Mechanochemical ball milling catalytic transfer hydrogenation (CTH) of aromatic nitro compounds using readily available and cheap ammonium formate as the hydrogen source is demonstrated as a simple, facile and clean approach for the synthesis of substituted anilines and selected pharmaceutically relevant compounds. The scope of mechanochemical CTH is broad, as the reduction conditions tolerate various functionalities, for example nitro, amino, hydroxy, carbonyl, amide, urea, amino acid and heterocyclic. The presented methodology was also successfully integrated with other types of chemical reactions previously carried out mechanochemically, such as amide bond formation by coupling amines with acyl chlorides or anhydrides and click-type coupling reactions between amines and iso(thio)cyanates. In this way, we showed that active pharmaceutical ingredients Procainamide and Paracetamol could be synthesized from the respective nitro-precursors on milligram and gram scale in excellent isolated yields.

Novel supramolecular ionogels with high ionic conductivity and variable mechanical strength prepared by gelation of ionic liquid [C₄mim][N(Tf)₂] with (S,S)-bis(phenylalaninol)oxamide.

The Hofmann-Löffler-Freytag (HLF) reaction is a method that employs N-chlorinated precursors in radical-mediated rearrangement cycles to synthesize pyrrolidine rings and C-H functionalized products. This study aims to elucidate the mechanism of the propagation cycle, identify the rate-limiting step, and uncover the factors influencing the regioselectivity of the HLF reaction. Combining experimental techniques─laser flash photolysis (LFP), electron paramagnetic resonance (EPR), and nuclear magnetic resonance (NMR)─with computational density functional theory (DFT) calculations and kinetic modeling, we challenge the previous assumption that the hydrogen atom transfer (HAT) step was rate-limiting and regioselectivity was under both thermodynamic and kinetic control. We have identified that the halogen atom transfer (XAT) step in the propagation cycle of the HLF reaction follows pseudo-first-order kinetics and has the largest transition-state barrier. Additionally, we observed that regioselectivity is exclusively controlled by the intramolecular hydrogen atom transfer kinetics, while no thermodynamic preference exists in the formation of C₆- and C₅-chlorinated products. Our work predicts how to accelerate the HLF reaction and how we can control the regioselectivity by the smarter selection of substrates based on calculations, which could provide better control of the reaction when implemented in organic synthesis.

Converting macrocycle lactams into bicyclic lactams is proposed as an additional way to further increase the metabolic stability of peptide-based drugs. Unfortunately, the synthesis of bicyclic lactams has to start almost from scratch. This study explores the Hofmann-Löffler-Freytag (HLF) reaction mechanism and products as a potential late-stage functionalisation strategy for facile conversion of macrocyclic to bicyclic ring. Laurolactam, a macrocyclic amide, exhibits significant potential for transformation into bioactive bicyclic structures with smaller, β-, γ-, δ-, and ε-lactam rings, further increasing rigidity and hydrolytic stability. With irradiation provided by a 370 nm lamp, light-induced rearrangement reaction was monitored using nuclear magnetic resonance (NMR), while involved radical intermediates were trapped using N - tert -butyl-α-phenylnitrone (PBN) spin-trap and characterised via EPR. While only two radical adduct types were identified in the electron para magnetic resonance (EPR) ( C -centered radical and chlorine radical), all eight possible products are observed in the NMR. Quantum chemical calculations provide deeper insights into reaction thermodynamics and kinetics, explaining why the N -centered radical was not observed. This research highlights the feasibility of using the HLF reaction to transform macrocyclic lactams into stable bicyclic drug candidates, paving the way for new therapeutic developments.