• Continuous and scalable synthesis of a porous organic cage by twin screw extrusion (TSE)

      Egleston, B.D.; Brand, M.C.; Greenwell, F.; Briggs, M.E.; James, S.L.; Cooper, A.I.; Crawford, Deborah E.; Greenaway, R.L. (2020-07)
      The continuous and scalable synthesis of a porous organic cage (CC3), obtained through a 10-component imine polycondensation between triformylbenzene and a vicinal diamine, was achieved using twin screw extrusion (TSE). Compared to both batch and flow syntheses, the use of TSE enabled the large scale synthesis of CC3 using minimal solvent and in short reaction times, with liquid-assisted grinding (LAG) also promoting window-to-window crystal packing to form a 3-D diamondoid pore network in the solid state. A new kinetically trapped [3+5] product was also observed alongside the formation of the targeted [4+6] cage species. Post-synthetic purification by Soxhlet extraction of the as-extruded ‘technical grade’ mixture of CC3 and [3+5] species rendered the material porous.
    • Continuous multi-step synthesis by extrusion - telescoping solvent-free reactions for greater efficiency

      Crawford, Deborah E.; Miskimmin, C.K.; Cahir, J.; James, S.L. (2017-11)
      Chemical manufacturing typically requires more than one step, involving multiple batch processes, which makes synthesis at scale laborious and wasteful. Herein, we demonstrate that several reactions can be telescoped into a single continuous process and/or be carried out as a continuous multi-component reaction (MCR), by twin screw extrusion (TSE), in the complete absence of solvent.
    • Efficient continuous synthesis of high purity deep eutectic solvents by twin screw extrusion

      Crawford, Deborah E.; Wright, L.A.; James, S.L.; Abbott, A.P. (2016-02)
      Mechanochemical synthesis has been applied to the rapid synthesis of Deep Eutectic Solvents (DESs), including Reline 200 (choline chloride : urea, 1 : 2), in a continuous flow methodology by Twin Screw Extrusion (TSE). This gave products in higher purity and with Space Time Yields (STYs), four orders of magnitude greater than for batch methods
    • Greener dye synthesis: continuous, solvent-free synthesis of commodity perylene diimides by twin-screw extrusion

      Cao, Q.; Crawford, Deborah E.; Shi, C.; James, S.L. (2020-03)
      A continuous, scalable, and solvent‐free method for the synthesis of various naphthalic imides and perylene diimides (PDIs) using twin‐screw extrusion (TSE) is reported. Using TSE, naphthalic imides were obtained quantitatively without the need for excess amine reactant or product purification. With good functional‐group tolerance, alkyl and benzyl amine derived PDIs (incl. commercial dyes) were obtained in 50–99 % yield. Use of K2CO3, enabled synthesis of more difficult aniline‐derived PDIs. Furthermore, an automated continuous TSE process for Pigments Black 31 and 32 is demonstrated, with a throughput rate of about 1500 g day−1, corresponding to a space time yield of about 30×103 kg m−3 day−1, which is 1–2 orders of magnitude greater than for solvent‐based batch methods. These methods provide substantial waste reductions and improved efficiency compared to conventional solvent‐based methods.
    • Mechanochemical dehydrocoupling of dimethylamine borane and hydrogenation reactions using Wilkinson's catalyst

      Schumacher, C.; Crawford, Deborah E.; Raguž, B.; Glaum, R.; James, S.L.; Bolm, C.; Hernández, J.G. (2018-07)
      Mechanochemistry enabled the selective synthesis of the recherche´ orange polymorph of Wilkinson’s catalyst [RhCl(PPh3)3]. The mechanochemically prepared Rh-complex catalysed the solvent-free dehydrogenation of Me2NHBH3 in a ball mill. The in situ-generated hydrogen (H2) could be utilised for Rh-catalysed hydrogenation reactions by ball milling.
    • Mechanoenzymatic peptide and amide bond formation

      Hernández, J.G.; Ardila-Fierro, K.J.; Crawford, Deborah E.; James, S.L.; Bolm, C. (2017-05)
      Mechanochemical chemoenzymatic peptide and amide bond formation catalysed by papain was studied by ball milling. Despite the high-energy mixing experienced inside the ball mill, the biocatalyst proved stable and highly efficient to catalyse the formation of α,α- and α,β-dipeptides. This strategy was further extended to the enzymatic acylation of amines by milling, and to the mechanosynthesis of a derivative of the valuable dipeptide L-alanyl-L-glutamine.
    • Papain-catalysed mechanochemical synthesis of oligopeptides by milling and twin-screw extrusion: application in the Juliá-Colonna enantioselective epoxidation

