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With the development of automated experimental platforms and optimization algorithms, chemists can easily optimize chemical reactions in an automated and high-throughput fashion. However, the modules in existing automated experimental platforms are operated in a predefined way without orchestrating with the optimization algorithm, thus leaving room for further efficiency improvement. Here, we introduced a framework of automated reaction optimization with parallelized scheduling (AROPS) to realize the integration of optimization algorithm and module scheduling. AROPS relies on a customized Bayesian optimizer to solve multi-reactor/analyzer reaction optimization problems with three different scheduling modes to arrange tasks for various experimental modules. In addition, a mechanism based on probability of improvement (PI) for discarding unpromising on-going experiments was developed to facilitate freeing-up valuable experimental resources in parallelized optimization. We tested the performance of AROPS using a hardware emulator on three typical benchmark reactions encountered in organic synthesis, illustrating that AROPS can trade off optimization time and cost according to the chemists’ preference.

Research-scale fully automated flow platform for reaction self-optimization with solids handling facilitates identification of optimal conditions for continuous manufacturing of pharmaceuticals while reducing amounts of raw materials consumed.

Electroorganic synthesis is a promising tool to design sustainable transformations and discover new reactivities. However, the added setup complexity caused by electrodes in the system impedes efficient screening of reaction conditions. Herein, we present a microfluidic platform that enables automated high-throughput experimentation (HTE) for electroorganic synthesis at a 15-microliter scale. Two HTE modules are demonstrated: 1) the rapid electrochemical reaction condition screening for a radical-radical cross-coupling reaction on micro-fabricated interdigitated electrodes, and 2) measurements of kinetics for mediated anodic oxidations using the microliter-scale cyclic voltammetry. The presented modular approach could be deployed for a range of other electroorganic chemistry applications beyond the demonstrated functionalities.

Cutting it close for radical coupling In principle, electrochemistry is an ideal method for radical coupling: One precursor oxidized at the anode pairs up with a counterpart that has been reduced at the cathode. The trouble is that either or both coupling partners might not stay stable long enough to meet in the middle. Mo et al. resolved this issue by closely spacing the electrodes in a microfluidics platform (see the Perspective by Liu et al. ). They showcase coupling of dicyanobenzene as the cathodic radical precursor with a variety of oxidatively generated partners. Science , this issue p. 1352 ; see also p. 1312

The first demonstration of aqueous surfactant-enabled Suzuki–Miyaura couplings run under flow conditions is described. In addition, use of an even more challenging heterogeneous nanoparticle catalyst, containing only 800 ppm of Pd (i.e., 0.08 mol%) in the form of Fe/ppm Pd nanoparticles, is sufficient using a continuous stirred-tank reactor (CSTR).

Visible-light photoredox reactions have been demonstrated to be powerful synthetic tools to access pharmaceutically relevant compounds. However, many photoredox reactions involve insoluble starting...

Electroorganic chemistry has emerged as an environmentally benign tool for synthetic chemists to achieve efficient transformations that are challenging with traditional reagent-based methods. Continuous flow chemistry brings pharmaceutical industry numerous advantages, but implementing electroorganic synthesis in flow is challenging, especially for electroorganic reactions with coupled electrode reactions and slow chemical reactions. We present a continuous electrolysis system engineered for N-hydroxyphthalimide (NHPI) mediated electrochemical aerobic oxidation of benzylic C-H bonds. First, a cation-exchange membrane prevents the crossover of the NHPI anion from anolyte to catholyte avoiding reductive decomposition of NHPI at the cathode, and enables the usage of a cost-effective reticulated vitreous carbon (RVC) cathode instead of a platinum electrode. Second, running the electrochemical flow cell with recycle streams accommodates the inherently slow kinetics of the chemical reaction without phthalimide-N-oxyl (PINO) radical self-decomposition at the anode, and allows the usage of gaseous oxygen as co-oxidant.

Chemical transformations used in fine chemical manufacturing often involve two-phase interaction for which mass transfer limitations can lead to prolonged reaction time and reduced productivity. We present a high-performance miniature continuous stirred-tank reactor (CSTR), with non-contact magnetic coupling providing intensive agitation inside the sealed miniaturized chamber. High-speed imaging of the biphasic hydrodynamics gives an estimated mass transfer coefficient (kLa) on the order of 10 s−1, comparable to commercial passive mixing flow reactors. Case studies with two important biphasic C–C bond-forming reactions: (i) asymmetric alkylation catalyzed by cinchonidine-derived phase-transfer catalyst, and (ii) biphasic Suzuki-Miyaura C–C coupling reactions, demonstrate the versatility of the CSTR unit. Moreover, a detailed kinetic model proposed for phase-transfer reaction systems controlled by the Makosza interfacial mechanism further cross-validates the mass transfer coefficient estimates.

