Computer-designed repurposing of chemical wastes into drugs.

As the chemical industry continues to produce considerable quantities of waste chemicals1,2, it is essential to devise 'circular chemistry'3-8 schemes to productively back-convert at least a portion of these unwanted materials into useful products. Despite substantial progress in the degradation of some classes of harmful chemicals9, work on 'closing the circle'-transforming waste substrates into valuable products-remains fragmented and focused on well known areas10-15. Comprehensive analyses of which valuable products are synthesizable from diverse chemical wastes are difficult because even small sets of waste substrates can, within few steps, generate millions of putative products, each synthesizable by multiple routes forming densely connected networks. Tracing all such syntheses and selecting those that also meet criteria of process and 'green' chemistries is, arguably, beyond the cognition of human chemists. Here we show how computers equipped with broad synthetic knowledge can help address this challenge. Using the forward-synthesis Allchemy platform16, we generate giant synthetic networks emanating from approximately 200 waste chemicals recycled on commercial scales, retrieve from these networks tens of thousands of routes leading to approximately 300 important drugs and agrochemicals, and algorithmically rank these syntheses according to the accepted metrics of sustainable chemistry17-19. Several of these routes we validate by experiment, including an industrially realistic demonstration on a 'pharmacy on demand' flow-chemistry platform20. Wide adoption of computerized waste-to-valuable algorithms can accelerate productive reuse of chemicals that would otherwise incur storage or disposal costs, or even pose environmental hazards.

Machine Learning Algorithm Guides Catalyst Choices for Magnesium-Catalyzed Asymmetric Reactions.

Organic-chemical literature encompasses large numbers of catalysts and reactions they can effect. Many of these examples are published merely to document the catalysts' scope but do not necessarily guarantee that a given catalyst is "optimal"-in terms of yield or enantiomeric excess-for a particular reaction. This paper describes a Machine Learning model that aims to improve such catalyst-reaction assignments based on the carefully curated literature data. As we show here for the case of asymmetric magnesium catalysis, this model achieves relatively high accuracy and offers out of-the-box predictions successfully validated by experiment, e.g., in synthetically demanding asymmetric reductions or Michael additions.

Machine Learning May Sometimes Simply Capture Literature Popularity Trends: A Case Study of Heterocyclic Suzuki-Miyaura Coupling.

Applications of machine learning (ML) to synthetic chemistry rely on the assumption that large numbers of literature-reported examples should enable construction of accurate and predictive models of chemical reactivity. This paper demonstrates that abundance of carefully curated literature data may be insufficient for this purpose. Using an example of Suzuki-Miyaura coupling with heterocyclic building blocks─and a carefully selected database of >10,000 literature examples─we show that ML models cannot offer any meaningful predictions of optimum reaction conditions, even if the search space is restricted to only solvents and bases. This result holds irrespective of the ML model applied (from simple feed-forward to state-of-the-art graph-convolution neural networks) or the representation to describe the reaction partners (various fingerprints, chemical descriptors, latent representations, etc.). In all cases, the ML methods fail to perform significantly better than naive assignments based on the sheer frequency of certain reaction conditions reported in the literature. These unsatisfactory results likely reflect subjective preferences of various chemists to use certain protocols, other biasing factors as mundane as availability of certain solvents/reagents, and/or a lack of negative data. These findings highlight the likely importance of systematically generating reliable and standardized data sets for algorithm training.

Rapid and Accurate Prediction of pKa Values of C-H Acids Using Graph Convolutional Neural Networks.

The ability to estimate the acidity of C-H groups within organic molecules in non-aqueous solvents is important in synthetic planning to correctly predict which protons will be abstracted in reactions such as alkylations, Michael additions, or aldol condensations. This Article describes the use of the so-called graph convolutional neural networks (GCNNs) to perform such predictions on the time scales of milliseconds and with accuracy comparing favorably with state-of-the-art solutions, including commercial ones. The crux of the method is to train GCNNs using descriptors that reflect not only topological but also chemical properties of atomic environments. The model is validated against adversarial controls, supplemented by the discussion of realistic synthetic problems (on which it correctly predicts the most acidic protons in >90% of cases), and accompanied by a Web application intended to aid the community in everyday synthetic planning.

Propagation of Oscillating Chemical Signals through Reaction Networks.

Akin to electronic systems that can tune to and process signals of select frequencies, systems/networks of chemical reactions also "propagate" time-varying concentration inputs in a frequency-dependent manner. Whereas signals of low frequencies are transmitted, higher frequency inputs are dampened and converted into steady-concentration outputs. Such behavior is observed in both idealized reaction chains as well as realistic signaling cascades, in the latter case explaining the experimentally observed responses of such cascades to input calcium oscillations. These and other results are supported by numerical simulations within the freely available Kinetix web application we developed to study chemical systems of arbitrary architectures, reaction kinetics, and boundary conditions.

Rheological and textural properties of microemulsion-based polymer gels with indomethacin.

In this paper, we present novel microemulsion (ME)-based semisolid polymer gels designed for topical administration of poorly water soluble non-steroidal anti-inflammatory drugs. Indomethacin (IND) was used as a model compound. The ME consisted of castor oil, water, Tween®80 as a surfactant and ethanol as cosurfactant. To obtain the desired consistency of the formulations Carbopol®960 was applied as a thickening agent. The aim of the study was to analyze in detail the mechanical properties of the obtained systems, with special attention paid to the features crucial for topical application. The rheological and textural experiments performed for samples with and without the incorporated drug clearly indicate that flow characteristics, viscoelastic properties and texture profiles were affected by the presence of IND. Novel semisolid formulations with IND described for the first time in this paper can be considered as an alternative for commercially available conventional topical dosage forms.

