Continuous-flow conditions

In the simplest case, the feed solution consists of a solvent A containing a consolute component C, which is brought into contact with a second solvent B. Eor efficient contact there must be a large interfacial area across which component C can transfer until equiHbrium is reached or closely approached. On the laboratory scale this can be achieved in a few minutes simply by hand agitation of the two Hquid phases in a stoppered flask or separatory fuimel. Under continuous flow conditions it is usually necessary to use mechanical agitation to promote coalescence of the phases. After sufficient time and agitation, the system approaches equiHbrium which can be expressed in terms of the extraction factor S for component C ... 

Although limited by sensitivity, chemical reaction monitoring via less sensitive nuclei (such as 13C) has also been reported. In 1987 Albert et al. monitored the electrochemical reaction of 2,4,6-tri-t-butylphenol by continuous flow 13C NMR [4]. More recently, Hunger and Horvath studied the conversion of vapor propan-2-ol (13C labeled) on zeolites using 1H and 13C in situ magic angle spinning (MAS) NMR spectroscopy under continuous-flow conditions [15]. 

SFC-NMR is available from 200 to 800 MHz, and is suitable for all common NMR-detected nuclei. SFC/SFE-NMR requires dedicated probe-heads for high pressure (up to 350 bar) and elevated temperature (up to 100 °C). SFC-NMR is carried out with conventional packed columns, using modifier, pressure and temperature gradients. The resolution of 1H NMR spectra obtained in SFE-NMR and SFC-NMR coupling under continuous-flow conditions approaches that of conventionally recorded NMR spectra. However, due to the supercritical measuring conditions, the 111 spin-lattice relaxation times 7) are doubled. 

Hunger, M. and Horvath, T.J. (1995) A new mas NMR probe for in-situ investigations of hydrocarbon conversion on solid catalysts under continuous-flow conditions, Chem. Soc. Client. Comm., 14, 1423. 

Scheme 4.28 1,3-Dipolar cycloaddition reactions under continuous-flow conditions.

Wan et al. [61] also reported the highly effective conversion of methane to aromatic hydrocarbons over Cu, Ni, Fe, and Al catalysts. The effects of the type of catalyst, its configuration, and the microwave irradiation conditions on reaction path and product selectivity were examined under both batch and continuous-flow conditions. 

Figure 6.34. Results from the hydroformylation of 1-octene carried out under continuous flow conditions with extra catalyst solution additional]...

The promising results obtained under batch-wise operation could be confirmed also under continuous-flow conditions. As schematically shown in Fig. 2, the substrate was injected with an HPLC pump into a stream of premixed CO2 and O2 before entering the reactor. The supercritical mixture was bubbled through the stationary PEG phase containing the Pd nanoparticles. 

Under continuous flow conditions involving feeding, aeration, settling, and reflux, a mixture of jD-chloronitrobenzene and 2,4-dinitrochlorobenzene was reduced 61-70% after 8-13 d by Arthrobacter simplex, a microorganism isolated from industrial waste. A similar experiment was conducted using two aeration columns. One column contained A. simplex, the other a mixture of A. simplex and microorganisms isolated from soil Streptomyces coelicolor, Fusarium sp., probably aquaeductum and Trichoderma viride). After 10 d, 89.5-91% of the nitro compounds was reduced. p-Chloronitrobenzene was reduced to 4-chloroaniline and six unidentified compounds (Bielaszczyk et al., 1967). 

Gas Phase Reactions Under Continuous Flow Conditions... 

Figure 12. Peptide synthesis under continuous flow conditions [31].

Shore and coworkers [64] used a capillary reactor with a Pd thin film and microwave-assisted continuous-flow conditions for Suzttki-Miyara and Heck coupling reactions. The Pd film was prepared by passing Pd(OAc)2 solution into the 1150 pm eapillary at 150°C resulting in a highly porous catalyst composed of nanometer-size grains. 

