Carbonylation flow scheme

Figure 1. Rhodium-catalyzed methanol carbonylation commercial process flow scheme [15].

Figure 6.8 (a) General flow scheme for the fluorination of alcohols and carbonyl compounds... 

Products with mass equal to the sum of the reagent masses also form, to different extents, in the reactions of 02 with ketones, namely acetone, CF3COCH3 and (CF3)2C0264. These adducts were tentatively assigned the structure of the bound tetrahedral adduct of nucleophilic carbonyl addition. While this reaction is the only one observed with acetone, it competes with H+ abstraction in the case of CF3COCH3 to form the stabilized enolate [CH2=C (CT)CF3] and with ET in the case of (CF3)2CO (electron affinity is ca 33.7 kcal moF1). In this latter case it was concluded that reaction of (CF3)2CO with Of occurs exclusively via ET and that the adduct forms in a secondary process via reaction of the primary product, the radical anion of (CF3)2CO with 302 present in the flow from the preparation of 02 (see Scheme 39). 

In the presence of strong acids such as aqueous H2SO4, carbonyl compounds may react with olefins to form unsaturated alcohols and other products, depending on the reaction conditions. Using H-mordenite as catalyst in a continuous-flow system, 10% conversion of formaldehyde to isoprene was observed at 300° using an isobutylene-to-HCHO (molar) ratio of 3.7. A carbonium ion-type reaction scheme, involving a Prins reaction (1,2) and a subsequent dehydration-rearrangement step... 

As an extension to a biphasic system reported previously, de Mello and coworkers [77] described the incorporation of a silica-supported Pd catalyst into a fluidic system and investigated the gas-solid-liquid carbonylation reaction of an aryl halide (24), an amine (134) and carbon monoxide (Scheme 6.33), to afford the respective N-benzylbenzamide (135). To conduct the reaction, a solution of aryl halide and amine, in THF, was pumped through the reactor at a flow rate of 10 pi min-1, where it was mixed with CO (2 seem) in a T-mixer, prior to passing through the packed-bed reactor [1 mm i.d. x 45 cm (length)]. Maintaining the system at 75 °C,... 

Scheme 6.33 An example of multi-phase carbonylation reactions performed under continuous flow.

Perfluoro-(2,5-dimethyl-l-oxa-2,5-diazacyclopentane) (57) decomposes slowly at room temperature in the absence of light to give 1 mol. equiv. of perfluoro-2-azapropene and a quantitative yield of a gum possessing an elemental analysis and F n.m.r. spectral characteristics consistent with the polymer [N(CF3)-0-CF2]n presumably homolytlc ring fission at an N—O bond is followed by j3-scission of the resultant biradical (59) [see Scheme 42 . (CF3)2N-0-N(CF3)2 + heat (CFs)2N-0 + (CFs)2N ->-(CF3)2N-N(CF3)2]. Flow pyrolysis of the diazacyclo-pentane at 150—200 °C and ca. 1 mmHg pressure in platinum yields trifluoronitro-somethane, carbonyl fluoride, perfluoro-2-azaiM opene, and traces of a yellow gas that possesses i.r. spectral characteristics identical with those reported for a... 

The use of ionic liquids and flow chemistry technologies attract increasing attention. Consequently, these novel tools have also been successfully used in carbonylative Sonogashira reactions by Ryu and colleagues [38, 39]. Various al-kynones were synthesized in moderate to good yields at a low pressure of CO in n-butyl methyl imidazolium hexafluorophosphate. The microreactor-based flow system was compared with typical batch conditions, and higher yields could be achieved with flow system (Scheme 5.13). 

Under mild conditions (1-4 bar CO, 25-60 °C), high yields of the desired produets were produced. Benzyl, allyl, aryl, and vinyl halides containing primary, secondary, or tertiary aleohol groups were readily converted to a variety of lactones, including phthalides and butenolides (Scheme 2.160a). Sinee then, 2-bromo benzyl aleohol has been tested as a substrate in various systems, such as carbonylation with a flow microreactor,[ C]-labelled compounds, and microwave-promoted with Mo(CO)g as a carbon monoxide source (Scheme 2.160b). Cobalt carbonyl as a cheaper catalyst was also applied in the intramolecular cyclization of aryl halides (Scheme 2.160c). ... 

However, gas substrates such as carbon monoxide (CO) can be easily introduced in a packed-bed reactor. ThanesNano researchers reported aminocarbonylation of aryl halides with amines and CO gas at high pressure and high temperature under flow conditions, which afforded the corresponding amides in moderate-to-high yield (Scheme 7.24) [101]. In this paper, they described that reaction parameters (solvent, base, catalyst, pressure, temperature, and so on) were rapidly optimized in the reactions, which required less than 2 min. As a continuous study, the authors reported a double carbonylation reaction of iodobenzene to give a-ketoamides in a flow reactor [102]. 

Hashimoto and coworkers accomplished the immobilization of chiral dirhodium (II) catalyst on a polystyrene-based copolymer. The polymer catalyst (55), which was packed in a gravity fed column, was successfully applied in a domino carbonyl ylide formation - dipolar cydoaddition under continuous-flow conditions (Scheme 7.39). The desired bicyclic adduct was obtained in high yield and high levels of asymmetric induction (up to 99% ee). The flow reactor was demonstrated by the retention of activity and enantioselectivity even after 60 h with a low metal leaching level (2.1 ppm) [146]. 

Scheme 7.39 Enantioselective carbonyl ylide cycloaddition using a continuous-flow system.

Carbonyl Group Reduction. The flow of new methods for reduction of acid derivatives and aldehydes or ketones to alcohols continues unabated. The Report last year (4,134) featured the sodium borohydride reduction of carboxylic acid derivatives, originally thought to be 2-thiazoline-2-thiol esters (14), to give alcohols in good yields. Full details of the method have now appeared (Scheme 8), and it seems that the acid derivatives are in fact the 3-acyl thiazolidine-2-thiones (IS) dissappearance of their yellow colour is an easy way to monitor the reduction. Carboxylic acids or their chlorides can also be reduced to primary alcohols in good yields at room temperature using a titanium tetrachloride-sodium borohydride combination. ... 

An example of a flow chemistry process is the Oppenauer oxidation of secondary benzylic alcohols using partially hydrated zirconia and various carbonyl compounds as oxidants (Scheme 53). The authors applied this procedure to electron-rich and electron-deficient substrates, with improvement in temperature (as low as 40 °C) and an easy reaction workup. The reuse of the catalyst was performed several times, without loss in catalytic efficiency. 

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