Is Organic Chemistry Really Growing Exponentially?

In terms of molecules and specific reaction examples, organic chemistry features an impressive, exponential growth. However, new reaction classes/types that fuel this growth are being discovered at a much slower and only linear (or even sublinear) rate. The proportion of newly discovered reaction types to all reactions being performed keeps decreasing, suggesting that synthetic chemistry becomes more reliant on reusing the well-known methods.

Scaffold-Directed Face Selectivity Machine-Learned from Vectors of Non-covalent Interactions.

This work describes a method to vectorize and Machine-Learn, ML, non-covalent interactions responsible for scaffold-directed reactions important in synthetic chemistry. Models trained on this representation predict correct face of approach in ca. 90 % of Michael additions or Diels-Alder cycloadditions.

Synergy between the crack pattern and substrate elasticity in colloidal deposits.

Desiccation cracks in colloidal deposits occur to release the excess strain energy arising from the competition between the drying induced shrinkage of the deposit and its adhesion to the substrate. Here we report remarkably different morphology of desiccation cracks in the dried patterns formed by the evaporation of sessile drops containing colloids on elastomer (soft) or glass (stiff) substrates. The change in the crack pattern, i.

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. However, the field has progressed greatly since the development of early programs such as LHASA, for which reaction choices at each step were made by human operators. Multiple software platforms are now capable of completely autonomous planning.

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.

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 reactors or on flow-chemistry designs, 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.

Shaping Microcrystals of Metal-Organic Frameworks by Reaction-Diffusion.

When components of a metal-organic framework (MOF) and a crystal growth modulator diffuse through a gel medium, they can form arrays of regularly-spaced precipitation bands containing MOF crystals of different morphologies. With time, slow variations in the local concentrations of the growth modulator cause the crystals to change their shapes, ultimately resulting in unusual concave microcrystallites not available via solution-based methods. The reaction-diffusion and periodic precipitation phenomena 1) extend to various types of MOFs and also MOPs (metal-organic polyhedra), and 2) can be multiplexed to realize within one gel multiple growth conditions, in effect leading to various crystalline phases or polycrystalline formations.

Computational design of syntheses leading to compound libraries or isotopically labelled targets.

Although computer programs for retrosynthetic planning have shown improved and in some cases quite satisfactory performance in designing routes leading to specific, individual targets, no algorithms capable of planning syntheses of entire target libraries - important in modern drug discovery - have yet been reported. This study describes how network-search routines underlying existing retrosynthetic programs can be adapted and extended to multi-target design operating on one common search graph, benefitting from the use of common intermediates and reducing the overall synthetic cost. Implementation in the Chematica platform illustrates the usefulness of such algorithms in the syntheses of either (i) all members of a user-defined library, or (ii) the most synthetically accessible members of this library.

Intermediate states of molecular self-assembly from liquid-cell electron microscopy.

Traditional single-molecule methods do not report whole-molecule kinetic conformations, and their adaptive shape changes during the process of self-assembly. Here, using graphene liquid-cell electron microscopy with electrons of low energy at low dose, we show that this approach resolves the time dependence of conformational adaptations of macromolecules for times up to minutes, the resolution determined by motion blurring, with DNA as the test case. Single-stranded DNA molecules are observed in real time as they hybridize near the solid surface to form double-stranded helices; we contrast molecules the same length but differing in base-pair microstructure (random, blocky, and palindromic hairpin) whose key difference is that random sequences possess only one stable final state, but the others offer metastable intermediate structures.

Synergy Between Expert and Machine-Learning Approaches Allows for Improved Retrosynthetic Planning.

When computers plan multistep syntheses, they can rely either on expert knowledge or information machine-extracted from large reaction repositories. Both approaches suffer from imperfect functions evaluating reaction choices: expert functions are heuristics based on chemical intuition, whereas machine learning (ML) relies on neural networks (NNs) that can make meaningful predictions only about popular reaction types. This paper shows that expert and ML approaches can be synergistic-specifically, when NNs are trained on literature data matched onto high-quality, expert-coded reaction rules, they achieve higher synthetic accuracy than either of the methods alone and, importantly, can also handle rare/specialized reaction types.