Glasnov, T. N. and Kappe, C.O. (2007). Microwave-Assisted Synthesis under Continuous-Flow Conditions. Macrorwo/. Rqp/JCoOTOTMW., 28, 395-410. 

In CSTR reactors, both phases are considered to be in complete mixed and continuous-flow condition. In the general case where reactants can be gases and liquids, the following material balances can be applied (for simplicity we consider constant-density systems) (Hopper et al., 2001)... 

In many early studies, it was assumed that peroxyl radical adducts of DMPO were responsible for spectra that looked very similar to that of the DMPO superoxide adduct (DMPO OOH), but it has since been shown that such spectra are from trapped primary alkoxyl radicals that arise via 02 addition to carbon-centred radicals arising, in turn, from the p-scission of secondary and tertiary alkoxyl radicals.131 Further evidence supporting the generation of DMPO adducts via these reactions has been furnished by Guo and colleagues, who have reported the HPLC/EPR and MS analysis of radical adducts formed from organic hydroperoxides.132 Peroxyl radical adducts of DMPO are in fact very unstable the BuOO adduct has been observed under continuous-flow conditions.133... 

Whereas much mechanistic information can be obtained by one of the above methods, any practical applications must be demonstrated under conditions similar to process operation, i.e., continuous flow. Small glass reactors which allow controlled addition of reagents by syringe pump and continuous removal and monitoring (IR spectroscopy) of product mixture have been developed. Much of the information obtained from semibatch operation has been reproduced under these continuous flow conditions. 

Scheme 2 Reaction protocol employed for the synthesis of 3-diamino-lH-isochromen-1-one 5 under continuous flow conditions.

An early example of an investigation into the use of n-BuLi 74 under continuous flow conditions was demonstrated by Schwalbe et al. (2004) and involved the in situ generation of C2F5-Li 75 and its subsequent nucleophilic addition to benzophenone 76 as depicted in Scheme 21. 

Scheme 38 Polymer-assisted derivatization of a steroid under continuous flow conditions.

In order to increase the efficiency of biocatalytic transformations conducted under continuous flow conditions, Honda et al. (2006, 2007) reported an integrated microfluidic system, consisting of an immobilized enzymatic microreactor and an in-line liquid-liquid extraction device, capable of achieving the optical resolution of racemic amino acids under continuous flow whilst enabling efficient recycle of the enzyme. As Scheme 42 illustrates, the first step of the optical resolution was an enzyme-catalyzed enantioselective hydrolysis of a racemic mixture of acetyl-D,L-phenylalanine to afford L-phenylalanine 157 (99.2-99.9% ee) and unreacted acetyl-D-phenylalanine 158. Acidification of the reaction products, prior to the addition of EtOAc, enabled efficient continuous extraction of L-phenylalanine 157 into the aqueous stream, whilst acetyl-D-phenylalanine 158 remained in the organic fraction (84—92% efficiency). Employing the optimal reaction conditions of 0.5 gl min 1 for the enzymatic reaction and 2.0 gl min-1 for the liquid-liquid extraction, the authors were able to resolve 240 nmol h-1 of the racemate. 

In 2005, Baxendale et al. reported the first enantioselective synthesis of 2-aryl-2,3-dihydro-3-benzofurancarboxamide neolignan (grossamide) 260 conducted under continuous flow conditions. As illustrated in Scheme 73, the first step of the reaction involved the synthesis of amide 261 via the coupling of ferulic acid 262 and tyramine 171, in the presence of PS-HOBt 263. Monitoring reaction progress by LC-MS, the authors were able to optimize this step to afford the amide 261 in 90% conversion however, prior to performing the second reaction step it was imperative to remove any residual tyramine 171. As Scheme 74 illustrates, this was achieved by... 

Typical results for the activity, expressed as the percentage conversion of the propane feed, the selectivity, expressed as the ((propene yield)/(propane reacted)%), and the carbon laydown are shown in Table 1 for a reaction carried out under continuous flow conditions at 873 K and a GHSV of 3000 hr 1. 

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