisted laser dispersion/ionization.

By the on-chip integration of a droplet generator in front of an emitter tip, droplets of non-polar solvents are generated in a free jet of an aqueous matrix. When an IR laser irradiates this free liquid jet consisting of water as the continuous phase and the non-polar solvent as the dispersed droplet phase, the solutes in the droplets are ionized. This ionization at atmospheric pressure enables the mass spectrometric analysis of non-polar compounds with the aid of a surrounding aqueous matrix that absorbs IR light. This works both for non-polar solvents such as n-heptane and for water non-miscible solvents like chloroform. In a proof of concept study, this approach is applied to monitor a photooxidation of N-phenyl-1,2,3,4-tetrahydroisoquinoline. By using water as an infrared absorbing matrix, analytes, dissolved in non-polar solvents from reactions carried out on a microchip, can be desorbed and ionized for investigation by mass spectrometry.

In situ monitoring of photocatalyzed isomerization reactions on a microchip flow reactor by IR-MALDI ion mobility spectrometry.

The visible-light photocatalytic E/Z isomerization of olefins can be mediated by a wide spectrum of triplet sensitizers (photocatalysts). However, the search for the most efficient photocatalysts through screenings in photo batch reactors is material and time consuming. Capillary and microchip flow reactors can accelerate this screening process. Combined with a fast analytical technique for isomer differentiation, these reactors can enable high-throughput analyses. Ion mobility (IM) spectrometry is a cost-effective technique that allows simple isomer separation and detection on the millisecond timescale. This work introduces a hyphenation method consisting of a microchip reactor and an infrared matrix-assisted laser desorption ionization (IR-MALDI) ion mobility spectrometer that has the potential for high-throughput analysis. The photocatalyzed E/Z isomerization of ethyl-3-(pyridine-3-yl)but-2-enoate (E-1) as a model substrate was chosen to demonstrate the capability of this device. Classic organic triplet sensitizers as well as Ru-, Ir-, and Cu-based complexes were tested as catalysts. The ionization efficiency of the Z-isomer is much higher at atmospheric pressure which is due to a higher proton affinity. In order to suppress proton transfer reactions by limiting the number of collisions, an IM spectrometer working at reduced pressure (max. 100 mbar) was employed. This design reduced charge transfer reactions and allowed the quantitative determination of the reaction yield in real time. Among 14 catalysts tested, four catalysts could be determined as efficient sensitizers for the E/Z isomerization of ethyl cinnamate derivative E-1. Conversion rates of up to 80% were achieved in irradiation time sequences of 10 up to 180 s. With respect to current studies found in the literature, this reduces the acquisition times from several hours to only a few minutes per scan.

Versatile Visible-Light-Driven Synthesis of Asymmetrical Phosphines and Phosphonium Salts.

Asymmetrically substituted tertiary phosphines and quaternary phosphonium salts are used extensively in applications throughout industry and academia. Despite their significance, classical methods to synthesize such compounds often demand either harsh reaction conditions, prefunctionalization of starting materials, highly sensitive organometallic reagents, or expensive transition-metal catalysts. Mild, practical methods thus remain elusive, despite being of great current interest. Herein, we describe a visible-light-driven method to form these products from secondary and primary phosphines. Using an inexpensive organic photocatalyst and blue-light irradiation, arylphosphines can be both alkylated and arylated using commercially available organohalides. In addition, the same organocatalyst can be used to transform white phosphorus (P4 ) directly into symmetrical aryl phosphines and phosphonium salts in a single reaction step, which has previously only been possible using precious metal catalysis.

Nonaqueous Micro Free-Flow Electrophoresis for Continuous Separation of Reaction Mixtures in Organic Media.

The continuous separation mechanism of micro free-flow electrophoresis (µFFE) is a straightforward, suitable tool for microscale purification of reaction mixtures. However, aqueous separation buffers and organic reaction solvents limit the applicability of this promising combination. Herein, we have explored nonaqueous micro free-flow electrophoresis for this purpose and present its suitability for a continuous workup of organic reactions performed in acetonitrile. After successful nonaqueous FFE separation of organic dyes, the approach was applied to continuously recover the photocatalyst [Ru(bpy)3]2+ from a homogeneous, acetonitrile-based reaction mixture. This approach opens up possibilities for further downstream processing of purified products and is also attractive for recycling of precious catalyst species.

A Toolbox Approach To Construct Broadly Applicable Metal-Free Catalysts for Photoredox Chemistry: Deliberate Tuning of Redox Potentials and Importance of Halogens in Donor-Acceptor Cyanoarenes.

