Author Correction: Controlling an organic synthesis robot with machine learning to search for new reactivity.

Change history: Owing to the misidentification of compound 22 in the original Letter, changes have been made to Fig. 5, Extended Data Fig. 2 and the main text; see accompanying Amendment.

Controlling an organic synthesis robot with machine learning to search for new reactivity.

The discovery of chemical reactions is an inherently unpredictable and time-consuming process1. An attractive alternative is to predict reactivity, although relevant approaches, such as computer-aided reaction design, are still in their infancy2. Reaction prediction based on high-level quantum chemical methods is complex3, even for simple molecules. Although machine learning is powerful for data analysis4,5, its applications in chemistry are still being developed6. Inspired by strategies based on chemists' intuition7, we propose that a reaction system controlled by a machine learning algorithm may be able to explore the space of chemical reactions quickly, especially if trained by an expert8. Here we present an organic synthesis robot that can perform chemical reactions and analysis faster than they can be performed manually, as well as predict the reactivity of possible reagent combinations after conducting a small number of experiments, thus effectively navigating chemical reaction space. By using machine learning for decision making, enabled by binary encoding of the chemical inputs, the reactions can be assessed in real time using nuclear magnetic resonance and infrared spectroscopy. The machine learning system was able to predict the reactivity of about 1,000 reaction combinations with accuracy greater than 80 per cent after considering the outcomes of slightly over 10 per cent of the dataset. This approach was also used to calculate the reactivity of published datasets. Further, by using real-time data from our robot, these predictions were followed up manually by a chemist, leading to the discovery of four reactions.

Publisher Correction: Controlling an organic synthesis robot with machine learning to search for new reactivity.

The chemical structure formatting in Fig. 5 has been corrected online.

Automated Library Generation and Serendipity Quantification Enables Diverse Discovery in Coordination Chemistry.

Library generation experiments are a key part of the discovery of new materials, methods, and models in chemistry, but the question of how to generate high quality libraries to enable discovery is nontrivial. Herein, we use coordination chemistry to demonstrate the automation of many of the workflows used for library generation in automated hardware including the Chemputer. First, we explore the target-oriented synthesis of three influential coordination complexes, to validate key synthetic operations in our system; second, the generation of focused libraries in chemical and process space; and third, the development of a new workflow for prospecting library formation. This involved Bayesian optimization using a Gaussian process as surrogate model combined with a metric for novelty (or serendipity) quantification based on mass spectrometry data. In this way, we show directed exploration of a process space toward those areas with rarer observations and build a picture of the diversity in product distributions present across the space. We show that this effectively "engineers" serendipity into our search through the unexpected appearance of acetic anhydride, formed in situ, and solvent degradation products as ligands in an isolable series of three Co(III) anhydride complexes.

Spontaneous formation of autocatalytic sets with self-replicating inorganic metal oxide clusters.

Here we show how a simple inorganic salt can spontaneously form autocatalytic sets of replicating inorganic molecules that work via molecular recognition based on the {PMo12} ≡ [PMo12O40]3- Keggin ion, and {Mo36} ≡ [H3Mo57M6(NO)6O183(H2O)18]22- cluster. These small clusters are able to catalyze their own formation via an autocatalytic network, which subsequently template the assembly of gigantic molybdenum-blue wheel {Mo154} ≡ [Mo154O462H14(H2O)70]14-, {Mo132} ≡ [MoVI72MoV60O372(CH3COO)30(H2O)72]42- ball-shaped species containing 154 and 132 molybdenum atoms, and a {PMo12}⊂{Mo124Ce4} ≡ [H16MoVI100MoV24Ce4O376(H2O)56 (PMoVI10MoV2O40)(C6H12N2O4S2)4]5- nanostructure. Kinetic investigations revealed key traits of autocatalytic systems including molecular recognition and kinetic saturation. A stochastic model confirms the presence of an autocatalytic network involving molecular recognition and assembly processes, where the larger clusters are the only products stabilized by the cycle, isolated due to a critical transition in the network.

