This thematic issue presents significant research results in automated chemical synthesis and consists of four reviews, twelve full research papers, and one letter. The contributions to this issue cover a wide range of topics, including flow chemistry, laboratory robotics, glycan assembly, reactor design, and 3D printing.
See related thematic issues:
Integrated multistep flow synthesis
Graphical Abstract
Figure 1: Disaccharide repeating unit of the S. pneumoniae serotype 3 CPS.
Figure 2: Building blocks and solid support for the automated solid-phase synthesis of S. pneumoniae serotype...
Scheme 1: Attempted assembly of SP3 trisaccharide 5 using glycosyl phosphate building blocks 1 and 2. Reagent...
Figure 3: HPLC chromatogram of the crude products of the attempted AGA of SP3 trisaccharide 5; conditions: YM...
Scheme 2: Attempted AGA of SP3 trisaccharide 9 using glycosyl phosphate building blocks 1 and 3. Reagents and...
Figure 4: HPLC chromatogram of the crude products of the attempted AGA of SP3 trisaccharide 9; conditions: YM...
Scheme 3: Automated synthesis of linker-bound glucuronic acid 10 using glycosyl phosphate building block 1. R...
Scheme 4: Automated synthesis of SP3 trisaccharide 5 using glycosyl phosphate building blocks 1 and 2. Reagen...
Figure 5: HPLC chromatogram of the crude products of the automated solid-phase SP3 trisaccharide 5 synthesis;...
Scheme 5: Global deprotection of SP3 trisaccharide 5. Reagents and conditions: a) LiOH, H2O2, THF, −5 °C to r...
Graphical Abstract
Figure 1: Steric interactions of the carbon monoxide coordination to the aryl complex intermediate.
Figure 2: A) molecular structure of complex 1; B) ball and stick representation of X-ray structure; C) ball a...
Figure 3: Reverse “tube-in-tube” reactor.
Scheme 1: Comparison of plug flow reactor carbonylation (left) and “tube-in-tube” reactor carbonylation (righ...
Scheme 2: Schematic diagram of the flow process.
Figure 4: Phosphine ligands used for the ortho-carbonylation reaction.
Scheme 3: The batch carbonylation of 2-chloro-1-iodobenzene in conventional lab (top) and using a Parr autocl...
Scheme 4: Structures of ortho-substituted carboxylic acids prepared via a continuous flow hydroxy-carbonylati...
Scheme 5: Flow carbonylation of 2-iodonaphtalene.
Figure 5: X-ray structure of substrate 33.
Scheme 6: Scale up synthesis of 2-chloro-4-fluorobenzoic acid (20).
Graphical Abstract
Scheme 1: Comparison of early C–N and C–O coupling reactions.
Figure 1: General flow scheme for catalytic Chan–Lam reaction.
Figure 2: Observed trend for the effect of changing oxygen pressure on the NMR yield of 19.
Figure 3: Comparison of 1H NMR spectra of non-purified (top) and QP-DMA purified (bottom) continuous flow syn...
Scheme 2: Scope of the catalytic Chan–Lam reaction in continuous flow.
Scheme 3: Syntheses of substrate 39.
Figure 4: NOESY NMR spectrum for 30 with the characteristic NOESY signal encircled.
Figure 5: NOESY NMR spectrum for 33 with the characteristic NOESY signal encircled.
Figure 6: NOESY NMR spectrum for 35 with the characteristic NOESY signal encircled.
Figure 7: Substrates that gave no products in flow.
Scheme 4: Scale-up procedure for 19.
Graphical Abstract
Scheme 1: PTSA-catalyzed diazotization and azo coupling reaction.
Scheme 2: Ferric hydrogen sulfate (FHS) catalyzed azo compound synthesis.
Scheme 3: Synthesis of azo compounds in the presence of silica supported boron trifluoride.
Scheme 4: Phase transfer catalyzed azo coupling of 5-methylresorcinol in microreactors.
Scheme 5: Synthesis of yellow pigment 12 in a micro-mixer apparatus.
Scheme 6: Continuous flow synthesis of Sudan II azo dye in LTF-MS microreactors.
Figure 1: pH profile plot at constant flow rate of 0.03 mL/min.
Figure 2: pH profile plot at a constant flow rate of 0.7 mL/min.
Scheme 7: Azo coupling reaction under acidic conditions.
