An autonomous portable platform for universal chemical synthesis.

Robotic systems for synthetic chemistry are becoming more common, but they are expensive, fixed to a narrow set of reactions, and must be used within a complex laboratory environment. A portable system that could synthesize known molecules anywhere, on demand, and in a fully automated way, could revolutionize access to important molecules. Here we present a portable suitcase-sized chemical synthesis platform containing all the modules required for synthesis and purification. The system uses a chemical programming language coupled to a digital reactor generator to produce reactors and executable protocols based on text-based literature syntheses. Simultaneously, the platform generates a reaction pressure fingerprint, used to monitor processes within the reactors and remotely perform a protocol quality control. We demonstrate the system by synthesizing five small organic molecules, four oligopeptides and four oligonucleotides, in good yields and purities, with a total of 24,936 base steps executed over 329 h of platform runtime.

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.

3D designed and printed chemical generators for on demand reagent synthesis.

Modern science has developed well-defined and versatile sets of chemicals to perform many specific tasks, yet the diversity of these reagents is so large that it can be impractical for any one lab to stock everything they might need. At the same time, isssues of stability or limited supply mean these chemicals can be very expensive to purchase from specialist retailers. Here, we address this problem by developing a cartridge -oriented approach to reactionware-based chemical generators which can easily and reliably produce specific reagents from low-cost precursors, requiring minimal expertise and time to operate, potentially in low infrastructure environments. We developed these chemical generators for four specific targets; transition metal catalyst precursor tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba)3], oxidising agent Dess-Martin periodinane (DMP), protein photolinking reagent succinimidyl 4,4'-azipentanoate (NHS-diazirine), and the polyoxometalate cluster {P8W48}. The cartridge synthesis of these materials provides high-quality target compounds in good yields which are suitable for subsequent utilization.

Digitization of multistep organic synthesis in reactionware for on-demand pharmaceuticals.

Chemical manufacturing is often done at large facilities that require a sizable capital investment and then produce key compounds for a finite period. We present an approach to the manufacturing of fine chemicals and pharmaceuticals in a self-contained plastic reactionware device. The device was designed and constructed by using a chemical to computer-automated design (ChemCAD) approach that enables the translation of traditional bench-scale synthesis into a platform-independent digital code. This in turn guides production of a three-dimensional printed device that encloses the entire synthetic route internally via simple operations. We demonstrate the approach for the γ-aminobutyric acid receptor agonist, (±)-baclofen, establishing a concept that paves the way for the local manufacture of drugs outside of specialist facilities.

Critical Influence of 5-Hydroxymethylfurfural Aging and Decomposition on the Utility of Biomass Conversion in Organic Synthesis.

Spectral studies revealed the presence of a specific arrangement of 5-hydroxymethylfurfural (5-HMF) molecules in solution as a result of a hydrogen-bonding network, and this arrangement readily facilitates the aging of 5-HMF. Deterioration of the quality of this platform chemical limits its practical applications, especially in synthesis/pharma areas. The model drug Ranitidine (Zantac®) was synthesized with only 15 % yield starting from 5-HMF which was isolated and stored as an oil after a biomass conversion process. In contrast, a much higher yield of 65 % was obtained by using 5-HMF isolated in crystalline state from an optimized biomass conversion process. The molecular mechanisms responsible for 5-HMF decomposition in solution were established by NMR and ESI-MS studies. A highly selective synthesis of a 5-HMF derivative from glucose was achieved using a protecting group at O(6) position.

Visible light mediated metal-free thiol-yne click reaction.

The carbon-sulfur bond formation reaction is of paramount importance for functionalized materials design, as well as for biochemical applications. The use of expensive metal-based catalysts and the consequent contamination with trace metal impurities are challenging drawbacks of the existing methodologies. Here, we describe the first environmentally friendly metal-free photoredox pathway to the thiol-yne click reaction. Using Eosin Y as a cheap and readily available catalyst, C-S coupling products were obtained in high yields (up to 91%) and excellent selectivity (up to 60 : 1). A 3D-printed photoreactor was developed to create arrays of parallel reactions with temperature stabilization to improve the performance of the catalytic system.