Catalytic gas–liquid reactions have potential as environmentally benign methods for organic synthesis, particularly hydrogenation and oxidation reactions. However, safety and scalability are concerns in the application of gas–liquid reactions. In this work, we develop and demonstrate a scalable, sustainable, and safe thin-layer membrane reactor for heterogeneous Pd-catalyzed hydrogenations and homogenous Cu(I)/TEMPO alcohol oxidations. The implementation of a Teflon amorphous fluoroplastic (AF) membrane and porous carbon cloth in the membrane reactor provides sufficient gas–liquid mass transfer to afford superior performance compared to conventional packed-bed or trickle-bed reactors. The membrane separates the gas from the liquid, which avoids the formation of explosive mixtures for oxygenation reactions and simplifies the two-phase hydrodynamics to facilitate scale-up by stacking modules, while significantly reducing gas consumption. In addition, 3-dimensional simulations deliver insights into the mass transfer and hydrodynamic behavior to inform optimal membrane reactor design and operation.

Continuous handling of solids creates challenges for realizing continuous production of pharmaceuticals and fine chemicals. We present a new miniature continuous stirred-tank reactor (CSTR) cascade to handle solid-forming reactions in flow. Single-phase residence time distribution (RTD) measurements of the CSTR cascade reveal nearly ideal CSTR mixing behavior of the individual units. Consistency of experimental and predicted conversions of a Diels–Alder reaction further confirms the CSTR performance. Two solid-forming reactions, (i) glyoxal reacting with cyclohexylamine to form N,N′-dicyclohexylethylenediimine, (ii) sulfonylation of 2-octanol with methanesulfonyl chloride, demonstrate the ability of the reactor cascade to transport solid particles continuously for hours without significant signs of clogging.

Membrane proteins present major challenges for structural biology. In particular, the production of suitable crystals for high-resolution structural determination continues to be a significant roadblock for developing an atomic-level understanding of these vital cellular systems. The use of detergents for extracting membrane proteins from the native membrane for either crystallization or reconstitution into model lipid membranes for further study is assumed to leave the protein with the proper fold with a belt of detergent encompassing the membrane-spanning segments of the structure. Small-angle X-ray scattering was used to probe the detergent-associated solution conformations of three membrane proteins, namely bacteriorhodopsin (BR), the Ste2p G-protein coupled receptor from Saccharomyces cerevisiae, and the Escherichia coli porin OmpF. The results demonstrate that, contrary to the traditional model of a detergent-associated membrane protein, the helical proteins BR and Ste2p are not in the expected, compact conformation and associated with detergent micelles, while the ?-barrel OmpF is indeed embedded in a disk-like micelle in a properly folded state. The comparison provided by the BR and Ste2p, both members of the 7TM family of helical membrane proteins, further suggests that the interhelical interactions between the transmembrane helices of the two proteins differ, such that BR, like other rhodopsins,more » can properly refold to crystallize, while Ste2p continues to prove resistant to crystallization from an initially detergent-associated state.« less

In this article, the room-temperature solution fluorescence quenching of electron-deficient anthracenes such as 9-cyanoanthracene (CNA), 9,10-dicyanoanthracene (DCNA), and 9,10-dichloroanthracene (DCLA) by polysilane copolymers was studied. The fluorescence quenching data was in conformity with the Stern-Volmer equation F 0 /F = 1 + K SV [Q], the F 0 /F-[Q] straight lines were drawn, and the fluorescence quenching constants K SV were obtained. By measuring the fluorescence lifetimes of the anthracenes, the fluorescence quenching rate constants k q were calculated. Based on experiments and references, we tentatively proposed that for the same polysilane copolymer quencher the fluorescence quenching was caused mainly by the polysilane Si-Si chain and affected in a small degree by the side substituents attached to the Si-Si chain. In addition, it was observed that the order of the fluorescence quenching rate constants k q of the above three electron-deficient anthracenes by the same polysilane copolymer was DCNA > CNA > DCLA, which is just in keeping with that of their electron deficiency.

Membrane proteins (MPs), which play vital roles in trans-membrane trafficking and signalling between cells and their external environment, comprise a major fraction of the expressed proteomes of many organisms. MP production for biophysical characterization requires detergents for extracting MPs from their native membrane and to solubilize the MP in solution for purification and study. In a proper detergent solution, the detergent-associated MPs retain their native fold and oligomerization state, key requirements for biophysical characterization and crystallization. SANS with contrast variation was performed to characterize BR in complex with OG to better understand the MP-detergent complex. Contrast variation makes it possible to not only probe the conformation of the entire structure but also investigate the conformation of the polypeptide chain within the BR-OG complex. The BR-OG SANS contrast variation series is not consistent with a compact structure, such as a trimeric BR complex surrounded by a belt of detergent. The data strongly suggest that the protein is partially unfolded through its association with the detergent micelles.