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Synthesis and enabling technologies

Chemists and material scientists can create molecules, compounds, materials and devices comprising infinite compositions, connectivities and arrangements, and hence choosing what to make and figuring out how to make it, are part of the compelling challenge. Once these entities are in hand, researchers are poised to probe their chemical, physical, biological or electronic properties, with the hope of advancing our conceptual knowledge or benefiting humankind or our society. This journey makes synthesis an enabling science; opening up innovations in healthcare, energy-related materials, to name a few, and driving the development of sustainable and renewable technologies.

To mark the launch of Nature Synthesis in January 2022, the editors have curated an online Collection of recent articles published by Nature Research on themes within the scope of Nature Synthesis. This Collection reflects our motivation to publish articles in the fields of both chemistry and materials science, with a focus on the synthesis, fabrication and processing of molecules, compounds and materials. The editors of Nature Synthesis are also keen to publish articles reporting technological advances that improve the synthesis of target products, in terms of ease, efficiency, speed or sustainability, as well as opening up synthetic routes to new and valuable products. These advances may include innovations in automation or machine learning. By featuring such breadth and diversity in content, we hope to bring together scientists from various disciplines, both in academia and industry.

Nature Synthesis will publish original research articles, reviews, and news & opinion articles, and is now open for submissions. To learn more about how to submit an article, please visit our For Authors pages.

Biosynthesis & organic synthesis

Analysis of two homologous groups of fungal pericyclases demonstrates how they can catalyse either an Alder-ene reaction—which has not previously been found in nature—or a hetero-Diels–Alder reaction.

Article | | Nature

A manganese-catalysed oxidative C(sp3)–H methylation method allows a methyl group to be selectively installed into medicinally important heterocycles, providing a way to improve pharmaceuticals and better understand the ‘magic methyl effect’.

Article | | Nature

Nitrogen is ‘deleted’ from secondary amines using anomeric amide reagents, which react with the amine to form an isodiazene, after which nitrogen gas is released and the resulting carbon radicals combine to form a carbon–carbon bond.

Article | | Nature

Inverting the order of nature’s two-phase biosynthesis of terpenes offers a strategy by which the synthesis of these compounds can be simplified. The key reaction is a palladium-catalysed polyenyne cycloisomerization that not only tolerates the presence of all of the oxygen functionalities but also is facilitated by them.

Article | | Nature Chemistry

In an effort to extend the important hydroformylation reaction, a palladium-catalysed carboformylation reaction has now been developed in which two new carbon–carbon bonds are created across an alkyne. This modular reaction relies on a CO shuffling process and uses an acid chloride as a dual carbon and CO source.

Article | | Nature Chemistry

Although azetidines represent highly desirable building blocks in drug discovery, methods for their efficient and straightforward synthesis remain underdeveloped. Now, it has been shown that highly functionalized azetidines can be prepared via an intermolecular [2+2] photocycloaddition reaction between cyclic oximes and alkenes, in a process enabled by a visible-light-mediated triplet energy transfer.

Article | | Nature Chemistry

O-methyl nitronate is a rare functional group in natural products. Now, the biosynthetic pathway to O-methyl nitronate, which involves O-methylation of a peptidyl carrier protein (PCP)-tethered nitronate, has been revealed. In some bacteria, the same PCP-tethered nitronate is shown to be oxidized by nitronate monooxygenases to provide nitrite and a PCP-tethered glyoxylate.

Article | | Nature Chemistry

Cross-coupling processes without the use of transition metals are challenging to achieve. Here, the authors show a transition-metal-free cross-coupling utilizing aryl(heteroaryl) methyl sulfoxides and alcohols to afford alkyl aryl(heteroaryl) ethers and propose a nucleophilic addition mechanism based on experiments and theory.

Article | Open Access | | Nature Communications

Several Hasubanan alkaloids have been synthesized in the past decades, however a divergent approach to access the 3 subclasses of such natural products has not been reported yet. Here, the authors show the enantioselective total syntheses of four representative members via a unified strategy leading to the three topologically different classes of alkaloids.

Article | Open Access | | Nature Communications

α-Pyridones and α-pyrones are ubiquitous structural motifs found in natural products and components of biologically active small molecules. Here, the authors report an oxidant-free Rh-catalyzed electrochemical divergent vinylic C–H annulation of acrylamides with alkynes to α-pyridones and cyclic imidates.