Pore "Softening" and Emergence of Breathability Effects of New Keplerate Nano-Containers.

The self-assembly of porous molecular nanocapsules offer unique opportunities to investigate a range of interesting phenomena and applications. However, to design nanocapsules with pre-defined properties, thorough understanding of their structure-property relation is required. Here, we report the self-assembly of two elusive members of the Keplerate family, [Mo132 Se60 O312 (H2 O)72 (AcO)30 ]42- {Mo132 Se60 } 1 and [W72 Mo60 Se60 O312 (H2 O)72 (AcO)30 ]42- {W72 Mo60 Se60 } 2, that have been synthesised using pentagonal and dimeric ([Mo2 O2 Se2 ]2+ ) building blocks and their structures have been confirmed via single crystal X-ray diffractions. Our comparative study involving the uptake of organic ions and the related ligand exchange of various ligand sizes by the {Mo132 Se60 } and previously reported Keplerates {Mo132 O60 }, {Mo132 S60 } based on the ligand exchange rates, revealed the emergence of increased "breathability" that dominates over the pore size as we transition from the {Mo132 S60 } to the "softer" {Mo132 Se60 } molecular nano-container.

Water-soluble Self-assembled {Pd84 }Ac Polyoxopalladate Nano-wheel as a Supramolecular Host.

Polyoxopalladates (POPs) are a class of self-assembling palladium-oxide clusters that span a variety of sizes, shapes and compositions. The largest of this family, {Pd84 }Ac , is constructed from 14 building units of {Pd6 } and lined on the inner and outer torus by 28 acetate ligands. Due to its high water solubility, large hydrophobic cavity and distinct 1 H NMR fingerprint {Pd84 }Ac is an ideal molecule for exploring supramolecular behaviour with small organic molecules in aqueous media. Molecular visualisation studies highlighted potential binding sites between {Pd84 }Ac and these species. Nuclear Magnetic Resonance (NMR) techniques, including 1 H NMR, 1 H Diffusion Ordered Spectroscopy (DOSY) and Nuclear Overhauser Spectroscopy (NOESY), were employed to study the supramolecular chemistry of this system. Here, we provide conclusive evidence that {Pd84 }Ac forms a 1 : 7 host-guest complex with benzyl viologen (BV2+ ) in aqueous solution.

Engineering Highly Reduced Molybdenum Polyoxometalates via the Incorporation of d and f Block Metal Ions.

The assembly of nanoscale polyoxometalate (POM) clusters has been dominated by the highly reduced icosahedral {Mo132 } "browns" and the toroidal {Mo154 } "blues" which are 45 % and 18 % reduced, respectively. We hypothesised that there is space for a greater diversity of structures in this immediate reduction zone. Here we show it is possible to make highly reduced mix-valence POMs by presenting new classes of polyoxomolybdates: [MoV 52 MoVI 12 H26 O200 ]42- {Mo64 } and [MoV 40 MoVI 30 H30 O215 ]20- {Mo70 }, 81 % and 57 % reduced, respectively. The {Mo64 } cluster archetype has a super-cube structure and is composed of five different types of building blocks, each arranged in overlayed Archimedean or Platonic polyhedra. The {Mo70 } cluster comprises five tripodal {MoV 6 } and five tetrahedral {MoV 2 MoVI 2 } building blocks alternatively linked to form a loop with a pentagonal star topology. We also show how the reaction yielding the {Mo64 } super-cube can be used in the enrichment of lanthanides which exploit the differences in selectivity in the self-assembly of the polyoxometalates.

Facile and Reproducible Electrochemical Synthesis of the Giant Polyoxomolybdates.

