Continuous-flow synthesis of fluorine-containing fine chemicals with integrated benchtop NMR analysis

Abstract

A compact lab plant was designed for the continuous-flow synthesis of fluorine-containing compounds and was combined with an NMR analysis platform based on a benchtop NMR spectrometer. The approach of a unified synthesis and analysis strategy for fine chemicals was applied to three different reactions, all employing fluorine as a chemical probe for online-19F NMR analysis. A high temperature synthesis for the deprotection of a CF2H group was done as well as Ruppert–Prakash reactions for the perfluoroalkylation of benzaldehyde as a model substrate. The C–H arylation of furan with a trifluoromethylated aryldiazonium salt was performed as an example of a photochemically catalyzed reaction. All three reaction classes challenge the synthesis and analysis setup differently according to sample preparation (premagnetization of bubble-free sample) and spectrometer sensitivity (signal to noise ratio, spectral resolution, scan number, substrate concentration and flow rate), but nonetheless prove the successful application of the continuous-flow synthesis of fluorinated fine chemicals with integrated online NMR analysis

NMR mit Tischgeräten und deren Anwendungen von der Materialwissenschaft bis zur organischen Chemie

“…Es können unterschiedliche Szenarien umgesetzt werden, z. B. Photokatalyse und ein Wechsel oder Verdampfen des Lösungsmittels zur Vermeidung von spektralen Interferenzen durch das Lösungsmittelsignal . Des Weiteren lassen sich 1 H‐, 19 F‐ und 13 C‐Mehrkern‐1D‐NMR‐Experimente sowie 2D‐Experimente wie COSY, J ‐aufgelöster und HSQC‐Spektroskopie problemlos implementieren.…”

“…Heterokerne haben eine höhere spektrale Dispersion als 1 H, wenn auch eine geringere Empfindlichkeit. In bestimmten Fällen eignen sie sich jedoch besser zur Reaktionsüberwachung . Signalüberlagerung kann auch in 2D‐Experimenten gemindert werden, die eine große Menge an Information liefern können.…”

Continuous-flow retro-Diels–Alder reaction: an efficient method for the preparation of pyrimidinone derivatives

“…The continuous-flow (CF) technology has gained significant importance in modern synthetic chemistry [ 1 – 3 ] and becomes a core technology in the pharmaceutical, agrochemical, and fine chemical industries [ 4 – 5 ]. The use of this technology opens a new door to a quick optimization, acceleration [ 6 ], and easy scale-up with a wide and growing range of chemical transformations in combination with an inherently safe and green nature [ 7 – 12 ].…”

Real‐time monitoring by proton relaxometry of radical polymerization reactions of acrylamide in aqueous solution

“…Among the spectroscopic methods mentioned, the absence of frequency‐domain nuclear magnetic resonance is symptomatic. Although a powerful spectroscopy, its exclusion from scenarios outside the controlled environment of an analytical laboratory is due largely to operational requirements, such as highly trained personnel, constant refilling of cryogenic gases, use of deuterated solvents, low analyte viscosity and absence of dissolved paramagnetic species …”

“…These spectrometers allow observation of the chemical displacements of abundant nuclei such as 1 H and 19 F, being smaller and requiring less maintenance than those based on superconducting magnets. However, they remain dependent on the use of special solvents and have limitations regarding high viscosity and the presence of paramagnetic species in the sample …”