Figure 3: pH profile plot at a constant flow rate of 0.03 mL/min.
Figure 4: pH profile plot at constant flow rate of 0.7 mL/min.
Figure 5: Temperature profile plot at constant pH 5.66.
Figure 6: Schematic representation of the microreactor set up.
Figure 7: Schematic representation of the microreactor set up.
Figure 8: Scaled up microreactor set up: PTFE tubing i.d. 1.5 mm a) Chemyx Fusion 100 classic syringe pump, b...
Graphical Abstract
Scheme 1: Reaction pathways of α-thio-β-chloroacrylamides.
Scheme 2: Typical three-step batch preparation of α-thio-β-chloroacrylamide.
Scheme 3: Batch process for preparation of α-chloroamide 1.
Scheme 4: Process for the conversion of 2-chloropropionyl chloride and p-toluidine to α-chloroamide 1 under o...
Scheme 5: Conversion of 1 to 2 in continuous mode using MeOH as solvent.
Scheme 6: Optimized process for the conversion of α-chloroamide 1 to α-thioamide 2 under flow conditions.
Scheme 7: Mechanism of the β-chloroacrylamide cascade process [29].
Scheme 8: Optimized flow process for conversion of α-thioamide 2 to α-thio-β-chloroacrylamide Z-3.
Graphical Abstract
Figure 1: Prusa i3 RepRap printer modified for the automated synthesis of ibuprofen. Left: Full view of robot...
Scheme 1: Synthetic route chosen for automated synthesis robot.
Figure 2: Top: The three reaction vessels printed for ibuprofen synthesis on different scales; bottom left: i...
Scheme 2: The digitisation of the synthesis of ibuprofen. This flow diagram shows the individual steps of the...
Graphical Abstract
Figure 1: Typical pilot scale single screw extruder (left) and a laboratory scale twin screw extruder (right)....
Figure 2: PTFE screw employed in single screw extrusion, with increasing root diameter (RD) from 45 mm to 95 ...
Figure 3: Modulated stainless steel intermeshing co-rotating screws employed typically in twin screw extrusio...
Scheme 1: Polymerisation of styrene using s-BuLi as an initiator.
Scheme 2: Telescoping process of the formation of polystyrene, followed by post polymerisation functionalisat...
Scheme 3: Proposed mechanism for the branching of polylactide. Adapted from [23].
Scheme 4: Chemical reaction between isocyanate and an alcohol to form polyurethane.
Figure 4: Representative diagram explaining the process involved in step growth polymerisation, which involve...
Scheme 5: Generic polycondensation reaction to produce polyamides.
Figure 5: Comparison of choline chloride/D-fructose DES prepared via twin screw extrusion (left) and conventi...
Scheme 6: Synthesis of HKUST-1, ZIF-8 and Al(fumarate)OH by twin screw extrusion. Adapted from [2].
Figure 6: Synthesis of Ni(NCS)2(PPh3)2 and [Ni(salen)] by twin screw extrusion. Adapted from [2].
Graphical Abstract
Scheme 1: Automated synthesis of 4a.
Figure 1: Full picture of ChemKonzert, showing two reaction vessels (RF1 and RF2), a centrifugal separator (S...
Graphical Abstract
Scheme 1: The reaction of (R)-(−)-carvone (1) with semicarbazide to form the corresponding semicarbazone 2.
Figure 1: CAD model of SL reactor design RD1 (left), RD1 with attached sprung clip (centre), commercially ava...
Figure 2: Energy versus wavelength spectra comparing the amount of stray light being picked up by the detecto...
Figure 3: Reactor set-up for carvone optimisation using RD1 as an inline spectroscopic flow cell. Reagents we...
Figure 4: RD1 held in place within the DAD compartment of an Agilent 1100 HPLC.
Figure 5: Optimisation plot for the SIMPLEX optimisation of semicarbazone 2. Optimum reaction conditions with...
Figure 6: SLM reactor RD2 (left), CAD model of RD2 (right). External dimensions of RD2 are 100 (length) × 20 ...
Figure 7: RD2 held in place within the thermostatted Agilent 1100 series column department.
Figure 8: Optimisation plot for the SIMPLEX optimisation of semicarbazone 1. Optimum reaction conditions were...
Scheme 2: The reaction of pentafluoropyridine (3) with 2-(methylamino)phenol (4) to form the corresponding fu...
