Fully Automated Flow Protocol for C(sp3)-C(sp3) Bond Formation from Tertiary Amides and Alkyl Halides.

Herein, we present a novel C(sp3)-C(sp3) bond-forming protocol via the reductive coupling of abundant tertiary amides with organozinc reagents prepared in situ from their corresponding alkyl halides. Using a multistep fully automated flow protocol, this reaction could be used for both library synthesis and target molecule synthesis on the gram-scale starting from bench-stable reagents. Additionally, excellent chemoselectivity and functional group tolerance make it ideal for late-stage diversification of druglike molecules.

Polarised Optical Emission from Organic Anisotropic Microoptical Waveguides Grown by Ambient Pressure Vapour-deposition.

Ambient pressure chemical vapour deposition of 5,5'-bis((2-(trifluoromethyl)phenyl)ethynyl)-2,2'-bithiophene provides ultrapure needle-shaped crystals. The crystal's supramolecular structure consists of an array of hydrogen bonds and π-π interactions leading to anisotropic arrangements. The cyan emitting crystals exhibit an optical waveguiding tendency with guided polarised optical emissions due to anisotropic molecular arrangements.

Mechanical Processing of Naturally Bent Organic Crystalline Microoptical Waveguides and Junctions.

Precise mechanical processing of optical microcrystals involves complex microscale operations viz. moving, bending, lifting, and cutting of crystals. Some of these mechanical operations can be implemented by applying mechanical force at specific points of the crystal to fabricate advanced crystalline optical junctions. Mechanically compliant flexible optical crystals are ideal candidates for the designing of such microoptical junctions. A vapor-phase growth of naturally bent optical waveguiding crystals of 1,4-bis(2-cyanophenylethynyl)benzene (1) on a surface forming different optical junctions is presented. In the solid-state, molecule 1 interacts with its neighbors via CH⋅⋅⋅N hydrogen bonding and π-π stacking. The microcrystals deposited at a glass surface exhibit moderate flexibility due to substantial surface adherence energy. The obtained network crystals also display mechanical compliance when cut precisely with sharp atomic force microscope cantilever tip, making them ideal candidates for building innovative T- and Δ-shaped optical junctions with multiple outputs. The presented micromechanical processing technique can also be effectively used as a tool to fabricate single-crystal integrated photonic devices and circuits on suitable substrates.

Formation of quaternary carbons through cobalt-catalyzed C(sp3)-C(sp3) Negishi cross-coupling.

Formation of all-carbon-substituted quaternary carbons is a key challenge in organic and medicinal chemistry. We report a cobalt-catalyzed C(sp3)-C(sp3) cross-coupling that allows for the introduction of benzyl, heteroarylmethylzinc and allyl groups to halo-carbonyl substrates. The cross-coupling reaction is selective for C(sp3)-over C(sp2)-halides, in contrast to most used catalytic metals, and allows access to novel scaffolds of pharmaceutical interest. NMR mechanistic studies suggest the presence of Co(0) complexes as catalytic species.

Insights into the mechanism of the formation of noble metal nanoparticles by in situ NMR spectroscopy.

High-resolution solution Nuclear Magnetic Resonance (NMR) spectroscopy has been used to gain insights into the mechanism of the formation of gold, platinum and gold-platinum alloyed nanoparticles using metal precursors and tetrakis(hydroxymethyl)phosphonium chloride (THPC) as starting materials. THPC is widely used in nanochemistry as a reductant and stabilizer of nanoparticles, however the identity of the species responsible for each role is unknown. The multinuclear study of the reaction media by NMR spectroscopy allowed us to elucidate the structure of all the compounds that participate in the transformation from the metal salt precursor to the reduced metal that forms the nanoparticle, thus clarifying the controversy found in the literature regarding the formation of THPC-based compounds. The progress of the reaction was monitored from the initial moments of the synthesis to the end of the reaction and after long periods of time. Insights into the dual role of THPC were gained, identifying methanol and hydrogen as the actual reducing agents, and tris(hydroxymethyl)phosphine oxide (THPO) as the real stabilizing agent. Finally, the different stabilities of gold and platinum nanoparticles can be attributed to the different catalytic activities of the metals.

Photoinduced Palladium-Catalyzed Negishi Cross-Couplings Enabled by the Visible-Light Absorption of Palladium-Zinc Complexes.

A visible-light-induced Negishi cross-coupling is enabled by the activation of a Pd0 -Zn complex. With this photocatalytic method, the scope of deactivated aryl halides that can be employed in the Negishi coupling was significantly expanded. NMR experiments conducted in the presence and absence of light confirmed that the formation of the palladium-zinc complex is key for accelerating the oxidative addition step.

