Choose an application

• Reference Manager
• EndNote
• RefWorks (Direct export to RefWorks)

α-hydroxyketone derivatives are organic scaffolds widely encountered in natural or pharmaceutical active compounds. Many synthetic routes were reported in the literature but within the actual context of developing greener chemical processes, strategies involving transition-metal free synthesis using widely available molecular oxygen as the oxidizing source will be considered. Procedures for the hydroxylation of ketones with molecular oxygen have been already reported in batch but left with quite unresolved safety issues. This work aimed at developing a continuous-flow system allowing the safe hydroxylation of ketone-substrates using the intrinsic properties of flow chemistry.
Herein, we report a green and safe continuous flow procedure towards the synthesis of α-hydroxylated ketones. Conditions were first developed on a model substrate, namely, isobutyrophenone. The reaction conditions involved FDA class 3 and Chem21 green solvents, including ethanol and DMSO, as well as reactants presenting a low toxicity profile. Once all parameters were optimized, the conditions were applied to a small library of substrates to assess its efficiency. Enolizable ketones or esters were selected as potential substrates. Our procedure was then used for the synthesis of an important α-hydroxylated ketone intermediate for the preparation of active pharmaceutical ingredient ketamine. This synthesis worked efficiently under our conditions since total conversion and selectivity was achieved. The reaction conditions were next transposed to a larger mesofluidic pilot scale reactor, thus enabling the preparation of 1.3 kg per day with high conversions and selectivity.

continuous-flow, hydroxylation, enolizable ketones --- Physique, chimie, mathématiques & sciences de la terre > Chimie

Choose an application

• Reference Manager
• EndNote
• RefWorks (Direct export to RefWorks)

The nanotechnology field has found a wide range of utilities in our daily life and has deeply impacted the way of conceiving the world. Nanoparticles are inherently endowed with a high surface-to-volume ratio and possess remarkable size- and shape-dependent properties. The protocols for the preparation of nanoparticles are therefore really demanding for the accurate tailoring of size, shape and size dispersion control. The emergence of continuous flow technology and its application to the nanotechnology field has greatly improved the quality of such protocols by enabling accurate control of the local parameters, homogeneous mixing, fast thermal and mass transfers, convenient and fast monitoring, high reproducibility and fast lab-to-market transitions. Within this context, this research program aimed at the development of novel, potentially scalable, flow processes for the preparation of two types of nanoparticles, namely, cadmium selenide quantum dots and gold nanoparticles. The assets of continuous flow manufacturing were exploited to afford robust protocols aiming at potentially industrial productions. Their development was also thought in the context of sustainability. Aqueous protocols were developed to ease the implementation of further biological functionalizations.&#13;&#13;The first section of this work is devoted to the development of a novel water-soluble selenide precursor for the continuous flow synthesis of cadmium selenide quantum dots. The optimization of the synthesis of the novel Se precursor was first carried out before taking care of the quantum dots production. Different process parameters such as pH, ligand concentration, temperature and selenide-to-cadmium ratio, were first optimized under batch conditions and compared to those obtained in fluidic reactors. The preliminary observations (slow kinetics) led to a significant modification of the process with the segregation of the nucleation step from the growth process in two independent concatenated flow modules. Small nuclei were obtained rapidly at elevated temperatures (> 200 °C), moderate pressure (17 to 25 bar) and short residence times (< 10 s). The competing surface fluorescence was not completely suppressed. The optimization of this two-step protocol is still undergoing to afford a size-tunable production. Due to the nature of the ligand, CdSexSy alloys capped by thiolates were actually obtained.&#13;&#13;The second part of this work is dedicated to the development of a scalable photochemical flow process towards spherical gold nanoparticles. This protocol emerged as a potential and robust alternative to the well-known high-temperature citrate reduction. In this protocol, an unprecedented water-soluble acylphosphinate photoinitiator was identified for the preparation of gold nanoparticles. Upon exposure with UV irradiation, it underwent a Norrish type I cleavage and produced radicals able to reduce chloroauric acid into Au(0), eventually leading to the formation of nanoparticles. One of the main breakthroughs of this research program was the identification of robust and reproducible conditions that precluded the formation of a gold coating on the internal surfaces of the reactor. Such an issue is described in the literature and is seen as a major obstacle for the development of scalable and robust processes towards gold nanoparticles. The optimized protocol included the addition of external stabilizing ligands as well as finely tuned experimental parameters. Such ligands were also used to ensure stability for the nanoparticles over time. pH fluctuations were limited by working in a phosphate buffer. The implementation of an in-line UV spectrometer enabled real-time process monitoring for the optimization at the lab-scale. The optimized conditions were successfully transposed to pilot and production scales for the very first time of the history of continuous flow gold nanoparticle synthesis. A productivity of 65 g/day for a residence time as short as 10 s was achieved.&#13;&#13;This work opens new perspectives for the development of robust protocols towards high-value added nanoparticles and highlights the potential assets of continuous flow technology in the nanotechnology field.

