Marnix van der Kolk

Aromatic fluorination and radiofluorination reactions offer a potent approach to synthesizing a variety of compounds that feature a fluorine atom. Organic fluorinated compounds have widespread applications in various fields, encompassing agrochemicals, pharmaceuticals, and materials science. This review summarizes recent advancements in the field and highlights notable accomplishments achieved.

Abstract

The formation of carbon-fluorine (C−F) bonds is an important research field in organic synthesis because inserting a fluorine atom into an organic compound can alter its physicochemical properties, such as metabolic stability and permeability. Due to this unique property, organic fluorinated compounds, especially aryl fluorides, have a wide range of applications in various fields, including agrochemicals, pharmaceuticals, and materials science. Therefore, numerous metal- or metal-free-mediated fluorination reactions have been developed to synthesize aryl fluorides. In this mini-review, we summarize recent ten years’ advances in fluorination reactions for the synthesis of aryl fluorides.

Aromatic and aliphatic amines are key intermediates in the synthesis of pharmaceuticals, dyes, and agrochemicals. These amines are often sourced from nitro compounds. The hydrogenation of nitro compounds into amines requires harsh reaction conditions (e.g., high pressures and/or high temperatures) or additives that are usually toxic. Here we demonstrate hydrogenation of nitro compounds into amines in the hydrogenation compartment of a membrane reactor. The hydrogen is sourced from water in an adjacent electrolysis compartment, separated by a hydrogen-permeable palladium membrane. Modifications of the palladium membrane with catalysts enabled a wide range of commercially relevant nitro compounds to be hydrogenated into amines without any additives at ambient pressure and room temperature. This membrane reactor also enables nitro hydrogenation to occur at high concentrations and with high functional group tolerance.

Single-atom catalysts (SACs) hold the potential to combine the benefits of both heterogeneous and homogeneous catalysis. In this issue of Chem, Beller and co-workers demonstrate the selective insertion of transient copper carbenes into diverse X‒H (X = C, N, O, S) bonds with excellent functional-group tolerance by using a porous Al2O3-supported SAC.

In this work, a concept for an open chemistry knowledge base was developed to integrate chemical research results into a collaboratively usable platform. To achieve this, we enhanced Semantic MediaWiki (SMW) to support the collection and structured summary of chemical data contained in publications. We implemented tools for capturing chemical structures in machine-readable formats and designed data forms along with a data model to ensure standardized input and organization of research results. These enhancements allow for effective data comparison and contextual analysis within an expandable Wiki environment. The use of the platform was specifically demonstrated by organizing and comparing research in the area of “CO2 reduction in homogeneous photocatalytic systems,” showcasing its potential to significantly enhance the collaborative collection of research outcomes.

Fragmented sleep is independently associated with an increased risk of both general and abdominal obesity among Chinese young adults.

Nature Synthesis, Published online: 29 May 2024; doi:10.1038/s44160-024-00558-w

Automated iterative small-molecule synthesis has generally been limited to around one carbon–carbon bond-forming step per day. Now, a next-generation automated synthesizer enables rapid, automated, iterative synthesis of a variety of small molecules. Improvements to chemistry and automation leads to a tenfold decrease in reaction time over previous automated platforms.

Nature, Published online: 29 May 2024; doi:10.1038/s41586-024-07446-5

By controlling C–C bond formation in catalytic arylation, lignin can be efficiently extracted from biomass and converted into benign bisphenols that can be used as replacements for their fossil-based counterparts.

Aromatic compounds have found paramount utility on account of their stability, characteristic interactions, defined molecular shape and the numerous synthetic approaches for their synthesis, which include a diversity of cyclization reactions. In contrast, the cleavage of the inert aromatic carbon-carbon bonds remained largely unfeasible due to the unfavourable energetics of disrupting aromaticity in the formation of ring-opened products. For non- aromatic structures, alkene metathesis catalysed by transition metal alkylidenes is established as one of the most versatile carbon-carbon bond-forming and breaking reactions. However, despite remarkable advancements, strategies to open aromatic compounds by metathesis remained elusive. Herein we disclose the feasibility of aromatic ring-opening metathesis (ArROM) to cleave a diversity of aromatic rings, including tetraphene, naphthalene, indole, benzofuran and phenanthrenes by employing Schrock- Hoveyda molybdenum alkylidene catalysts. The reactions for each of the ring systems thereby proceed through unique alkylidene intermediates. We further show the possibility for stereoselective aromatic ring-opening metathesis with exquisite catalyst control over the configuration of atropisomers. Aromatic ring-opening metathesis is therefore a viable and efficient approach to catalytically transform and interconvert various aromatics without the requirement for any reagents or photoexcitation.

We report how the reaction mechanism and site-selectivity of 2-halopyridine oxidative addition to L2Pd(0) are both controlled by frontier molecular orbital symmetry. Comparing oxidative addition rates for pairs of 2-chloro-3-EDG-pyridines / 2-chloro-5-EDG-pyridines (EDG = electron-donating group: NH2, OMe and F) to Pd(PCy3)2 reveals the 3-EDG isomers undergo oxidative addition ~100 times faster than their 5-EDG counterparts (∆ΔG‡OA = 10.4-11.6 kJ mol-1). Experimental and computational mechanistic studies reveal that the LUMO symmetries of the substrates control the oxidative addition mechanism. For the 3-EDG derivatives, high LUMO orbital coefficients at the reactive C2 position, and antibonding LUMO symmetry through the C2=N bond of the pyridine lead to a nucleophilic displacement oxida-tive addition mechanism. Conversely, the LUMO of the 5-EDG derivatives has a node through the C5–C2 plane, lead-ing to minimal orbital contribution at the reactive carbon. The higher energy LUMO+1 has substantial density at C2, but minimal orbital density at the nitrogen. This leads to 5-EDG substrates undergoing a 3-centered insertion oxida-tive addition mechanism. These orbital symmetry effects also control site-selectivity for multihalogenated pyridines, which we investigate for both electron-donating and electron-withdrawing substituents. Incorporating simple fron-tier orbital based molecular descriptors to a quantitative multivariate linear model for oxidative addition leads to im-proved prediction accuracy for both relative rates and site-selectivity of substituted 2-halopyridine oxidative addition to L2Pd(0).

Nature Chemistry, Published online: 20 May 2024; doi:10.1038/s41557-024-01539-4

Electrophilic halogenation approaches often suffer from low reactivity and chemoselectivity when it comes to complex compounds. Now a class of halogenating reagents based on anomeric amides that can halogenate complex bioactive molecules with diverse functional groups and heterocycles has been developed. The higher reactivity of these anomeric amide reagents is attributed to the energy stored in the pyramidalized nitrogen.

A new cross-coupling of trifluoromethyl arenes has been realized via multiphoton photoredox catalysis. A series of valuable α,α-difluorobenzylic compounds can be generated while the the addition of D₂O leads to highly deuterated derivatives.

Abstract

A new cross-coupling of trifluoromethyl arenes has been realized via multiphoton photoredox catalysis. Trifluoromethyl arenes were demonstrated to undergo selective mono-defluorinative alkylation under mild reaction conditions providing access to a series of valuable α,α-difluorobenzylic compounds. The reaction shows broad substrate scope and general functional group tolerance. In addition to the electron-deficient trifluoromethyl arenes that are easily reduced to the corresponding radical anion, more challenging electron-rich substrates were also successfully applied. Steady-State Stern-Volmer quenching studies indicated that the trifluoromethyl arenes were reduced by the multiphoton excited Ir-based photocatalyst.