Atomically precise gold nanoclusters (AuNCs) are interesting nanomaterials with potential applications in catalysis, bioimaging and optoelectronics. Their compositions and properties are commonly evaluated by various analytical techniques, including UV-vis spectroscopy, NMR spectroscopy, ESI mass spectrometry, and single-crystal X-ray diffraction. While these techniques have provided detailed insights into the structure and properties of nanoclusters, synthetic methods still suffer from a lack of in situ and real-time reaction monitoring methodologies. This limits insight into the mechanism of formation of AuNCs and hinders attempts at optimization. We have demonstrated the utility of HPLC-MS as a monitoring methodology in the synthesis of two NHC-protected gold nanoclusters: [Au13(NHC)9Cl3]2+ and [Au24(NHC)14Cl2H3]3+. Herein we show that HPLC coupled with mass spectrometry and 13C NMR spectroscopy of labelled derivatives enables new insight into critical reaction dynamics of AuNCs synthesis and rapid reaction optimization.

Kinetic investigations can provide critical mechanistic information for the optimization of the reaction parameters and reaction development. Modern kinetic analyses such as RPKA and VTNA provide many advantages over traditional initial rate methods and are especially powerful when coupled with reaction monitoring technologies. While these are robust analytical methods, the lack of careful observation and optimization can lead to misinterpretation of the data. In this Perspective, we highlight some commonly overlooked considerations in kinetic studies based on our experiences and present a general guide to proper optimization of reactions and analytics prior to acquiring kinetic data.

Monitoring the reaction progress of biphasic reaction mixtures has long presented a significant challenge to modern analytical techniques. While a multitude of widely utilized chemical transformations have been performed under such conditions, in-line separation and analysis of each phase have not been possible, inhibiting detailed kinetic and mechanistic studies of these important processes. Herein, we disclose a novel sampling technology capable of accurately monitoring reaction progress in biphasic mixtures using online high-performance liquid chromatography (HPLC) and multinuclear flow nuclear magnetic reso-nance (NMR) spectroscopy. A biphasic sampling platform was devel-oped to circulate a single phase of a biphasic reaction mixture for anal-ysis using these techniques. The utility of this methodology was demonstrated through analysis of boronic acid distribution and specia-tion under basic conditions as well as for monitoring the reaction prog-ress of a biphasic Suzuki-Miyaura cross-coupling.

Automated chemical synthesizers have become more common in recent years but struggle to apply rigid procedures to broad substrate scopes. We have developed an adaptive auto-synthesizer that uses online HPLC and FTIR measurements to adapt to the changing reactivities of different substrates, allowing precise control of reaction conditions. To do so, we designed a flexibly-timed procedure consisting of specific actions performed by our platform when specific reaction-monitoring checkpoints are met. Online HPLC allowed our system to autonomously separate, label and quantify most reaction components, with orthogonal FTIR enabling non-UV active species to be additionally tracked. We tested our platform with CDI-mediated multistep amidation reactions using a variety of different acid and amine substrates. To demonstrate the high reproducibility and control afforded by our system, we determined the relative rates of both acid activation and subsequent amidation, providing insight into substrate reactivities and the reaction mechanism.

Solid-liquid slurries are vital and increasingly prevalent in the pharmaceutical and chemical industries. Despite the importance of these heterogeneous systems, process control and optimization are fundamentally hindered by a lack of compatible real-time analytical techniques. We present herein an online HPLC monitoring platform enabling access to real-time compositional information on slurries. We demonstrate the system by investigating the heterogeneous synthesis reaction of tetrabenazine. Furthermore, we integrated our online HPLC platform with the orthogonal monitoring techniques of a pH probe and a microscopic imaging probe to provide additional mechanistic insight. These combined insights enable the optimization of tetrabenazine synthesis in terms of reaction time, byproduct formation, and diastereomeric purity of the final product.

A palladium-dihydroxyterphenylphosphine (DHTP) catalyst was successfully applied to the direct C3-arylation of N-unsubstituted indoles with aryl chlorides, triflates, and nonaflates. This catalyst showed C3-selectivity, whereas catalysts with other structurally related ligands exhibited N1-selectivity. Complex formation between the lithium salts of the ligand and the indole is assumed to accelerate the arylation at the C3 position. Reactions using 3-alkylindoles afforded 3,3-disubstituted indolenines, which can be further converted to the corresponding indoline derivatives.

The direct C3-arylation of N-unsubstituted indoles with aryl chlorides and triflates has been realized using a palladium-dihydroxyterphenylphosphine (DHTP) catalyst. The site selectivity is different from that obtained with other structurally related ligands. This unique feature of the DHTP ligand is attributed to complex formation between the lithium salts of the ligand and the indole. The method was applied to the late-stage derivatization of pharmaceuticals having a chloro group.

Si nanowires were grown on Si(111) substrates, and the shape modification of the nanowires was demonstrated. With the Au catalyst, the highly symmetric faceted silicide solid particle in the Au-Si eutectic solution was formed on the top of the nanowires, and the solid catalyst defined the shape of the Si nanowire. Namely, the VLS growth mechanism was followed by the VSS growth mechanism, and the modified shaped faceted Si nanowire was formed during the VSS growth. This result makes us to expect to control the shape of the nanowires by the formation of facetted silicide particles grown during the Au catalytic growth. (c) 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim