An integrated self-optimizing programmable chemical synthesis and reaction engine.

Robotic platforms for chemistry are developing rapidly but most systems are not currently able to adapt to changing circumstances in real-time. We present a dynamically programmable system capable of making, optimizing, and discovering new molecules which utilizes seven sensors that continuously monitor the reaction. By developing a dynamic programming language, we demonstrate the 10-fold scale-up of a highly exothermic oxidation reaction, end point detection, as well as detecting critical hardware failures. We also show how the use of in-line spectroscopy such as HPLC, Raman, and NMR can be used for closed-loop optimization of reactions, exemplified using Van Leusen oxazole synthesis, a four-component Ugi condensation and manganese-catalysed epoxidation reactions, as well as two previously unreported reactions, discovered from a selected chemical space, providing up to 50% yield improvement over 25-50 iterations. Finally, we demonstrate an experimental pipeline to explore a trifluoromethylations reaction space, that discovers new molecules.

Recent advances in electrochemical sensor technologies for THC detection-a narrative review.

BACKGROUND: Δ9-tetrahydrocannabinol (THC) is the main psychoactive component and one of the most important medicinal compounds in cannabis. Whether in human body fluids and breath or in laboratory and field samples, rapid and easy detection of THC is crucial. It provides insights into the impact of THC on human organism and its medicinal benefits, it guides the cannabis growers to determine different stages of the growth of the plant in the field, and eventually it helps scientists in the laboratory to assure the quality of the products and determine their potency or better understand the product development procedures. The significance of fast THC detection in forensic analysis also cannot be overlooked. Electrochemical sensor technologies are currently in the focus of attention for fast, easy, and low-cost detection of THC. METHOD: In this work, we review the recent advances in sensor technologies developed for the purpose of fast and accurate THC detection. The research works performed mostly in the past decade and those detecting THC directly without any derivatization were the main target of this review. The scope of this narrative review was the reports on detecting THC in synthetic samples and plants as well as oral fluid. RESULTS: Electrochemical sensor technologies are sensitive enough and have the potential for fast, easy, and low-cost detection of THC for roadside testing, THC trending in growing cannabis plants, THC product development and formulation for medical purposes, etc., and they can provide an alternative for costly chromatography and mass spectrometry-based methods. CONCLUSION: The main challenges facing these sensors, however, are nonspecific interaction and the interference of compounds and species from the matrix. Special requirement for storing sensors modified with antibodies or proteins is another challenge in this field. Preparing long-lasting and reusable sensors is a field worthy of attention.

Standardization and Control of Grignard Reactions in a Universal Chemical Synthesis Machine using online NMR.

A big problem with the chemistry literature is that it is not standardized with respect to precise operational parameters, and real time corrections are hard to make without expert knowledge. This lack of context means difficult reproducibility because many steps are ambiguous, and hence depend on tacit knowledge. Here we present the integration of online NMR into an automated chemical synthesis machine (CSM aka. "Chemputer" which is capable of small-molecule synthesis using a universal programming language) to allow automated analysis and adjustment of reactions on the fly. The system was validated and benchmarked by using Grignard reactions which were chosen due to their importance in synthesis. The system was monitored in real time using online-NMR, and spectra were measured continuously during the reactions. This shows that the synthesis being done in the Chemputer can be dynamically controlled in response to feedback optimizing the reaction conditions according to the user requirements.

Convergence of multiple synthetic paradigms in a universally programmable chemical synthesis machine.

Although the automatic synthesis of molecules has been established, each reaction class uses bespoke hardware. This means that the connection of multi-step syntheses in a single machine to run many different protocols and reactions is not possible, as manual intervention is required. Here we show how the Chemputer synthesis robot can be programmed to perform many different reactions, including solid-phase peptide synthesis, iterative cross-coupling and accessing reactive, unstable diazirines in a single, unified system with high yields and purity. Developing universal and modular hardware that can be automated using one software system makes a wide variety of batch chemistry accessible. This is shown by our system, which performed around 8,500 operations while reusing only 22 distinct steps in 10 unique modules, with the code able to access 17 different reactions. We also demonstrate a complex convergent robotic synthesis of a peptide reacted with a diazirine-a process requiring 12 synthetic steps.

Oxidative Cleavage of Alkene C=C Bonds Using a Manganese Catalyzed Oxidation with H2O2 Combined with Periodate Oxidation.

A one-pot multi-step method for the oxidative cleavage of alkenes to aldehydes/ketones under ambient conditions is described as an alternative to ozonolysis. The first step is a highly efficient manganese catalyzed epoxidation/cis-dihydroxylation of alkenes. This step is followed by an Fe(III) assisted ring opening of the epoxide (where necessary) to a 1,2-diol. Carbon-carbon bond cleavage is achieved by treatment of the diol with sodium periodate. The conditions used in each step are not only compatible with the subsequent step(s), but also provide for increased conversion compared to the equivalent reactions carried out on the isolated intermediate compounds. The described procedure allows for carbon-carbon bond cleavage in the presence of other alkenes, oxidation sensitive moieties and other functional groups; the mild conditions (r.t.) used in all three steps make this a viable general alternative to ozonolysis and especially for use under flow or continuous batch conditions.

Organic synthesis in a modular robotic system driven by a chemical programming language.

The synthesis of complex organic compounds is largely a manual process that is often incompletely documented. To address these shortcomings, we developed an abstraction that maps commonly reported methodological instructions into discrete steps amenable to automation. These unit operations were implemented in a modular robotic platform by using a chemical programming language that formalizes and controls the assembly of the molecules. We validated the concept by directing the automated system to synthesize three pharmaceutical compounds, diphenhydramine hydrochloride, rufinamide, and sildenafil, without any human intervention. Yields and purities of products and intermediates were comparable to or better than those achieved manually. The syntheses are captured as digital code that can be published, versioned, and transferred flexibly between platforms with no modification, thereby greatly enhancing reproducibility and reliable access to complex molecules.

H2O2 Oxidation by FeIII-OOH Intermediates and Its Effect on Catalytic Efficiency.

The oxidation of the C-H and C=C bonds of hydrocarbons with H2O2 catalyzed by non-heme iron complexes with pentadentate ligands is widely accepted as involving a reactive FeIV=O species such as [(N4Py)FeIV=O]2+ formed by homolytic cleavage of the O-O bond of an FeIII-OOH intermediate (where N4Py is 1,1-bis(pyridin-2-yl)-N,N-bis(pyridin-2-ylmethyl)methanamine). We show here that at low H2O2 concentrations the FeIV=O species formed is detectable in methanol. Furthermore, we show that the decomposition of H2O2 to water and O2 is an important competing pathway that limits efficiency in the terminal oxidant and indeed dominates reactivity except where only sub-/near-stoichiometric amounts of H2O2 are present. Although independently prepared [(N4Py)FeIV=O]2+ oxidizes stoichiometric H2O2 rapidly, the rate of formation of FeIV=O from the FeIII-OOH intermediate is too low to account for the rate of H2O2 decomposition observed under catalytic conditions. Indeed, with excess H2O2, disproportionation to O2 and H2O is due to reaction with the FeIII-OOH intermediate and thereby prevents formation of the FeIV=O species. These data rationalize that the activity of these catalysts with respect to hydrocarbon/alkene oxidation is maximized by maintaining sub-/near-stoichiometric steady-state concentrations of H2O2, which ensure that the rate of the H2O2 oxidation by the FeIII-OOH intermediate is less than the rate of the O-O bond homolysis and the subsequent reaction of the FeIV=O species with a substrate.

Transient Formation and Reactivity of a High-Valent Nickel(IV) Oxido Complex.

A reactive high-valent dinuclear nickel(IV) oxido bridged complex is reported that can be formed at room temperature by reaction of [(L)2Ni(II)2(µ-X)3]X (X = Cl or Br) with NaOCl in methanol or acetonitrile (where L = 1,4,7-trimethyl-1,4,7-triazacyclononane). The unusual Ni(IV) oxido species is stabilized within a dinuclear tris-µ-oxido-bridged structure as [(L)2Ni(IV)2(µ-O)3]2+. Its structure and its reactivity with organic substrates are demonstrated through a combination of UV-vis absorption, resonance Raman, 1H NMR, EPR, and X-ray absorption (near-edge) spectroscopy, ESI mass spectrometry, and DFT methods. The identification of a Ni(IV)-O species opens opportunities to control the reactivity of NaOCl for selective oxidations.

Influence of Ligand Architecture in Tuning Reaction Bifurcation Pathways for Chlorite Oxidation by Non-Heme Iron Complexes.

Reaction bifurcation processes are often encountered in the oxidation of substrates by enzymes and generally lead to a mixture of products. One particular bifurcation process that is common in biology relates to electron transfer versus oxygen atom transfer by high-valent iron(IV)-oxo complexes, which nature uses for the oxidation of metabolites and drugs. In biomimicry and bioremediation, an important reaction relates to the detoxification of ClOx- in water, which can lead to a mixture of products through bifurcated reactions. Herein we report the first three water-soluble non-heme iron(II) complexes that can generate chlorine dioxide from chlorite at ambient temperature and physiological pH. These complexes are highly active oxygenation oxidants and convert ClO2- into either ClO2 or ClO3¯ via high-valent iron(IV)-oxo intermediates. We characterize the short-lived iron(IV)-oxo species and establish rate constants for the bifurcation mechanism leading to ClO2 and ClO3- products. We show that the ligand architecture of the metal center plays a dominant role by lowering the reduction potential of the metal center. Our experiments are supported by computational modeling, and a predictive valence bond model highlights the various factors relating to the substrate and oxidant that determine the bifurcation pathway and explains the origins of the product distributions. Our combined kinetic, spectroscopic, and computational studies reveal the key components necessary for the future development of efficient chlorite oxidation catalysts.

Identification and spectroscopic characterization of nonheme iron(III) hypochlorite intermediates.

Fe(III)-hypohalite complexes have been implicated in a wide range of important enzyme-catalyzed halogenation reactions including the biosynthesis of natural products and antibiotics and post-translational modification of proteins. The absence of spectroscopic data on such species precludes their identification. Herein, we report the generation and spectroscopic characterization of nonheme Fe(III)-hypohalite intermediates of possible relevance to iron halogenases. We show that Fe(III)-OCl polypyridylamine complexes can be sufficiently stable at room temperature to be characterized by UV/Vis absorption, resonance Raman and EPR spectroscopies, and cryo-ESIMS. DFT methods rationalize the pathways to the formation of the Fe(III)-OCl, and ultimately Fe(IV)=O, species and provide indirect evidence for a short-lived Fe(II)-OCl intermediate. The species observed and the pathways involved offer insight into and, importantly, a spectroscopic database for the investigation of iron halogenases.

Identification and Spectroscopic Characterization of Nonheme Iron(III) Hypochlorite Intermediates.

FeIII-hypohalite complexes have been implicated in a wide range of important enzyme-catalyzed halogenation reactions including the biosynthesis of natural products and antibiotics and post-translational modification of proteins. The absence of spectroscopic data on such species precludes their identification. Herein, we report the generation and spectroscopic characterization of nonheme FeIII-hypohalite intermediates of possible relevance to iron halogenases. We show that FeIII-OCl polypyridylamine complexes can be sufficiently stable at room temperature to be characterized by UV/Vis absorption, resonance Raman and EPR spectroscopies, and cryo-ESIMS. DFT methods rationalize the pathways to the formation of the FeIII-OCl, and ultimately FeIV=O, species and provide indirect evidence for a short-lived FeII-OCl intermediate. The species observed and the pathways involved offer insight into and, importantly, a spectroscopic database for the investigation of iron halogenases.

Pyridyl-1,2,4-triazole diphenyl boron complexes as efficient tuneable blue emitters.

The detection of nuclear radiation necessitates the availability of new generations of tunable blue emitting fluorophores with high emission quantum yields. Here we show that pyridyl-1,2,4-triazole based diphenyl boron complexes can provide highly tuneable emission through facile modification of the C5 position of the 1,2,4-triazolato ring. The series of complexes prepared show a wide range of emission from near-UV to green, enabling fine control over the spectral overlap with detectors used in scintillator technology.