Article | Open Access | | Nature Communications

Inorganic & organometallic synthesis

Silyl-substituted silicon–carbonyl complexes that are stable at room temperature have been prepared by exposure of highly reactive bis(silyl)silylenes to carbon monoxide. The compounds show structural features and reactivity that are reminiscent of their ubiquitous transition-metal–carbonyl counterparts, including π-backbonding and ligand liberation as well as substitution and functionalization reactions.

Article | | Nature Chemistry

The vast majority of species capable of converting dinitrogen to ammonia rely on transition metals. Now, a boron compound has been shown to mediate the one-pot binding, cleavage and reduction of N2 to ammonium salts under mild conditions through a complex cascade mechanism involving multiple reduction–protonation sequences.

Article | | Nature Chemistry

A wide variety of organic and inorganic compounds show π-aromaticity, yet for all-metal systems it has remained restricted to compounds with three to five atoms. Now, the anionic cluster [Th@Bi12]4− has been shown to exhibit π-aromaticity, with a significant ring current despite relying on the delocalization of only two π-electrons.

Article | | Nature Chemistry

Unlike ferrocene and its cationic counterpart ferrocenium, the ferrocene monoanion is an unusual species that has been observed through low-temperature electrochemical studies. Now, a family of isostructural 3d metallocenates has been isolated that consists of a manganocene, a cobaltocene and a high-spin ferrocene anion stabilized by cyclopentadienyl ligands bearing bulky aliphatic groups.

Article | | Nature Chemistry

Metallocenes are attractive mechanophores because they are stable in the absence of force, yet reactive under tension. Now, covalently bridging the two cyclopentadienyl (Cp) ligands of ferrocenes embedded in a polymer has been shown to alter their mechanochemical reactivity, leading to a faster dissociation of the Fe–Cp bond, which occurs through a peeling mechanism rather than a shearing one.

Article | | Nature Chemistry

It is difficult to investigate the chemical properties of superheavy elements, which are only available an atom at a time and rapidly decay. A co-precipitation method with samarium has now been developed that suggests rutherfordium would form hydroxide precipitates—but not ammine ones—if it were possible to perform these experiments on macroscopic quantities.

Article | | Nature Chemistry

Although iron–sulfur cofactors are known to carry out biological nitrogen fixation, how these clusters bind dinitrogen remains poorly understood. Now, a dinitrogen complex of a synthetic iron–sulfur cluster has been characterized, and electronic cooperation in the cluster has been shown to result in strong N–N bond activation.

Article | | Nature Chemistry

Obtaining mechanistic data after the rate-determining step of a chemical reaction is difficult but essential for its understanding. Now, a Ru(iv) side-on peroxo complex has been isolated following the rate-determining step of the water oxidation reaction (O–O bond formation) carried out using a Ru-based molecular catalyst.

Article | | Nature Chemistry

Nitrous-oxide-mediated oxidation reactions can be effectively promoted by iron-containing zeolites, although structural information on the interaction between oxidant and metal centre is limited. Here, the authors report the characterization of the N2O-ligated Fe(ii) active site in iron-exchanged zeolite beta.

Article | | Nature Catalysis

Manganese-based hydrogenation catalysts are sensitive to high temperatures and may degrade under industrially relevant conditions. Here, the authors report a highly efficient manganese pincer pre-catalyst displaying high TOF values (up to 41 000 h−1) and stability (TON up to 200 000) at loadings as low as 5-200 ppm.

Article | Open Access | | Nature Communications

Materials & self-assembly

Polycarbonates and polyesters with materials properties like those of high-density polyethylene can be recycled chemically by depolymerization to their constituent monomers, re-polymerization yielding material with uncompromised processing and materials properties.

Article | | Nature

The copolymerization of CO2 with epoxides is an attractive approach for valorizing waste products and improving sustainability in polymer manufacturing. Now, a heterodinuclear Mg(ii)Co(ii) complex has been shown to act as a highly active and selective catalyst for this reaction at low CO2 pressure. The synergy between the two metals was investigated using polymerization kinetics.

Article | | Nature Chemistry

Layered COFs are attractive precursors for two-dimensional materials but they are difficult to cleave into mono- or few-layer sheets. Pseudorotaxane moieties have now been embedded into layered COFs to facilitate their cleavage into sheets of uniform thickness. Crown-ether macrocycles within the COF backbone bind to ionic viologen guests, leading to electrostatic repulsion between layers.