continuous flow technology --- nanoparticles --- quantum dots --- Physique, chimie, mathématiques & sciences de la terre > Chimie

Choose an application

• Reference Manager
• EndNote
• RefWorks (Direct export to RefWorks)

Nitroso species and their wide variety are known for decades and are involved in numerous applications such as hetero Diels-Alder reactions or electrophilic aminations on α-ketones. However, they intrinsic poor stability, toxicity and their relative hazardous profile tuned down their potential use at an industrial-scale. In a conventional batch reactor, these reactions are relatively long (20-45 min) and the conversions associated are uncomplete.&#13;In this work, safe and efficient continuous-flow procedures for the preparation of α-chloro-nitroso species from aqueous sodium hypochlorite and oximes were developed. The conditions were first developed in a microfluidic setup, and next transposed to an industrial mesofluidic flow reactor. The lab-scale continuous-flow setup developed in this project affords complete conversion within minutes for different kinds of starting oximes (aliphatic and alicyclic, including chiral substrates). The process is very safe, and in-line IR analysis complements the control over the process conditions. The setup is amenable to the generation of libraries of α-chloro-nitroso and sustains productivities of up to 6 mL min-1, delivering ready-to-use α-chloro-nitroso species. &#13;The scope of the method was next assessed with a concrete application of α-chloro-nitroso species toward the synthesis of pharmacological active norephedrine. The optimized strategy toward norephedrine from propiophenone involved four steps with an overall isolated yield of 53%. Besides, several α-chloro-nitroso classes (aliphatic, alicyclic and chiral) were tested. In the last part of this work, we assessed the full development of a continuous-flow process toward norephedrine from a propiophenone derivative. Encouraging preliminary data was obtained.

Nitroso --- α-chloro-nitroso --- Hetero Diels-Alder --- Electrophilic amination --- Continuous-Flow processes --- Physique, chimie, mathématiques & sciences de la terre > Chimie

Choose an application

• Reference Manager
• EndNote
• RefWorks (Direct export to RefWorks)

N-Hydroxycarbamates play a key role as intermediates for a variety of compounds either in the pharmaceutical or pesticide industry. The most common synthetic pathway relies on the use of chloroformates intermediates yielded from the use of hazardous phosgene or derivatives such as CDI and hydroxylamine. In this master thesis, the production of N-hydroxycarbamates is disclosed as a two-step procedure relying on a key non-symmetrical carbonate intermediate. Continuous flow technology will be used as a means to intensify the reaction and its parameters. The non-symmetrical carbonate will act as a surrogate to phosgene-derived chloroformates and will be produced using commercially available and innocuous dimethyl carbonate. The robustness of the carbonation reaction under flow conditions was assessed by testing 17 benzyl alcohol derivatives. Conversions ranging from 66% to 96% were observed while testing derivatives with either electron withdrawing or donating groups on the aromatic ring. The reaction was performed in the presence of 3 mol% of TBD as the organocatalyst, 66 equivalents of dimethyl carbonate as both reagent and solvent as well as 1 equivalent of the tested benzyl alcohol derivative. A 10 min residence time was required alongside a 100 psi pressure and 80 °C for the reaction to proceed. The hydroxylamination reaction of non-symmetrical carbonate intermediate was then envisioned resulting in its implementation under both microwave irradiation and later continuous flow conditions with mixed yet encouraging results (66% conversion and 48% selectivity). The optimized continuous flow reaction relied on the use of 1 equivalent of the carbonate substrate, 5 equivalents of hydroxylamine and 0.5 equivalents of gadolinium triflate in 30 min at 80 °C under a 130 psi of counter-pressure. A small scope of previously synthesized carbonates was used to evaluate the efficiency of the reaction offering conversions ranging from 17% to 70% and selectivities from 34% to 49%. Finally, the reaction was tested as a “one-pot” process leading to promising results (22% conversion and 66% selectivity).

Continuous flow --- Flow chemistry --- Carbonation --- Organocatalysis --- Hydroxylamination --- N-Hydroxycarbamate --- Physique, chimie, mathématiques & sciences de la terre > Chimie

Choose an application

• Reference Manager
• EndNote
• RefWorks (Direct export to RefWorks)

Analytical chemistry --- Chemical laboratory practice --- Chemistry, Analytic --- Instrumental analysis --- Analyse instrumentale --- Instruments --- Instruments. --- Chemistry, Analytic - Instruments. --- Electrochemical instrumentation --- Chromatographic instrumentation --- Spectrochemical instrumentation --- Mass spectrometry --- Titration(Automated) --- Continuous flow analyzers --- Thermoanalytical instrumentation --- Laboratory chemical instruments --- Computer in analytical chemistry