The targeted choice of specific photocatalysts has been shown to play a critical role for the successful realization of challenging photoredox catalytic transformations. Herein, we demonstrate the successful implementation of a rational design strategy for a series of deliberate structural manipulations of cyanoarene-based, purely organic donor-acceptor photocatalysts, using 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN) as a starting point. Systematic modifications of both the donor substituents as well as the acceptors' molecular core allowed us to identify strongly oxidizing as well as strongly reducing catalysts (e.g., for an unprecedented detriflation of unactivated naphthol triflate), which additionally offer remarkably balanced redox potentials with predictable trends. Especially halogen arene core substitutions are instrumental for our targeted alterations of the catalysts' redox properties. Based on their preeminent electrochemical and photophysical characteristics, all novel, purely organic photoredox catalysts were evaluated in three challenging, mechanistically distinct classes of benchmark reactions (either requiring balanced, highly oxidizing or strongly reducing properties) to demonstrate their enormous potential as customizable photocatalysts, that outperform and complement prevailing typical best photocatalysts.

A synergistic LUMO lowering strategy using Lewis acid catalysis in water to enable photoredox catalytic, functionalizing C-C cross-coupling of styrenes.

Easily available α-carbonyl acetates serve as convenient alkyl radical source for an efficient, photocatalytic cross-coupling with a great variety of styrenes. Activation of electronically different α-acetylated acetophenone derivatives could be effected via LUMO lowering catalysis using a superior, synergistic combination of water and (water-compatible) Lewis acids. Deliberate application of fac-Ir(ppy)3 as photocatalyst to enforce an oxidative quenching cycle is crucial to the success of this (umpolung type) transformation. Mechanistic particulars of this dual catalytic coupling reaction have been studied in detail using both Stern-Volmer and cyclic voltammetry experiments. As demonstrated in more than 30 examples, our water-assisted LA/photoredox catalytic activation strategy allows for excess-free, equimolar radical cross-coupling and subsequent formal Markovnikov hydroxylation to versatile 1,4-difunctionalized products in good to excellent yields.

Unlocking the Potential of Phenacyl Protecting Groups: CO2-Based Formation and Photocatalytic Release of Caged Amines.

Orthogonal protection and deprotection of amines remain important tools in synthetic design as well as in chemical biology and material research applications. A robust, highly efficient, and sustainable method for the formation of phenacyl-based carbamate esters was developed using CO2 for the in situ preparation of the intermediate carbamates. Our mild and broadly applicable protocol allows for the formation of phenacyl urethanes of anilines, primary amines, including amino acids, and secondary amines in high to excellent yields. Moreover, we demonstrate the utility by a mild and convenient photocatalytic deprotection protocol using visible light. A key feature of the [Ru(bpy)3](PF6)2-catalyzed method is the use of ascorbic acid as reductive quencher in a neutral, buffered, two-phase acetonitrile/water mixture, granting fast and highly selective deprotection for all presented examples.

An N-Heterocyclic Carbene-Mediated, Enantioselective and Multicatalytic Strategy to Access Dihydropyranones in a Sequential Three-Component One-Pot Reaction.

The multicatalytic generation of 3,5,6-trisubstituted 3,4-dihydropyranones with high enantioselectivity using a highly convergent strategy starting from commercially available precursors is reported. The operationally simple three-step, one-pot protocol merges H-bond and NHC catalysis to provide crucial, reactive ß-unsubstituted enones from nitroalkenes as latent 1,2-biselectrophiles. These intermediates are directly funneled into a further NHC-catalyzed formal hetero-Diels-Alder reaction to deliver manifold chiral C(4)-unsubstituted dihydropyranones (typical ee >98%), allowing aliphatic and heteroaromatic substituents and hence expanding the scope of this Michael addition/lactonization.

Nitroalkenes as Latent 1,2-Biselectrophiles - A Multicatalytic Approach for the Synthesis of 1,4-Diketones and Their Application in a Four-Step One-Pot Reaction to Polysubstituted Pyrroles.

An NHC-catalyzed nitro-Stetter/elimination/Stetter reaction sequence employs nitroalkenes as latent 1,2-dication synthons providing a novel access to highly useful symmetrical and unsymmetrical 2-aryl substituted 1,4-diketone building blocks from commercially available aldehyde precursors. For less activated (aliphatic) aldehydes, a cooperative catalytic strategy has been developed via the merger of NHC and H-bonding catalysis. To further showcase the versatility of our approach, a great variety of these unprecedented 1,4-diketones are used to efficiently synthesize polysubstituted pyrroles-including those with hetaryl substituents-in good to excellent yields in a multicatalytic metal-free, four-step one-pot cascade reaction under mild, yet robust, conditions.

