Computational planning of the synthesis of complex natural products

Training algorithms to computationally plan multistep organic syntheses has been a challenge for more than 50 years(1-7). However, the field has progressed greatly since the development of early programs such as LHASA(1,7), for which reaction choices at each step were made by human operators. Multiple software platforms(6,8-14) are now capable of completely autonomous planning. But these programs 'think' only one step at a time and have so far been limited to relatively simple targets, the syntheses of which could arguably be designed by human chemists within minutes, without the help of a computer. Furthermore, no algorithm has yet been able to design plausible routes to complex natural products, for which much more far-sighted, multistep planning is necessary(15,16) and closely related literature precedents cannot be relied on. Here we demonstrate that such computational synthesis planning is possible, provided that the program's knowledge of organic chemistry and data-based artificial intelligence routines are augmented with causal relationships(17,18), allowing it to 'strategize' over multiple synthetic steps. Using a Turing-like test administered to synthesis experts, we show that the routes designed by such a program are largely indistinguishable from those designed by humans. We also successfully validated three computer-designed syntheses of natural products in the laboratory. Taken together, these results indicate that expert-level automated synthetic planning is feasible, pending continued improvements to the reaction knowledge base and further code optimization. A synthetic route-planning algorithm, augmented with causal relationships that allow it to strategize over multiple steps, can design complex natural-product syntheses that are indistinguishable from those designed by human experts

One-Pot, Three-Phase Recycling of Metals from Li-Ion Batteries in Rotating, Concentric-Liquid Reactors

Efficient recycling of spent lithium-ion batteries (LIBs) is essential for making their numerous applications sustainable. Hydrometallurgy-based separation methods are an indispensable part of the recycling process but remain limited by the extraction efficiency and selectivity, and typically require numerous binary liquid-liquid extraction steps in which the capacity of the extracting organic phase or partition coefficient of extracted metals become an overall bottleneck. Herein, rotating reactors are described, in which the aqueous feed, organic extractant, and aqueous acceptor phases are all present in the same rotating vessel and can be vigorously stirred and emulsified without the coalescence of aqueous layers. In this arrangement, the extractant molecules are not equilibrated with the feed and, instead, "shuttle" between the feed/extractant and the extractant/acceptor interfaces multiple times, with each such molecule ultimately transferring approximately ten metal ions. This shuttling allows for using extractant concentrations much lower than in previous designs even for extremely concentrated feeds and, simultaneously, ensures unprecedented speed and selectivity of the one-pot processes. These experimental results are accompanied by theoretical considerations of the selectivity versus speed trends as well as discussion of parameters essential for system upscaling.11Nsciescopu

Materials, assemblies and reaction systems under rotation

When liquids or solid materials rotate, they impart centrifugal and/or shear forces. This Review surveys rotary devices and systems in which such forces control small-scale flows, self-organization phenomena, materials synthesis or chemical reactivity at molecular and macro-molecular levels. Centrifugal forces directed away from the rotation axis enable various separations or lab-on-a-disc systems and can shape interfaces or deposit thin films of functional materials. When these forces act on particles lighter than the rotating fluid, they can provide the basis for colloidal crystallization or trapping; when the direction of rotation changes, they can simulate microgravity conditions and affect motility patterns of living organisms. Shear forces, by contrast, can promote crystallization, couple to molecular-scale assembly and affect its chiral outcomes. Combining centrifugal and shear forces is useful in establishing rotating reactors to accelerate reaction kinetics, modulate chemical reactivity, enable multistep syntheses or support complex extractions. Through these and other examples, we illustrate that rotating reaction vessels can enable new types of chemical experimentation, with outcomes that are not always understood. We argue that rotating systems for studying such processes will become more common given advances in remotely controlled sensors and spectrometers that can monitor the contents of rotating vessels

Materials, assemblies and reaction systems under rotation

When liquids or solid materials rotate, they impart centrifugal and/or shear forces. This Review surveys rotary devices and systems in which such forces control small-scale flows, self-organization phenomena, materials synthesis or chemical reactivity at molecular and macro-molecular levels. Centrifugal forces directed away from the rotation axis enable various separations or lab-on-a-disc systems and can shape interfaces or deposit thin films of functional materials. When these forces act on particles lighter than the rotating fluid, they can provide the basis for colloidal crystallization or trapping; when the direction of rotation changes, they can simulate microgravity conditions and affect motility patterns of living organisms. Shear forces, by contrast, can promote crystallization, couple to molecular-scale assembly and affect its chiral outcomes. Combining centrifugal and shear forces is useful in establishing rotating reactors to accelerate reaction kinetics, modulate chemical reactivity, enable multistep syntheses or support complex extractions. Through these and other examples, we illustrate that rotating reaction vessels can enable new types of chemical experimentation, with outcomes that are not always understood. We argue that rotating systems for studying such processes will become more common given advances in remotely controlled sensors and spectrometers that can monitor the contents of rotating vessels.11Nsciescopu

Concentric liquid reactors for chemical synthesis and separation

Recent years have witnessed increased interest in systems that are capable of supporting multistep chemical processes without the need for manual handling of intermediates. These systems have been based either on collections of batch reactors1 or on flow-chemistry designs2,3,4, both of which require considerable engineering effort to set up and control. Here we develop an out-of-equilibrium system in which different reaction zones self-organize into a geometry that can dictate the progress of an entire process sequence. Multiple (routinely around 10, and in some cases more than 20) immiscible or pairwise-immiscible liquids of different densities are placed into a rotating container, in which they experience a centrifugal force that dominates over surface tension. As a result, the liquids organize into concentric layers, with thicknesses as low as 150 micrometres and theoretically reaching tens of micrometres. The layers are robust, yet can be internally mixed by accelerating or decelerating the rotation, and each layer can be individually addressed, enabling the addition, sampling or even withdrawal of entire layers during rotation. These features are combined in proof-of-concept experiments that demonstrate, for example, multistep syntheses of small molecules of medicinal interest, simultaneous acid???base extractions, and selective separations from complex mixtures mediated by chemical shuttles. We propose that ???wall-less??? concentric liquid reactors could become a useful addition to the toolbox of process chemistry at small to medium scales and, in a broader context, illustrate the advantages of transplanting material and/or chemical systems from traditional, static settings into a rotating frame of reference

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