ABSTRACT
Molecular oxygen is arguably the greenest reagent available to the organic chemist. Most commonly, a diluted form of oxygen gas, consisting of less than 10 % O2 in N2 ("synthetic air"), is used in pharmaceutical and fine chemical batch manufacturing to effectively address safety concerns when handling molecular oxygen. Concentrations of O2 in N2 below 10 % are generally required to prevent the risk of combustions in the presence of flammable organic solvents ("limiting oxygen concentration"). Nonetheless, the use of pure oxygen is more efficient than using O2 diluted with N2 and can often provide enhanced reaction rates, resulting in significant improvements in product quality and process efficiency. This Concept takes into account recent studies to make the argument that, for liquid-phase aerobic oxidations, pure oxygen can indeed be handled safely on large scale by employing continuous-flow reactors, while also providing highly convincing synthetic and manufacturing benefits.
Subject(s)
Oxygen/chemistry , Pharmaceutical Preparations/chemistry , Safety , Solvents/chemistryABSTRACT
We report an operationally simple and rapid continuous flow radical C-C bond formation under Minisci-type reaction conditions. The transformations are performed at or below room temperature employing hydrogen peroxide (H2 O2 ) and dimethylsulfoxide (DMSO) as reagents in the presence of an FeII catalyst. For electron-rich aromatic and heteroaromatic substrates, C-C bond formation proceeds satisfactorily with electrophilic radicals including . CF3 , . C4 F9 , . CH2 CN, and . CH2 CO2 Et. In contrast, electron-poor substrates exhibit minimal reactivity. Importantly, trifluoromethylations and nonafluororobutylations using CF3 I and C4 F9 I as reagents proceed exceedingly fast with high conversion for selected substrates in residence times of a few seconds. The attractive features of the present process are the low cost of the reagents and the extraordinarily high reaction rates. The direct application of the protocol to dihydroergotamine, a complex ergot alkaloid, yielded the corresponding trifluoromethyl ergoline derivative within 12 seconds in a continuous flow microreactor on a 0.6â kg scale. The trifluoromethyl derivative of dihydroergotamine is a promising therapeutic agent for the treatment of migraines.
ABSTRACT
To efficiently drive chemical reactions, it is often necessary to influence an equilibrium by removing one or more components from the reaction space. Such manipulation is straightforward in open systems, for example, by distillation of a volatile product from the reaction mixture. Herein we describe a unique high-temperature/high-pressure gas/liquid continuous-flow process for the rhodium-catalyzed decarbonylation of aldehydes. The carbon monoxide released during the reaction is carried with a stream of an inert gas through the center of the tubing, whereas the liquid feed travels as an annular film along the wall of the channel. As a consequence, carbon monoxide is effectively vaporized from the liquid phase into the gas phase and stripped from the reaction mixture, thus driving the equilibrium to the product and preventing poisoning of the catalyst. This approach enables the catalytic decarbonylation of a variety of aldehydes with unprecedented efficiency with a standard coil-based flow device.
ABSTRACT
The decomposition of 5-benzhydryl-1H-tetrazole in an N-methyl-2-pyrrolidone/acetic acid/water mixture was investigated under a variety of high-temperature reaction conditions. Employing a sealed Pyrex glass vial and batch microwave conditions at 240 °C, the tetrazole is comparatively stable and complete decomposition to diphenylmethane requires more than 8 h. Similar kinetic data were obtained in conductively heated flow devices with either stainless steel or Hastelloy coils in the same temperature region. In contrast, in a flow instrument that utilizes direct electric resistance heating of the reactor coil, tetrazole decomposition was dramatically accelerated with rate constants increased by two orders of magnitude. When 5-benzhydryl-1H-tetrazole was exposed to 220 °C in this type of flow reactor, decomposition to diphenylmethane was complete within 10 min. The mechanism and kinetic parameters of tetrazole decomposition under a variety of reaction conditions were investigated. A number of possible explanations for these highly unusual rate accelerations are presented. In addition, general aspects of reactor degradation, corrosion and contamination effects of importance to continuous flow chemistry are discussed.
ABSTRACT
Reported is the first study of the influence of reactor configuration on the efficiency of a challenging ring-closing metathesis (RCM) reaction. With the intention of increasing the generality of RCM scaleup and reducing its dependence on substrate modification, macrocyclization of an unmodified, low effective-molarity diene was explored using different reactor types, in conjunction with a commercial, homogeneous Grubbs catalyst. Optimized performance is compared for a conventional batch reactor (BR), a continuous plug-flow reactor (PFR), and a continuous stirred-tank reactor (CSTR). In the PFR, maximum conversion is achieved most rapidly, but product yields and selectivity are adversely affected by co-entrapment of ethylene with the catalyst, substrate, and product in the traveling "plug". Use of the CSTR, in which ethylene is efficiently swept out, affords an order-of-magnitude increase in total turnover numbers, and reduces the required catalyst loadings by 25× relative to the BR (to 0.2â mol %), while improving RCM yields and selectivity to quantitative levels. Continuous-flow methodologies that support liberation of the ethylene co-product thus show great promise for industrial uptake of RCM.
ABSTRACT
Microstructured devices offer unique transport capabilities for rapid mixing, enhanced heat and mass transfer and can handle small amounts of dangerous or unstable materials. The integration of reaction kinetics into fluid dynamics and transport phenomena is essential for successful application from process design in laboratory to chemical production. Strategies to implement production campaigns up to tons of pharmaceutical chemicals are discussed, based on Lonza projects.