Carboranes as Aryl Mimetics in Catalysis: A Highly Active Zwitterionic NHC-Precatalyst.

Modern catalysis takes advantage of aryl-based interactions to tune and control reactions. In the design of N-heterocyclic-carbene catalysts, both the electronic and steric nature of the nitrogen substituents play a crucial role. Although hydrocarbon-based systems and especially aryl residues have contributed considerably to overcome multifaceted catalytic challenges, the unique properties of carborane moieties, including delocalized charge, potential planar chirality, and well-known thermodynamic stability, offer unprecedented opportunities to develop new catalysts while being employed as aryl mimetics. We report a straightforward synthetic route to a novel zwitterionic triazolium-based N-heterocyclic carbene (NHC) precatalyst bearing a 7,8-dicarba-nido-undecaboranyl substituent. The catalyst's excellent activity and its broad applicability are demonstrated in a wide range of organocatalytic transformations. Comparison of the performance with known N-aryl NHC catalysts offers preliminary insights into the stereoelectronic nature of this nido-carboranyl substituent.

On-chip integration of organic synthesis and HPLC/MS analysis for monitoring stereoselective transformations at the micro-scale.

We present a microfluidic system, seamlessly integrating microflow and microbatch synthesis with a HPLC/nano-ESI-MS functionality on a single glass chip. The microfluidic approach allows to efficiently steer and dispense sample streams down to the nanoliter-range for studying reactions in quasi real-time. In a proof-of-concept study, the system was applied to explore amino-catalyzed reactions, including asymmetric iminium-catalyzed Friedel-Crafts alkylations in microflow and micro confined reaction vessels.

Visible Light Mediated Reductive Cleavage of C-O Bonds Accessing α-Substituted Aryl Ketones.

C-O σ-bonds in multifaceted benzoin derivatives can be effectively cleaved as acetates using catalytic amounts of [Ru(bpy)3]Cl2 as photoredox catalyst in combination with Hantzsch ester and triethylamine as a sacrificial electron donor. This mild and operationally simple method is applicable to a great variety of substrates. Homo- and cross-benzoins, which are easily accessed by NHC (N-heterocyclic carbene) catalysis, with both electron-withdrawing and electron-donating substituents, including aryl halogenides, can be employed. The deoxygenated counterparts are isolated in good to excellent yields. These broadly accessible, α-substituted (nonsymmetric) aryl ketones are versatilely applicable for further transformations as illustrated by the syntheses of 2-arylbenzofurans.

No photocatalyst required--versatile, visible light mediated transformations with polyhalomethanes.

A visible light mediated, but photocatalyst-free method for the oxidative α-CH functionalization of tertiary amines with a broad scope of carbon- and heteroatom nucleophiles using polyhalomethanes has been developed. In addition, the pivotal visible light triggered activation of polyhalomethanes offers mild conditions for efficient Kharasch-type additions onto non-activated olefins. Preliminary mechanistic studies are reported.

Aerobic oxidation of NHC-catalysed aldehyde esterifications with alcohols: benzoin, not the Breslow intermediate, undergoes oxidation.

Benzoin (and neither the Breslow intermediate nor the NHC-aldehyde tetrahedral adduct) has been unambiguously identified as the oxidised species in aerobic NHC-catalysed aldehyde esterifications.

NHC-catalysed aerobic aldehyde-esterifications with alcohols: no additives or cocatalysts required.

A highly efficient, broad scope, additive-free mild protocol for the oxidative carbene-catalysed esterification of aldehydes (including the related aqueous oxidation to acids) has been developed.

Application of microflow conditions to visible light photoredox catalysis.

Applications of microflow conditions for visible light photoredox catalysis have successfully been developed. Operationally simple microreactor and FEP (fluorinated ethylene propylene copolymer) tube reactor systems enable significant improvement of several photoredox reactions using different photocatalysts such as [Ru(bpy)(3)](2+) and Eosin Y. Apart from rate acceleration, this approach facilitates previously challenging transformations of nonstabilized intermediates. Additionally, the productivity of the synergistic, catalytic enantioselective photoredox α-alkylation of aldehydes was demonstrated to be increased by 2 orders of magnitude.