Visible-Light-Induced Nickel-Catalyzed Negishi Cross-Couplings by Exogenous-Photosensitizer-Free Photocatalysis.

The merging of photoredox and transition-metal catalysis has become one of the most attractive approaches for carbon-carbon bond formation. Such reactions require the use of two organo-transition-metal species, one of which acts as a photosensitizer and the other one as a cross-coupling catalyst. We report herein an exogenous-photosensitizer-free photocatalytic process for the formation of carbon-carbon bonds by direct acceleration of the well-known nickel-catalyzed Negishi cross-coupling that is based on the use of two naturally abundant metals. This finding will open new avenues in cross-coupling chemistry that involve the direct visible-light absorption of organometallic catalytic complexes.

Pushing nuclear magnetic resonance sensitivity limits with microfluidics and photo-chemically induced dynamic nuclear polarization.

Among the methods to enhance the sensitivity of nuclear magnetic resonance (NMR) spectroscopy, small-diameter NMR coils (microcoils) are promising tools to tackle the study of mass-limited samples. Alternatively, hyperpolarization schemes based on dynamic nuclear polarization techniques provide strong signal enhancements of the NMR target samples. Here we present a method to effortlessly perform photo-chemically induced dynamic nuclear polarization in microcoil setups to boost NMR signal detection down to sub-picomole detection limits in a 9.4T system (400 MHz 1H Larmor frequency). This setup is unaffected by current major drawbacks such as the use of high-power light sources to attempt uniform irradiation of the sample, and accumulation of degraded photosensitizer in the detection region. The latter is overcome with flow conditions, which in turn open avenues for complex applications requiring rapid and efficient mixing that are not easily achievable on an NMR tube without resorting to complex hardware.

Illumination of Nanoliter-NMR Spectroscopy Chips for Real-Time Photochemical Reaction Monitoring.

We report the use of a small-volume nuclear-magnetic-resonance (NMR)-spectroscopy device with integrated fiber-optics for the real-time detection of UV-vis-light-assisted chemical reactions. An optical fiber is used to guide the light from LEDs or a laser diode positioned safely outside the magnet toward the 25 nL detection volume and placed right above the microfluidic channel, irradiating the transparent back of the NMR chip. The setup presented here overcomes the limitations of conventional NMR systems for in situ UV-vis illumination, with the microchannel permitting efficient light penetration even in highly concentrated solutions, requiring lower-power light intensities, and enabling high photon flux. The efficacy of the setup is illustrated with two model reactions activated at different wavelengths.

Grignard Reagents on a Tab: Direct Magnesium Insertion under Flow Conditions.

An on-demand preparation of organomagnesium reagents is presented using a new flow protocol. The risks associated with the activation of magnesium are circumvented by a new on-column initiation procedure. Required amounts of solutions with a precise titration were obtained. Telescoped flow or batch reactions allow access to a diverse set of functional groups.

NMR reaction monitoring in flow synthesis.

Recent advances in the use of flow chemistry with in-line and on-line analysis by NMR are presented. The use of macro- and microreactors, coupled with standard and custom made NMR probes involving microcoils, incorporated into high resolution and benchtop NMR instruments is reviewed. Some recent selected applications have been collected, including synthetic applications, the determination of the kinetic and thermodynamic parameters and reaction optimization, even in single experiments and on the µL scale. Finally, software that allows automatic reaction monitoring and optimization is discussed.

Diels-Alder reactions in confined spaces: the influence of catalyst structure and the nature of active sites for the retro-Diels-Alder reaction.

Diels-Alder cycloaddition between cyclopentadiene and p-benzoquinone has been studied in the confined space of a pure silica zeolite Beta and the impact on reaction rate due to the concentration effect within the pore and diffusion limitations are discussed. Introduction of Lewis or Brønsted acid sites on the walls of the zeolite strongly increases the reaction rate. However, contrary to what occurs with mesoporous molecular sieves (MCM-41), Beta zeolite does not catalyse the retro-Diels-Alder reaction, resulting in a highly selective catalyst for the cycloaddition reaction.

Triazine-Carbon Nanotubes: New Platforms for the Design of Flavin Receptors.

The synthesis of functionalised carbon nanotubes as receptors for riboflavin (RBF) is reported. Carbon nanotubes, both single-walled and multi-walled, have been functionalised with 1,3,5-triazines and p-tolyl chains by aryl radical addition under microwave irradiation and the derivatives have been fully characterised by using a range of techniques. The interactions between riboflavin and the hybrids were analysed by using fluorescence and UV/Vis spectroscopic techniques. The results show that the attached functional groups minimise the π-π stacking interactions between riboflavin and the nanotube walls. Comparison of p-tolyl groups with the triazine groups shows that the latter have stronger interactions with riboflavin because of the presence of hydrogen bonds. Moreover, the triazine derivatives follow the Stern-Volmer relationship and show a high association constant with riboflavin. In this way, artificial receptors in catalytic processes could be designed through specific control of the interaction between functionalised carbon nanotubes and riboflavin.