Confined 1D Propulsion of Metallodielectric Janus Micromotors on Microelectrodes under Alternating Current Electric Fields.

There is mounting interest in synthetic microswimmers ("micromotors") as microrobots as well as a model system for the study of active matters, and spatial navigation is critical for their success. Current navigational technologies mostly rely on magnetic steering or guiding with physical boundaries, yet limitations with these strategies are plenty. Inspired by an earlier work with magnetic domains on a garnet film as predefined tracks, we present an interdigitated microelectrodes (IDE) system where, upon the application of AC electric fields, metallodielectric (e.

Dynamic Assembly of Small Parts in Vortex-Vortex Traps Established within a Rotating Fluid.

Stable, purely fluidic particle traps established by vortex flows induced within a rotating fluid are described. The traps can manipulate various types of small parts, dynamically assembling them into high-symmetry clusters, cages, interlocked architectures, jammed colloidal monoliths, or colloidal formations on gas bubbles. The strength and the shape of the trapping region can be controlled by the strengths of one or both vortices and/or by the system's global angular velocity.

Selection of cost-effective yet chemically diverse pathways from the networks of computer-generated retrosynthetic plans.

As the programs for computer-aided retrosynthetic design come of age, they are no longer identifying just one or few synthetic routes but a multitude of chemically plausible syntheses, together forming large, directed graphs of solutions. An important problem then emerges: how to select from these graphs and present to the user manageable numbers of top-scoring pathways that are cost-effective, promote convergent linear solutions, and are chemically diverse so that they do not repeat only minor variations in the same chemical theme. This paper describes a family of reaction network algorithms that address this problem by (i) using recursive formulae to assign realistic prices to individual pathways and (ii) applying penalties to chemically similar strategies so that they are not dominating the top-scoring routes.

Automatic mapping of atoms across both simple and complex chemical reactions.

Mapping atoms across chemical reactions is important for substructure searches, automatic extraction of reaction rules, identification of metabolic pathways, and more. Unfortunately, the existing mapping algorithms can deal adequately only with relatively simple reactions but not those in which expert chemists would benefit from computer's help. Here we report how a combination of algorithmics and expert chemical knowledge significantly improves the performance of atom mapping, allowing the machine to deal with even the most mechanistically complex chemical and biochemical transformations.

Charged Metal Nanoparticles for Chemoelectronic Circuits.

Although metal nanoparticles (NPs) stabilized with self-assembled monolayers (SAMs) of various organic ligands have proven useful in applications ranging from chemical sensing, to bionanotechnology, to plasmonics and energy conversion, they have not been widely considered as suitable building blocks of electronic circuitry, largely because metals screen electric fields and prevent electrically tunable conductivity. However, when metal nanoparticles a few nanometers in size are stabilized by charged ligands and placed under bias, the counterions surrounding the NPs can redistribute and establish local electric fields that feed back into the electronic currents passing through the nanoparticles' metallic cores. Herein, the manner in which the interplay between counterion gradients and electron flows can be controlled by using different types of SAMs is discussed.

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.

Lévy-like movement patterns of metastatic cancer cells revealed in microfabricated systems and implicated in vivo.

Metastatic cancer cells differ from their non-metastatic counterparts not only in terms of molecular composition and genetics, but also by the very strategy they employ for locomotion. Here, we analyzed large-scale statistics for cells migrating on linear microtracks to show that metastatic cancer cells follow a qualitatively different movement strategy than their non-invasive counterparts. The trajectories of metastatic cells display clusters of small steps that are interspersed with long "flights".

Ionic Janus Liquid Droplets Assembled and Propelled by Electric Field.