Article | | Nature Chemistry

Fluorinated polyacetylene has typically proven to be inaccessible using traditional polymer synthesis, but there is much interest in its predicted properties. Now, a mechanochemical unzipping strategy has succeeded in the synthesis of a gold-coloured, semiconducting fluorinated polyacetylene with improved stability in air compared to polyacetylene.

Article | | Nature Chemistry

Iron-catalysed [2+2] cycloaddition/oligomerization of neat butadiene affords (1,n′-divinyl)oligocyclobutane—a telechelic, crystalline material consisting of 1,3-enchained cyclobutyl units. This oligocyclobutane can be chemically recycled to pure butadiene using the same iron catalyst employed in its synthesis, demonstrating design principles for next-generation plastic materials that can be returned to pristine monomer.

Article | | Nature Chemistry

Lustrous flexible thin films of semiconducting cyclic polyacetylene (c-PA) have been synthesized and characterized. Rapid and efficient tungsten-catalysed acetylene polymerization conditions produce temporarily soluble c-PA, enabling the in situ derivatization of this typically insoluble polymer. Compelling evidence for the cyclic topology—and its influence on the physical properties of the polymer—are presented.

Article | | Nature Chemistry

Constructing molecular cages from entangled molecules is a complex task requiring precise topological control. Here, the authors thread together six metal-peptide rings into a giant cubic molecular capsule with a defined cavity and 24 crossover points.

Article | Open Access | | Nature Communications

The controllable synthesis of organometallic polymers that can be used in ultrahigh information storage and anti-counterfeiting security has been an unsolved challenge. Here, the authors show sequence-controlled electrosynthesis of organometallic polymers with exquisite insertion of multiple and distinct monomers.

Article | Open Access | | Nature Communications

The introduction of shape anisotropy at the nanoscale is a potent way to access new properties and functionalities. This Review appraises different methods for the bottom-up synthesis of anisotropic nanoparticles, and highlights the unique properties and applications of these materials with otherwise inaccessible functionality.

Review Article | | Nature Reviews Chemistry

Incorporating the mechanical bond into polymer architectures allows access to polymers with high-mobility elements, leading to unique material properties. This Review outlines the structure–property relationships of materials based on either polyrotaxanes (including slide-ring materials and daisy-chain polymers) or polycatenanes, and looks towards future applications and technologies.

Review Article | | Nature Reviews Materials

Technology-enabled synthesis

An automated synthesis instrument comprising a series of continuous flow modules that are radially arranged around a central switching station can achieve both linear and convergent syntheses.

Article | | Nature

A mobile robot autonomously operates analytical instruments in a wet chemistry laboratory, performing a photocatalyst optimization task much faster than a human would be able to.

Article | | Nature

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.

Article | | Nature

Bayesian optimization is applied in chemical synthesis towards the optimization of various organic reactions and is found to outperform scientists in both average optimization efficiency and consistency.

Article | | Nature

Automated synthesis technologies are often highly specialized, focusing only on a narrow set of reaction classes. Now, solid-phase peptide synthesis, iterative Suzuki–Miyaura cross-coupling and diazirine chemistry have all been automated using the same universal platform architecture. A convergent 12-step synthesis demonstrates the utility of the reported Chemputer system.

Article | | Nature Chemistry

Organic chemical reactions can be divided into classes that allow chemists to use the knowledge they have about optimal conditions for specific reactions in the context of other reactions of similar type. Schwaller et al. present here an efficient method based on transformer neural networks that learns a chemical space in which reactions of a similar class are grouped together.

Article | | Nature Machine Intelligence

Translating discovery scale vial-based batch reactions to continuous flow scale-up conditions is limited by significant time and resource constraints. Here, the authors report a photochemical droplet microfluidic platform, which enables high throughput reaction discovery in flow to generate pharmaceutically relevant compound libraries.

Article | Open Access | | Nature Communications

Predictive computational approaches are fundamental to accelerating solid-state inorganic synthesis. This work demonstrates a computational tractable approach constructed from available thermochemistry data and based on a graph-based network model for predicting solid-state inorganic reaction pathways.

Article | Open Access | | Nature Communications

Although strategies for the automated assembly of compounds of pharmaceutical relevance is a growing field of research, the synthesis of small-molecule pharmacophores remains a predominantly manual process. Now, an automated six-step synthesis of prexasertib is achieved by multistep solid-phase chemistry in a continuous-flow fashion using a chemical recipe file that enables automated scaffold modification through both early and late-stage diversification.

Article | | Nature Chemistry