Determination of Kinetic Parameters within a Single Nonisothermal On-Flow Experiment by Nanoliter NMR Spectroscopy.

Conventional methods to determine the kinetic parameters for a certain reaction require multiple, separate isothermal experiments, resulting in time- and material-consuming processes. Here, an approach to determine the kinetic information within a single nonisothermal on-flow experiment is presented, consuming less than 10 µmol of reagents and having a total measuring time of typically 10 min. This approach makes use of a microfluidic NMR chip hyphenated to a continuous-flow microreactor and is based on the capabilities of the NMR chip to analyze subnanomole quantities of material in the 25 nL detection volume. Importantly, useful data are acquired from the microreactor platform in specific isothermal and nonisothermal frames. A model fitting the experimental data enables rapid determination of kinetic parameters, as demonstrated for a library of isoxazole and pyrazole derivatives.

Influence of Polarity and Activation Energy in Microwave-Assisted Organic Synthesis (MAOS).

The aim of this work was to determine the parameters that have decisive roles in microwave-assisted reactions and to develop a model, using computational chemistry, to predict a priori the type of reactions that can be improved under microwaves. For this purpose, a computational study was carried out on a variety of reactions, which have been reported to be improved under microwave irradiation. This comprises six types of reactions. The outcomes obtained in this study indicate that the most influential parameters are activation energy, enthalpy, and the polarity of all the species that participate. In addition to this, in most cases, slower reacting systems observe a much greater improvement under microwave irradiation. Furthermore, for these reactions, the presence of a polar component in the reaction (solvent, reagent, susceptor, etc.) is necessary for strong coupling with the electromagnetic radiation. We also quantified that an activation energy of 20-30 kcal mol(-1) and a polarity (µ) between 7-20 D of the species involved in the process is required to obtain significant improvements under microwave irradiation.

DFT studies on cobalt-catalyzed cyclotrimerization reactions: the mechanism and origin of reaction improvement under microwave irradiation.

A DFT computational mechanistic study of the [2+2+2] cyclotrimerization of a diyne with benzonitrile, catalyzed by a cobalt complex, has been carried out. Three alternative catalytic cycles have been examined together with the precatalytic step (responsible for the induction period). The favored mechanism takes place by means of an intramolecular metal-assisted [4+2] cycloaddition. The beneficial role of microwave activation has been studied. It is concluded that microwave irradiation can decrease the catalytic induction period through thermal effects and can also increase the triplet lifetime and promote the reaction, thus improving the final yield.

Few-layer graphenes from ball-milling of graphite with melamine.

We report a simple, practical scalable procedure to produce few-layer graphene sheets using ball-milling. Commercially available melamine can be efficiently used to exfoliate graphite and generate concentrated water or DMF dispersions.

Ball-milling modification of single-walled carbon nanotubes: purification, cutting, and functionalization.

Single-walled carbon nanotubes (SWNTs) can be successfully cut with relatively homogeneous sizes using a planetary mill. The optimized conditions produce highly dispersible SWNTs that can be efficiently functionalized in a variety of synthetic ways. As clearly shown by Raman spectroscopy, the milling/cutting procedure compares very favorably with the most common way of purifying SWNTs, namely, treatment with strong oxidizing acids. Moreover a similar milling process can be used to functionalize and cut pristine SWNTs by one-step nitrene chemistry.

Influence of polarity on the scalability and reproducibility of solvent-free microwave-assisted reactions.

Organic reactions performed in the absence of solvent in domestic ovens without appropriate temperature control are generally considered as not reproducible, particularly when different instruments are used. For this reason, reproducibility has historically been one of the major issues associated with Microwave-Assisted Organic Synthesis (MAOS) especially when domestic ovens are involved. The lack of reproducibility limits the general applicability and the scale up of these reactions. In this work several solvent-free reactions previously carried out in domestic ovens have been translated into a single-mode microwave reactor and then scaled up in a multimode oven. The results show that most of these reactions, although not considered as reproducible, can be easily updated and applied in microwave reactors using temperature-controlled conditions. Furthermore, computational calculations can assist to explain and/or predict whether a reaction will be reproducible or not.

Versatile microwave-induced reactions for the multiple functionalization of carbon nanotubes.

Carbon nanotubes (CNTs) have been readily functionalized by microwave activation using two different reactions affording functional derivatives characterized by two orthogonally protected amino groups. The doubly functionalized CNTs can serve as multipurpose, versatile synthons in materials science and biological applications.