A universal multistage cascade CSTR has been developed that is suitable for a wide range of continuous-flow processes. Coined by our group the “Freactor” (free-to-access reactor), the new reactor integrates the efficiency of pipe-flow processing with the advanced mixing of a CSTR, delivering a general “plug-and-play” reactor platform which is well-suited to multiphasic continuous-flow chemistry. Importantly, the reactor geometry is easily customized to accommodate reactions requiring long residence times (≥3 h tested).

A route to access the privileged imidazo[1,2-a]pyridine scaffold in one step, 1–10 minutes using only aqueous NaOH, is reported.

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A new, dynamic diastereomeric crystallization method has been developed, in which the mother liquors are continuously separated, racemized over a fixed-bed catalyst, and recirculated to the crystallizer in a resolution−racemization−recycle (R 3 ) process. Separating the racemization from crystallization overcomes problems of using catalysts in situ, that suffer conflicting sets of conditions, inhibition, and separation. Continuous racemization has been achieved through the covalent attachment of [IrCp*I 2 ] 2 SCRAM catalyst to Wang resin solid support to give a fixed-bed catalyst. One tertiary and a variety of secondary optically enriched amines have been racemized efficiently, with residence times compatible with the crystallization (2.25−30 min). The catalyst demonstrates lower turnover (TOF) than the homogeneous analogue but with reuse shows a long lifetime (e.g., 40 recycles, 190 h) giving acceptable turnover number (TON) (up to 4907). The slow release of methylamine during racemization of N-methyl amines was found to inactivate the catalyst, which could be partially reactivated using hydroiodic acid. Dynamic crystallization is achieved in the R 3 process through the continual removal of the more soluble diastereomer and supply of the less soluble one. The solubility of the diastereomers was determined, and the difference correlates to the rate of resolution but is also affected by the rates of racemization, crystal growth, and dissolution. A variety of cyclic and acyclic amine salts were resolved using mandelic acid (MA) and ditoluoyl tartaric acid (DTTA) with higher resolvability (S = yield × d.e.) than the simple diastereomeric crystallization alone. Comparing resolvabilities, resolutions were 1.6−44 times more effective with the R 3 process than batch, though one case was worse. Further investigation of this revealed an unusual thermodynamic switching behavior: rac-N-methylphenethylamine was initially resolved as an (S,S)-bis-alkylammonium tartrate crystal but over time became the equivalent (R,S) salt. Thermal, mixing, concentration, stoichiometry, and seeding conditions were all found to affect the onset of the switching behavior which is only associated with difunctional resolving reagents.

A low energy, high selectivity approach to the catalytic hydrodeoxygenation of phenols is reported using batch or continuous flow methods to react 3 equivalents of phenol with cyanuric chloride then hydrogenolyzing the triarylcyanurate intermediate to give 3 equivalents of de oxo aromatic. The use of cyanuric chloride compares favorably with existing activation methods, showing improved scalability, atom efficiency and economics. The scope of both the activation and hydrogenolysis stages are explored using lignin related phenols. Initial development has identified that continuous stir tank reactors (CSTRs) enable a multi phasic process for converting guaiacol to anisole, and at steady state overcome the catalyst deactivation issues observed in batch, seemingly caused by the cyanurate by product. Green chemistry aspects, and the potential for industrial adoption are discussed. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 3 conditions, 4 however it has often required catalytic reforming at >300 o C temperature, resulting in over reduction with complex product mixtures and catalyst deactivation. 5 For example cobalt molybdenum sulfide on alumina catalyst at 300 o C and 50 bar has been shown to convert 84% of the guaiacol to give 34% phenol, 11% catechol, 3% anisole, 1% benzene and the remainder saturated products. 6 The extreme conditions are required because the aromatic C O bond is strong with a length of 1.37 Å and bond energy of 460 kJ.mol 1 , compared to the aliphatic C O bond of 1.43 Å and 358 kJ.mol 1 . 7 In the organic laboratory the hydrogenolysis of phenolic compounds is usually carried out by activation with trifluoromethanesulfonyl chloride followed by reduction; however the cost of making triflates and the associated waste make this method too expensive and wasteful to consider for bulk production. 8 Reports of aryl alkyl ether reduction, using either nickel catalysts and silane reductants, or better from an industrial perspective, a combination of metal triflate and palladium catalysts with hydrogen, both illustrate the difficulties in this transformation. 9 Another reported phenol activation method is reacting phenyl tetrazolium chloride with the phenol to make the corresponding 5 aryloxy 1 phenyltetrazoyl ethers, with similar disadvantages and low atom efficiency. 10 The electron withdrawing and resonance stabilizing tetrazolyl group can weaken the aromatic C O bond, facilitating its cleavage by catalytic hydrogenolysis. Alves has used X ray crystal structures to show lengthening of the aromatic C O bond to 1.42 Å, with the bond energy reduced by around 100 kJ.mol 1 . 11 A better industrial reagent is cyanuric chloride, made from cyanogen chloride. It is used widely in the manufacture of fiber reactive dyes and agrochemicals, and is produced at >100 ktpa at about £1.50/kg. 12 Furthermore it has the ...

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