Figure 9: Optimisation plot for the SIMPLEX optimisation of the fused polycyclic heterocycle 5. Two optimal d...
Figure 10: SLM reactor design RD3 (left), CAD model of RD3 (right). External dimensions of RD3 are 89 (length)...
Figure 11: Optimisation plot for the SIMPLEX optimisation of semicarbazone 2. Optimum reaction conditions were...
Graphical Abstract
Scheme 1: Diels–Alder reaction of myrcene (1), with various dienophiles 2.
Figure 1: Kinetic studies of the Diels–Alder reaction between myrcene (1) and acrylic acid (2b); a) for diffe...
Figure 2: Comparison of conversions in three different reactors for the Diels–Alder reaction of myrcene (1) w...
Graphical Abstract
Figure 1: A framework of closed-loop or self-optimisation combining smart DoE algorithms, process analytics, ...
Scheme 1: Catalytic reaction scheme showing C–H activation of an aliphatic secondary amine 1 to form the azir...
Scheme 2: A simplified reaction mechanism based on literature [21], showing intermediate B and the side reaction ...
Figure 2: Schematics of the automated continuous-flow system used for model development and ‘black-box’ seque...
Figure 3: Results of experiments from the MBDoE in Table 2, conducted for parameter estimation, and their correspond...
Figure 4: Results of in silico iterations of the multi-objective active learner (MOAL) algorithm [26]. Each itera...
Figure 5: Results of the optimisation driven by a statistical algorithm and in the absence of a physical proc...
Graphical Abstract
Scheme 1: In-flask (batch) preparation of imidazo[1,2-a]pyridin-2-yl-1,2,4-oxadiazoles (S1P1 agonists) [27].
Scheme 2: Gram-scale synthesis of mGlu5 NAM by continuous flow in combination with microfluidic extraction.
Scheme 3: Gram-scale synthesis of imidazo[1,2-a]pyridin-2-yl-1,2,4-oxadiazole S1P1 agonist scaffold by contin...
Graphical Abstract
Figure 1: Graphical representation of (a) conventional flow cell with a saddle-shaped RF coil and (b) flow ca...
Figure 2: Possible geometries of NMR coils.
Figure 3: The NMR pulse sequence used for NOESY with WET solvent suppression [28].
Figure 4: Reaction of p-phenylenediamine with isobutyraldehyde. (a) Flow tube and (b) 1H NMR stacked plot (40...
Figure 5: Scheme and experimental setup of the flow system.
Figure 6: (a) Microfluidic probe. (b) Microreactor holder. (c) Stripline NMR chip holder. (d) Arrangement of ...
Figure 7: Acetylation of benzyl alcohol. Spectra at (a) 9 s and (b) 3 min. Stoichiometry: benzyl alcohol/DIPE...
Figure 8: a) Design of MICCS and b) schematic diagram of MICCS–NMR [45]. CH2Cl2 solutions of oxime ether and trie...
Scheme 1: Proposed reaction mechanism.
Figure 9: Flowsheet of the experimental setup used to study the reaction kinetics of the oligomer formation i...
Figure 10: Design of the experimental setup used to combine on-line NMR spectroscopy and a batch reactor. Repr...
Figure 11: Reaction system 1,3-dimethylurea/formaldehyde. Main reaction pathway and side reactions [47].
Figure 12: (a) Experimental setup for the reaction. (b) Reaction samples analyzed independently by NMR. (c) Pl...
Figure 13: (a) Schematics of two microreactor cohorts of sample fractions. (b) Reaction product concentration ...
Figure 14: NMR analysis of the reaction of benzaldehyde (2 M in CH3CN) and benzylamine (2 M in CH3CN) (1:1), r...
Figure 15: Flow diagram showing the self-optimizing reactor system. Reproduced with permission from reference [50]...
Graphical Abstract
Figure 1: m-Sulfamoylbenzamides as Sirtuin 2 inhibitors (SIRT2) or suppressor of polyglutamine aggregation (p...
Figure 2: Syrris AFRICA system.
Graphical Abstract
Scheme 1: Target reaction – intramolecular cyclisation of 1 followed by N-methylation with methanol to yield ...
Figure 1: Simplified schematic demonstrating a self-optimising reactor [34,35,37,44]. The reagents are pumped into the sys...
Figure 2: Result of the SNOBFIT optimisation for N-methylpiperidine (2b) with and without CO2 showing yields ...