Giant polyoxomolybdates are traditionally synthesized by chemical reduction of molybdate in aqueous solutions, generating complex nanostructures such as the highly symmetrical spherical {Mo102} and {Mo132}, ring-shaped {Mo154} and {Mo176}, and the gigantic protein sized {Mo368}, which combines both positive and negative curvature. These complex polyoxometalates are known to be highly sensitive to reaction conditions and are often difficult to reproduce, especially {Mo368}, which is often produced in yields far below 1%, meaning further investigation has always been limited. While the electrochemical properties of these materials have been studied, their electrochemical synthesis has not been explored. Herein, we demonstrate an alternative reliable synthetic method by means of electrochemistry. By using electrochemical synthesis, we have shown the synthesis of various reported polyoxomolybdates, along with some unreported structures with unique features that have yet to be reported by traditional synthetic methods. The six different giant polyoxomolybdates that were obtained via electrochemical synthesis range from the spherical {Mo102-xFex} and {Mo132} to the ring-shaped {Mo148} and {Mo154-x}, as well as the largest known polyoxometalate {Mo368}, with improved yield (up to 26.1% for {Mo368}), increased reproducibility, and shorter crystallization time compared to chemical reduction methods.

Enantioselective Recognition of Racemic Amino Alcohols in Aqueous Solution by Chiral Metal-Oxide Keplerate {Mo132 } Cluster Capsules.

Determining the relative configuration or enantiomeric excess of a substance may be achieved using NMR spectroscopy by employing chiral shift reagents (CSRs). Such reagents interact noncovalently with the chiral solute, resulting in each chiral form experiencing different magnetic anisotropy; this is then reflected in their NMR spectra. The Keplerate polyoxometalate (POM) is a molybdenum-based, water-soluble, discrete inorganic structure with a pore-accessible inner cavity, decorated by differentiable ligands. Through ligand exchange from the self-assembled nanostructure, a set of chiral Keplerate host molecules has been synthesised. By exploiting the interactions of analyte molecules at the surface pores, the relative configuration of chiral amino alcohol guests (phenylalaninol and 2-amino-1-phenylethanol) in aqueous solvent was establish and their enantiomeric excess was determined by 1 H NMR using shifts of ΔΔδ=0.06 ppm. The use of POMs as chiral shift reagents represents an application of a class that is yet to be well established and opens avenues into aqueous host-guest chemistry with self-assembled recognition agents.

Exploring the Geometric Space of Metal-Organic Polyhedrons (MOPs) of Metal-Oxo Clusters.

Metal organic polyhedra (MOPs) such as coordination cages and clusters are increasingly utilized across many fields, but their geometrically selective assembly during synthesis is nontrivial. When ligand coordination along these polyhedral edges is arranged in an unsymmetrical mode or the bridging ligand itself is nonsymmetric, a vast combinatorial space of potential isomers exists complicating formation and isolation. Here we describe two generalizable combinatorial methodologies to explore the geometrical space and enumerate the configurational isomers of MOPs with discrimination of the chiral and achiral structures. The methodology has been applied to the case of the octahedron {Bi6Fe13L12} which has unsymmetrical coordination of a carboxylate ligand (L) along its edges. For these polyhedra, the enumeration methodology revealed 186 distinct isomers, including 74 chiral pairs and 38 achiral. To explore the programming of these, we then used a range of ligands to synthesize several configurational isomers. Our analysis demonstrates that ligand halo-substituents influence isomer symmetry and suggests that more symmetric halo-substituted ligands counterintuitively yield lower symmetry isomers. We performed mass spectrometry studies of these {Bi6Fe13L12} clusters to evaluate their stability and aggregation behavior in solution and the gas phase showing that various isomers have different levels of aggregation in solution.

Synthesis, Assembly, and Sizing of Neutral, Lanthanide Substituted Molybdenum Blue Wheels {Mo90Ln10}.