      Ardila-Fierro, K.; Crawford, Deborah E.; Körner, A.; James, S.L.; Bolm, C.; Hernández, J.G. (2018-01)
      The oligomerisation of L-amino acids by papain was studied in a mixer ball mill and in a planetary ball mill. The biocatalyst proved stable under the ball milling conditions providing the corresponding oligopeptides in good to excellent yields and with a variable degree of polymerisation. Both parameters were found to be dependent on the reaction conditions and on the nature of the amino acid (specifically on its side-chain size and hydrophobicity). In addition, the chemoenzymatic oligomerisation was demonstrated by utilising twin-screw extrusion technology, which allowed for a scalable continuous process. Finally, the synthesised oligo(L-Leu) 2b proved to be active as a catalyst in the Juliá–Colonna enantioselective epoxidation of chalcone derivatives.
    • Synthesis by extrusion: continuous, large-scale preparation of MOFs using little or no solvent

      Crawford, Deborah E.; Casaban, J.; Haydon, R.; Giri, N.; McNally, T.; James, S.L. (2015-03)
      Grinding solid reagents under solvent-free or low-solvent conditions (mechanochemistry) is emerging as a general synthetic technique which is an alternative to conventional solvent-intensive methods. However, it is essential to find ways to scale-up this type of synthesis if its promise of cleaner manufacturing is to be realised. Here, we demonstrate the use of twin screw and single screw extruders for the continuous synthesis of various metal complexes, including Ni(salen), Ni(NCS)2(PPh3)2 as well as the commercially important metal organic frameworks (MOFs) Cu3(BTC)2 (HKUST-1), Zn(2-methylimidazolate)2 (ZIF-8, MAF-4) and Al(fumarate)(OH). Notably, Al(fumarate)(OH) has not previously been synthesised mechanochemically. Quantitative conversions occur to give products at kg h−1 rates which, after activation, exhibit surface areas and pore volumes equivalent to those of materials produced by conventional solvent-based methods. Some reactions can be performed either under completely solvent-free conditions whereas others require the addition of small amounts of solvent (typically 3–4 mol equivalents). Continuous neat melt phase synthesis is also successfully demonstrated by both twin screw and single screw extrusion for ZIF-8. The latter technique provided ZIF-8 at 4 kg h−1. The space time yields (STYs) for these methods of up to 144 × 103 kg per m3 per day are orders of magnitude greater than STYs for other methods of making MOFs. Extrusion methods clearly enable scaling of mechanochemical and melt phase synthesis under solvent-free or low-solvent conditions, and may also be applied in synthesis more generally.
    • Translating solid state organic synthesis from a mixer mill to a continuous twin screw extruder

      Cao, Q.; Howard, J.L.; Crawford, Deborah E.; James, S.L.; Browne, D.L. (2018-09)
      A study on the translation of a solid-state synthetic reaction from a mechanochemical mixer-mill to a continuous twin-screw extruder is discussed herein. The study highlights some considerations to be made and parameters to be tested in the context of a model fluorination reaction, which is the first organic fluorination to be attempted using extrusion. Upon optimization, which features the first use of grinding auxiliary solids to enable effective synthetic extrusion, the difluorination reaction was successfully translated to the extruder, leading to a 100-fold improvement in Space Time Yield (STY); 29 kg m−3 day−1 in a mixer mill to 3395 kg m−3 day−1 in a twin screw extruder.
    • Use of batch mixing to investigate the continuous solvent-free mechanical synthesis of OLED materials by twin-screw extrusion (TSE)

      Crawford, Deborah E.; James, S.L.; McNally, T. (2018-01)
      Mechanochemical synthesis has the potential to change the way in which chemistry is conducted, particularly with regard to removing or dramatically reducing the need for solvents. Recently, it has been demonstrated that mechanochemistry can be carried out continuously and on large scale through the use of twin-screw extrusion (TSE). TSE has successfully been applied to the synthesis of cocrystals, metal organic frameworks (MOFs), deep eutectic solvents (DESs), metal complexes, and organic condensation reactions. However, while TSE provides a route for mechanochemical synthesis to be developed into a continuous, high-volume manufacturing process, little is currently understood about how to best optimize the various process parameters involved. Herein, we investigate the use of a batch mixer that has been previously used in polymer processing, to optimize mechanochemical reactions performed by extrusion. In particular, reactions between 8-hydroxyquinoline (Hq) and metal acetate salts of zinc or aluminum to give quinolinate complexes Znq2·AcOH and Alq3·AcOH, which are of interest for organic light-emitting diode (OLED) applications, have been investigated. The manner in which the progress of the reaction correlates with the machine torque, temperature, and specific mechanical energy (SME) imparted by the batch mixer has been elucidated. Significantly, this knowledge enabled optimization of the mechanochemical reactions by TSE through the key parameters of screw speed, feed rate, temperature, and particle size.