Scheme 2: Cyclisation and N-alkylation of 1,4- and 1,6-amino alcohols.
Scheme 3: a) Reactions highlighting the incorporation of CO2 in to 16. b) High temperature reaction of 15 yie...
Scheme 4: Summary of products obtained from the reactions of amino alcohols over γ-Al2O3 in scCO2.
Figure 3: Diagram of the high pressure equipment used in the experiments.
Graphical Abstract
Scheme 1: Common reaction pathways for alkyne hydrogenation reactions.
Figure 1: Schematic representation of most common reactor types for batch and continuous-flow partial hydroge...
Figure 2: Schematic representation of flow regimes in microchannels; (a) bubbly flow, (b) slug/Taylor or segm...
Figure 3: Sketch of typical continuous flow apparatus for liquid-phase catalytic alkynes hydrogenation reacti...
Scheme 2: Hydrogenation reactions of terminal alkynes with potential products and labelling scheme.
Figure 4: Structure of Pd@mpg-C3N4 (a), Pd(HHDMA)@C (b), Pd(Pb)@CaCO3 (c) and Pd@Al2O3 (d) catalysts. The str...
Figure 5: Sketch of composition (left) and optical image of Pd@MonoBor monolithic reactor (right). Adapted wi...
Figure 6: X-ray tomography 3D-reconstruction image of MonoBor [133]. Unpublished image from the authors.
Figure 7: Representative TEM image of titanate nanotubes with immobilized PdNP (arrows). Adapted with permiss...
Figure 8: Conversion and selectivity vs. time-on-stream for the continuous-flow hydrogenation of 6 over Pd@Mo...
Figure 9: Continuous-flow hydrogenation of 3, 6 and 7 over different catalytic reactor systems. Data from ref...
Scheme 3: Hydrogenation reactions of internal alkynes with potential products and labelling scheme.
Figure 10: Continuous-flow hydrogenation of 11 over Pd@MonoBor catalyst. a) Conversion and selectivity as a fu...
Figure 11: Conversion and selectivity vs time-on-stream for the continuous-flow hydrogenation of 11 over Pd@Mo...
Figure 12: Continuous-flow hydrogenation reaction of 11 over packed-bed catalysts. Adapted with permission fro...
Figure 13: Images of the bimodal TiO2 monolith with well-defined macroporosity: (a, b) optical; (c) X-ray tomo...
Figure 14: Selectivity of the continuous-flow partial hydrogenation reaction of 3 and 4 over packed-bed Pd cat...
Graphical Abstract
Figure 1: A number of experiments for various optimization algorithms [46].
Figure 2: Symbols used for block and P&ID diagrams.
Scheme 1: Multistep synthesis of olanzapine (Hartwig et al. [10])
Figure 3: (A) Block diagram representation of the process shown in Scheme 1, (B) piping and instrumentation diagram o...
Scheme 2: Multistep flow synthesis for tamoxifen (Murray et al. [11]).
Figure 4: (A) Block diagram representation of the process shown in Scheme 2, (B) piping and instrumentation diagram o...
Figure 5: (A) Block diagram representation of the process shown in Scheme 3, (B) piping and instrumentation diagram o...
Scheme 3: Multistep flow synthesis of rufinamide (Zhang et al. [14]).
Figure 6: (A) Block diagram representation of the process shown in Scheme 4, (B) piping and instrumentation diagram o...
Scheme 4: Multistep synthesis for (±)-Oxomaritidine (Baxendale et al. [9]).
Figure 7: (A) Block diagram representation of the process shown in Scheme 5, (B) piping and instrumentation diagram o...
Scheme 5: Multistep synthesis for ibuprofen (Snead and Jamison [60]).
Scheme 6: Multistep synthesis for cinnarizine and buclizine derivatives (Borukhova et al. [23])
Figure 8: (A) Block diagram representation of the process shown in Scheme 6, (B) piping and instrumentation diagram o...
Scheme 7: Multistep synthesis for (S)-rolipram (Tsubogo et al. [4])
Figure 9: (A) Block diagram representation of the process shown in Scheme 7 (colours for each reactor shows different...
Figure 10: (A) Block diagram representation of the process shown in Scheme 8, (B) piping and instrumentation diagram o...
Scheme 8: Multistep synthesis for amitriptyline (Kupracz and Kirschning [7]).