Polyoxometalate molybdenum blue (MB) complexes typically exist as discrete multianionic clusters and are composed of repeating Mo building units. MB wheels such as {Mo176} and {Mo154} are made from pentagon-centered {Mo8} building blocks joined by equal number of {Mo1} units as loin, and {Mo2} dimer units as skirt along the ring edge, with the ring sizes of the MB wheels modulated by the {Mo2} units. Herein we report a new class of contracted lanthanide-doped MB structures that have replaced all the {Mo2} units with lanthanide ions on the inner rim, giving the general formula {Mo90Ln10}. We show three examples of this new decameric {Mo90Ln10} (Ln = La, Ce, and Pr) framework synthesized by high temperature reduction and demonstrate that later Ln ions result in {Mo92Ln9} (Ln = Nd, Sm), conserving one {Mo2} linker unit in its structure, as a consequence of the lanthanide contraction. Remarkably the {Mo90Ln10} compounds are the first examples of charge-neutral molybdate wheels as confirmed by BVS, solubility experiments, and redox titrations. We detail our full synthetic optimization for the isolation of these clusters and complete characterization by X-ray, TGA, UV-vis, and ICP studies. Finally, we show that this fine-tuned self-assembly process can be utilized to selectively enrich Ln-MB wheels for effective separation of lanthanides.

Design and fabrication of memory devices based on nanoscale polyoxometalate clusters.

Flash memory devices--that is, non-volatile computer storage media that can be electrically erased and reprogrammed--are vital for portable electronics, but the scaling down of metal-oxide-semiconductor (MOS) flash memory to sizes of below ten nanometres per data cell presents challenges. Molecules have been proposed to replace MOS flash memory, but they suffer from low electrical conductivity, high resistance, low device yield, and finite thermal stability, limiting their integration into current MOS technologies. Although great advances have been made in the pursuit of molecule-based flash memory, there are a number of significant barriers to the realization of devices using conventional MOS technologies. Here we show that core-shell polyoxometalate (POM) molecules can act as candidate storage nodes for MOS flash memory. Realistic, industry-standard device simulations validate our approach at the nanometre scale, where the device performance is determined mainly by the number of molecules in the storage media and not by their position. To exploit the nature of the core-shell POM clusters, we show, at both the molecular and device level, that embedding [(Se(IV)O3)2](4-) as an oxidizable dopant in the cluster core allows the oxidation of the molecule to a [Se(v)2O6](2-) moiety containing a {Se(V)-Se(V)} bond (where curly brackets indicate a moiety, not a molecule) and reveals a new 5+ oxidation state for selenium. This new oxidation state can be observed at the device level, resulting in a new type of memory, which we call 'write-once-erase'. Taken together, these results show that POMs have the potential to be used as a realistic nanoscale flash memory. Also, the configuration of the doped POM core may lead to new types of electrical behaviour. This work suggests a route to the practical integration of configurable molecules in MOS technologies as the lithographic scales approach the molecular limit.

An Autonomous Chemical Robot Discovers the Rules of Inorganic Coordination Chemistry without Prior Knowledge.

We present a chemical discovery robot for the efficient and reliable discovery of supramolecular architectures through the exploration of a huge reaction space exceeding ten billion combinations. The system was designed to search for areas of reactivity found through autonomous selection of the reagent types, amounts, and reaction conditions aiming for combinations that are reactive. The process consists of two parts where reagents are mixed together, choosing from one type of aldehyde, one amine and one azide (from a possible family of two amines, two aldehydes and four azides) with different volumes, ratios, reaction times, and temperatures, whereby the reagents are passed through a copper coil reactor. Next, either cobalt or iron is added, again from a large number of possible quantities. The reactivity was determined by evaluating differences in pH, UV-Vis, and mass spectra before and after the search was started. The algorithm was focused on the exploration of interesting regions, as defined by the outputs from the sensors, and this led to the discovery of a range of 1-benzyl-(1,2,3-triazol-4-yl)-N-alkyl-(2-pyridinemethanimine) ligands and new complexes: [Fe(L1 )2 ](ClO4 )2 (1); [Fe(L2 )2 ](ClO4 )2 (2); [Co2 (L3 )2 ](ClO4 )4 (3); [Fe2 (L3 )2 ](ClO4 )4 (4), which were crystallised and their structure confirmed by single-crystal X-ray diffraction determination, as well as a range of new supramolecular clusters discovered in solution using high-resolution mass spectrometry.