Expanded-ring N-heterocyclic carbenes efficiently stabilize gold(I) cations, leading to high activity in π-acid-catalyzed cyclizations.

A series of six- and seven-membered expanded-ring N-heterocyclic carbene (er-NHC) gold(I) complexes has been synthesized using different synthetic approaches. Complexes with weakly coordinating anions [(er-NHC)AuX] (X(-) = BF4(-), NTf2(-), OTf(-)) were generated in solution. According to their (13)C NMR spectra, the ionic character of the complexes increases in the order X(-) = Cl(-) < NTf2(-) < OTf(-) < BF4(-). Additional factors for stabilization of the cationic complexes are expansion of the NHC ring and the attachment of bulky substituents at the nitrogen atoms. These er-NHCs are bulkier ligands and stronger electron donors than conventional NHCs as well as phosphines and sulfides and provide more stabilization of [(L)Au(+)] cations. A comparative study has been carried out of the catalytic activities of five-, six-, and seven-membered carbene complexes [(NHC)AuX], [(Ph3 P)AuX], [(Me2S)AuX], and inorganic compounds of gold in model reactions of indole and benzofuran synthesis. It was found that increased ionic character of the complexes was correlated with increased catalytic activity in the cyclization reactions. As a result, we developed an unprecedentedly active monoligand cationic [(THD-Dipp)Au]BF4 (1,3-bis(2,6-diisopropylphenyl)-3,4,5,6-tetrahydrodiazepin-2-ylidene gold(I) tetrafluoroborate) catalyst bearing seven-membered-ring carbene and bulky Dipp substituents. Quantitative yields of cyclized products were attained in several minutes at room temperature at 1 mol % catalyst loadings. The experimental observations were rationalized and fully supported by DFT calculations.

Efficient general procedure to access a diversity of gold(0) particles and gold(I) phosphine complexes from a simple HAuCl4 source. Localization of homogeneous/heterogeneous system's interface and field-emission scanning electron microscopy study.

Soluble gold precatalysts, aimed for homogeneous catalysis, under certain conditions may form nanoparticles, which dramatically change the mechanism and initiate different chemistry. The present study addresses the question of designing gold catalysts, taking into account possible interconversions and contamination at the homogeneous/heterogeneous system's interface. It was revealed that accurate localization of boundary experimental conditions for formation of molecular gold complexes in solution versus nucleation and growth of gold particles opens new opportunities for well-known gold chemistry. Within the developed concept, a series of practical procedures was created for efficient synthesis of soluble gold complexes with various phosphine ligands (R3P)AuCl (90-99% yield) and for preparation of different types of gold materials. The effect of the ligand on the particles growth in solution has been observed and characterized with high-resolution field-emission scanning electron microscopy (FE-SEM) study. Two unique types of nanostructured gold materials were prepared: hierarchical agglomerates and gold mirror composed of ultrafine smoothly shaped particles.

Catalytic adaptive recognition of thiol (SH) and selenol (SeH) groups toward synthesis of functionalized vinyl monomers.

An unprecedented sustainable procedure was developed to produce functionalized vinyl monomers H(2)C═C(R)(FG) starting from a mixture of sulfur and selenium compounds as a functional group donor (FG = S or Se). The reaction serves as a model for efficient utilization of natural resources of sulfur feedstock in oil and technological sources of sulfur/selenium. The catalytic system is reported with amazing ability to recognize SH/SeH groups in the mixture and selectively incorporate them into valuable organic products via wastes-free atom-economic reaction with alkynes (HC≡CR). Formation of catalyst active site and the mechanism of the catalytic reaction were revealed by joint experimental and theoretical study. The difference in reactivity of µ(1)- and µ(2)-type chalcogen atoms attached to the metal was established and was shown to play the key role in the action of palladium catalyst. An approach to solve a challenging problem of dynamically changed reaction mixture was demonstrated using adaptive tuning of the catalyst. The origins of the adaptive tuning effect were investigated at molecular level and were found to be governed by the nature of metal-chalcogen bond.