Traditional Janus particle approaches to produce active motion are based on using solid particles, but it is interesting to consider liquid droplets instead, because for solid particles, the self-assembly of synthetic active matter requires moving objects to sit in a near-planar 2D geometry. Emulsions, cross-linked polymers, and porous materials have been proposed for 3D self-assembly but with limitations to propel them. It is now demonstrated that Janus liquid droplets can be used as building block in an active propulsion system.

Switchable counterion gradients around charged metallic nanoparticles enable reception of radio waves.

Mechanically flexible, easy-to-process, and environmentally benign materials capable of current rectification are interesting alternatives to "hard" silicon-based devices. Among these materials are metallic/charged-organic nanoparticles in which electronic currents though metal cores are modulated by the gradients of counterions surrounding the organic ligands. Although layers of oppositely charged particles can respond to both electronic and chemical signals and can function even under significant mechanical deformation, the rectification ratios of these "chemoelectronic" elements have been, so far, low.

The Influence of Distant Substrates on the Outcome of Contact Electrification.

The magnitudes of the charges developed on contact-electrified polymers depend on not only the properties of these materials but also the nature of distant substrates on which the polymers are supported. In particular, image charges induced in conductive substrates can decrease charges on the polymers by arc discharge through the surrounding gas. This mode of charge dissipation occurs on timescales of milliseconds and can be prevented by insulating the sharp edges of the conductive supports.

Longer-Lasting Electron-Based Microscopy of Single Molecules in Aqueous Medium.

Use of electron-based microscopy in aqueous media has been held back because aqueous samples tend to suffer from water radiolysis and other chemical degradation caused by the high energy of incident electrons. Here we show that aqueous liquid pockets in graphene liquid cells at room temperature display significantly improved stability when using deuterated water, DO. Reporting transmission electron microscopy (TEM) experiments based on common imaging conditions, we conclude that use of DO outperforms adding radical scavengers to HO regardless of imaging details; it increases the lifetime of dissolved organic macromolecules by a factor of 2-5, and it delays by even longer the appearance of radiolysis-induced bubbles, by a factor of time up to 10.

Artificial Heliotropism and Nyctinasty Based on Optomechanical Feedback and No Electronics.

Although plants are typically not considered an inspiration for designing motile robots, they do perform a variety of intricate motion patterns, including diurnal cycles of sun tracking (heliotropism) and leaf opening (nyctinasty). In real plants, these motions are controlled by complex, feedback-based biological mechanisms that, to date, have been mimicked only in computer-controlled artificial systems. This work demonstrates both heliotropism and nyctinasty in a system in which few simple, but strategically positioned thermo-responsive springs and lenses form a feedback loop controlling these motions and substantiating a behavioral analogy to "plants.

Discovery and Enumeration of Organic-Chemical and Biomimetic Reaction Cycles within the Network of Chemistry.

Analysis of the chemical-organic knowledge represented as a giant network reveals that it contains millions of reaction sequences closing into cycles. Without realizing it, independent chemists working at different times have jointly created examples of cyclic sequences that allow for the recovery of useful reagents and for the autoamplification of synthetically important molecules, those that mimic biological cycles, and those that can be operated one-pot.

Measurements of growing surface tension of amorphous-amorphous interfaces on approaching the colloidal glass transition.

There is mounting evidence indicating that relaxation dynamics in liquids approaching their glass transition not only become increasingly cooperative, but the relaxing regions also become more compact in shape. Of the many theories of the glass transition, only the random first-order theory-a thermodynamic framework-anticipates the surface tension of relaxing regions to play a role in deciding both their size and morphology. However, owing to the amorphous nature of the relaxing regions, even the identification of their interfaces has not been possible in experiments hitherto.

Heterogeneous Catalysis "On Demand": Mechanically Controlled Catalytic Activity of a Metal Surface.

A metal surface passivated with a tightly packed self-assembled monolayer (SAM) can be made catalytically active upon the metal's mechanical deformation. This deformation renders the SAM sparser and exposes additional catalytic sites on the metal's surface. If the deformation is elastic, return of the metal to the original shape "heals" the SAM and nearly extinguishes the catalytic activity.