Anisotropic Polyoxometalate Cages Assembled via Layers of Heteroanion Templates.

The synthesis of anisotropic redox-active polyoxometalates (POMs) that can switch between multiple states is critical for understanding the mechanism of assembly of structures with a high aspect ratio, as well as for their application in electronic devices. However, a synthetic methodology for the controlled growth of such clusters is lacking. Here we describe a strategy, using the heteroanion-directed assembly, to produce a family of 10 multi-layered, anisotropic POM cages templated by redox-active pyramidal heteroanions with the composition [W16Mo2O54(XO3)]n-, [W21Mo3O75/76(XO3)2]m-, and [W26Mo4O93(XO3)3]o- for the double, triple, and quadruple layered clusters, respectively. It was found that the introduction of reduced molybdate is essential for self-assembly and results in mixed-metal (W/Mo) and mixed-valence (WVI/MoV) POM cages, as confirmed by an array of analytical techniques. To probe the archetype in detail, a tetrabutyl ammonium (TBA) salt derivative of a fully oxidized two-layered cage is produced as a model structure to confirm that all the cages are a statistical mixture of isostructures with variable ratios of W/Mo. Finally, it was found that multilayered POM cages exhibit dipolar relaxations due to the presence of the mixed valence WVI/MoV metal centers, demonstrating their potential use for electronic materials.

Stereoselective Assembly of Gigantic Chiral Molybdenum Blue Wheels Using Lanthanide Ions and Amino Acids.

The synthesis of chiral polyoxometalates (POMs) is a challenge because of the difficulty to induce the formation of intrinsically chiral metal-oxo frameworks. Herein we report the stereoselective synthesis of a series of gigantic chiral Mo Blue (MB) POM clusters 1-5 that are formed by exploiting the synergy between coordinating lanthanides ions as symmetry breakers to produce MBs with chiral frameworks decorated with amino acids ligands; these promote the selective formation of enantiopure MBs. All the compounds share the same framework archetype, based on {Mo124Ce4}, which forms an intrinsically chiral Δ or Λ configurations, controlled by the configurations of functionalized chiral amino acids. The chirality and stability of 1-5 in solution are confirmed by circular dichroism, 1H NMR, and electrospray ion mobility-mass spectrometry studies. In addition, the framework of the {Mo124Ce4} MB not only behaves as a host able to trap a chiral {Mo8} cluster that is not accessible by traditional synthesis but also promotes the transformation of tryptophan to kynurenine in situ. This work demonstrates the potential and applicability of our synthetic strategy to produce gigantic chiral POM clusters capable of host-guest chemistry and selective synthetic transformations.

Controlling the Reactivity of the [P8 W48 O184 ]40- Inorganic Ring and Its Assembly into POMZite Inorganic Frameworks with Silver Ions.

The construction of pure-inorganic framework materials with well-defined design rules and building blocks is challenging. In this work, we show how a polyoxometalate cluster with an integrated pore, based on [P8 W48 O184 ]40- (abbreviated as {P8 W48 }), can be self-assembled into inorganic frameworks using silver ions, which both enable reactions on the cluster as well as link them together. The {P8 W48 } was found to be highly reactive with silver ions resulting in the in situ generation of fragments, forming {P9 W63 O235 } and {P10 W66 O251 } in compound (1) where these two clusters co-crystallize and are connected into a POMZite framework with 11 Ag+ ions as linkers located inside clusters and 10 Ag+ linking ions situated between clusters. Decreasing both the concentration of Ag+ ions, and the reaction temperature compared to the synthesis of compound (1), leads to {P8 W51 O196 } in compound 2 where the {P8 W48 } clusters are linked to form a new POMZite framework with 9 Ag+ ions per formula unit. Further tuning of the reaction conditions yields a cubic porous network compound (3) where {P8 W48 } clusters as cubic sides are joined by 4 Ag+ ions to give a cubic array and no Ag+ ions were found inside the clusters.