Unique bonding nature of carbon-substituted Be2 dimer inside the carbon (sp(2)) network.

Controlled doping of active carbon materials (viz., graphenes, carbon nanotubes etc.) may lead to the enhancement of their desired properties. The least studied case of C/Be substitution offers an attractive possibility in this respect. The interactions of Be2 with Be or C atoms are dominated by the large repulsive Pauli exchange contributions, which in turn offsets the attractive interactions leading to relatively small binding energies. The Be2 dimer, e.g., after being doped inside a planar carbon network, undergoes orbital adjustments due to charge transfer and unusual intermolecular interactions and is oriented perpendicular to the plane of the carbon network with the Be-Be bond center located inside the plane. The present theoretical investigation on the nature of bonding in C/Be2 exchange complexes, using state of the art quantum chemical techniques, reveals a sp(2) carbon-like bonding scheme in Be2 arising due to the molecular hybridization of σ and two π orbitals. The perturbations imposed by doped Be2 dimers exhibit a local character of the structural and electronic properties of the complexes, and the separation by two carbon atoms between beryllium active centers is sufficient to consider these centers as independent sites.

Delocalized, asynchronous, closed-loop discovery of organic laser emitters.

Contemporary materials discovery requires intricate sequences of synthesis, formulation, and characterization that often span multiple locations with specialized expertise or instrumentation. To accelerate these workflows, we present a cloud-based strategy that enabled delocalized and asynchronous design-make-test-analyze cycles. We showcased this approach through the exploration of molecular gain materials for organic solid-state lasers as a frontier application in molecular optoelectronics. Distributed robotic synthesis and in-line property characterization, orchestrated by a cloud-based artificial intelligence experiment planner, resulted in the discovery of 21 new state-of-the-art materials. Gram-scale synthesis ultimately allowed for the verification of best-in-class stimulated emission in a thin-film device. Demonstrating the asynchronous integration of five laboratories across the globe, this workflow provides a blueprint for delocalizing-and democratizing-scientific discovery.

Closed-loop optimization of general reaction conditions for heteroaryl Suzuki-Miyaura coupling.

General conditions for organic reactions are important but rare, and efforts to identify them usually consider only narrow regions of chemical space. Discovering more general reaction conditions requires considering vast regions of chemical space derived from a large matrix of substrates crossed with a high-dimensional matrix of reaction conditions, rendering exhaustive experimentation impractical. Here, we report a simple closed-loop workflow that leverages data-guided matrix down-selection, uncertainty-minimizing machine learning, and robotic experimentation to discover general reaction conditions. Application to the challenging and consequential problem of heteroaryl Suzuki-Miyaura cross-coupling identified conditions that double the average yield relative to a widely used benchmark that was previously developed using traditional approaches. This study provides a practical road map for solving multidimensional chemical optimization problems with large search spaces.

Computer-generated "synthetic contingency" plans at times of logistics and supply problems: scenarios for hydroxychloroquine and remdesivir.

A computer program for retrosynthetic planning helps develop multiple "synthetic contingency" plans for hydroxychloroquine and also routes leading to remdesivir, both promising but yet unproven medications against COVID-19. These plans are designed to navigate, as much as possible, around known and patented routes and to commence from inexpensive and diverse starting materials, so as to ensure supply in case of anticipated market shortages of commonly used substrates. Looking beyond the current COVID-19 pandemic, development of similar contingency syntheses is advocated for other already-approved medications, in case such medications become urgently needed in mass quantities to face other public-health emergencies.

Synthetic connectivity, emergence, and self-regeneration in the network of prebiotic chemistry.

The challenge of prebiotic chemistry is to trace the syntheses of life's key building blocks from a handful of primordial substrates. Here we report a forward-synthesis algorithm that generates a full network of prebiotic chemical reactions accessible from these substrates under generally accepted conditions. This network contains both reported and previously unidentified routes to biotic targets, as well as plausible syntheses of abiotic molecules. It also exhibits three forms of nontrivial chemical emergence, as the molecules within the network can act as catalysts of downstream reaction types; form functional chemical systems, including self-regenerating cycles; and produce surfactants relevant to primitive forms of biological compartmentalization. To support these claims, computer-predicted, prebiotic syntheses of several biotic molecules as well as a multistep, self-regenerative cycle of iminodiacetic acid were validated by experiment.

s-Block metallabenzene: aromaticity and hydrogen adsorption.

Second group metal dimers can replace the carbon atom in benzene to form metallabenzene (C5H6M2) compounds. These complexes possess some aromatic character and promising hydrogen adsorption properties. In this study, we investigated the aromatic character of these compounds using aromaticity indices and molecular orbital analysis. To determine the nature of interactions between hydrogen and the metallic center, variation-perturbational decomposition of interaction energy was applied together with ETS-NOCV analysis. The results obtained suggest that the aromatic character comes from three π orbitals located mainly on the C5H5(-) fragment. The high hydrogen adsorption energy (up to 6.5 kcal mol(-1)) results from two types of interaction. In C5H6Be2, adsorption is controlled by interactions between the empty metal orbital and the σ orbital of the hydrogen molecule (Kubas interaction) together with corresponding back-donation interactions. Other C5H6M2 compounds adsorb H2 due to Kubas interactions enhanced by H2-π interactions.