Ligand-Directed Template Assembly for the Construction of Gigantic Molybdenum Blue Wheels.

Template-mediated synthesis is a powerful approach to build a variety of functional materials and complex supramolecular systems. However, the systematic study of how templates structurally evolve from basic building blocks, and then affect the templated self-assembly, is critical to understanding and utilizing the underlying mechanism, to work towards designed assembly. Here we describe the templated self-assembly of a series of gigantic Mo Blue (MB) clusters 1-4 using l-ornithine as a structure-directing ligand. We show that by using l-ornithine as a structure director, we can form new template⊂host assemblies. Based on the structural relationship between encapsulated templates of {Mo8 } (1), {Mo17 } (2) and {Mo36 } (4), a pathway of the structural evolution of templates is proposed. This provides insight into how gigantic Mo Blue cluster rings form and could lead to full control over the designed assembly of gigantic Mo-blue rings.

Self-Sorting of Heteroanions in the Assembly of Cross-Shaped Polyoxometalate Clusters.

Heteroanion (HA) moieties have a key role in templating of heteropolyoxometalate (HPA) architectures, but clusters templated by two different templates are rarely reported. Herein, we show how a cross-shaped HPA-based architecture can self-sort the HA templates by pairing two different guests into a divacant {XYW15O54} building block, with four of these building block units being linked together to complete the cross-shaped architecture. We exploited this observation to incorporate HA templates into well-defined positions within the clusters, leading to the isolation of a collection of mixed-HA templated cross-shaped polyanions [(XYW15O54)4(WO2)4]32-/36- (X = H-P, Y = Se, Te, As). The template positions have been unambiguously determined by single crystal X-ray diffraction, NMR spectroscopy, and high-resolution electrospray ionization mass spectrometry; these studies demonstrated that the mixed template containing HPA clusters are the preferred products which crystallize from the solution. Theoretical studies using DFT calculations suggest that the selective self-sorting originates from the coordination of the template in solution. The cross-shaped polyoxometalate clusters are redox-active, and the ability of molecules to accept electrons is slightly modulated by the HA incorporated as shown by differential pulse voltammetry experiments. These results indicate that the cross-shaped HPAs can be used to select templates from solution, and themselves have interesting geometries, which will be useful in developing functional molecular architectures based upon HPAs with well-defined structures and electronic properties.

Directed Self-Assembly, Symmetry Breaking, and Electronic Modulation of Metal Oxide Clusters by Pyramidal Heteroanions.

Mixed valence/metal polyoxometalate (POM) clusters are one of the most interesting host species because they show the ability to incorporate a wide range of heteroatoms of various charges and geometries. We report herein the incorporation of pyramidal EO32- heteroanions (E=PH, S, Se, Te) that are responsible not only for directing the templated assembly of a family of mixed-metal POMs but also for the symmetry-breaking of the traditional Dawson architecture and modulation of the electronic characteristics of the cluster's shell. The isolated family of POMs consists of four members: (Me2 NH2 )5 Na2 [Mo11 V7 O52 (HPO3 )]⋅MeOH⋅5 H2 O (1), (NH4 )7 [Mo11 V7 O52 (SO3 )]⋅12 H2 O (2), K7 [Mo11 V7 O52 (SeO3 )] ⋅31 H2 O (3), and (Me2 NH2 )6 Na[Mo11 V7 O52 (TeO3 )]⋅15 H2 O (4), and were characterized by X-ray structural analysis, electrospray ionization mass spectrometry (ESI-MS), thermogravimetric analysis (TGA), UV/Vis, FTIR, elemental analysis, flame atomic absorption spectroscopy (FAAS), and inductively coupled plasma optical emission spectroscopy (ICP-OES). Cyclic voltammetry (CV) and electron paramagnetic resonance (EPR) spectroscopic studies in concert with density functional theoretical (DFT) calculations have been used to elucidate the effect of the heteroatom on the electronic properties of the cluster.