Flow chemistry and mechanochemistry

Flow: the basic variables

A flow reactor is often just a coil of PFA tubing of inner diameter 0.5–1 mm, fed by syringe or HPLC pumps and held at temperature. The time a slice of liquid spends inside is the residence time

A 10 mL coil fed at a combined 0.5 mL min^{-1} gives \tau = 20 min. Reaction time is therefore set by flow rate and reactor volume rather than by a clock, and the product leaving at steady state has all experienced the same conditions.

Narrow channels mean small distances. Flow is laminar: for water at 1 mL min^{-1} in a 1 mm tube the mean velocity is about 2 cm s^{-1} and the Reynolds number Re = \rho u d/\eta is around 20, far below turbulence. Mixing therefore relies on diffusion, with a time scale t \approx x^2/2D; across 100 µm with D \approx 10^{-9} m^2 s^{-1} that is a few seconds, and static mixers or T-pieces shorten it further. The high surface-to-volume ratio removes heat quickly, so an exotherm that would run away in a 20 L vessel stays isothermal.

What flow makes possible

• Hazardous intermediates: diazomethane, organic azides, acyl azides for Curtius rearrangements and ozonides can be made and consumed in-line so that only milligrams exist at once.
• Superheating: a back-pressure regulator keeps solvents liquid well above their boiling points, so a slow reaction in refluxing ethanol at 78 °C can run at 150 °C in minutes.
• Fast, selective chemistry: organolithium steps that need -78 °C in batch can run near 0 °C because a short, precisely controlled residence time intercepts the unstable intermediate before it decomposes.
• Photochemistry: thin channels are evenly illuminated, unlike a flask where the outer millimetres absorb almost all the light.
• Telescoping: several steps joined with in-line extraction or scavenger cartridges, monitored by in-line IR or UV.

Mechanochemistry

In a mixer mill a jar shakes back and forth at 25–35 Hz; in a planetary mill jars spin on a rotating disc. Impacts and shear crush particles, create fresh surfaces and local heating, and bring reagents into contact without a solvent. Adding a small amount of liquid, liquid-assisted grinding (LAG), often speeds reactions and can select between polymorphs. It is quantified by \eta, the volume of liquid per mass of solid in µL mg^{-1}: \eta = 0 is neat grinding, roughly 0–2 is LAG, and above about 10 is a slurry or solution. Typical successes include cocrystal and salt formation, amide couplings, Suzuki couplings, and metal–organic frameworks made directly from metal oxides. Reactions can even succeed where reagents are insoluble in every common solvent.

Both techniques have moved from curiosity to routine tools, and research now centres on understanding and automating them.

In flow, the frontier is closed-loop experimentation. Reactors with in-line HPLC, IR or benchtop NMR are coupled to Bayesian or other optimisation algorithms that choose the next set of conditions, mapping yield and impurity against temperature, residence time and stoichiometry with little human input. Continuous manufacturing of active pharmaceutical ingredients and final dosage forms is accepted by regulators, and end-to-end flow syntheses of drugs such as ibuprofen have been demonstrated on minute time scales. Electrochemistry and photoredox catalysis benefit particularly, because flow cells give small inter-electrode gaps and uniform light paths. Persistent difficulties are solids, which block narrow channels, and multiphase gas–liquid–solid systems, where kinetics depend on hydrodynamics that change on scale-up. Oscillatory and continuous stirred-tank cascades are common workarounds.

In mechanochemistry, the central open question is mechanism. Energy input from a mill is poorly defined: impact energy, frequency, ball mass, filling degree and bulk temperature all matter and are rarely reported consistently. In situ synchrotron powder diffraction and Raman spectroscopy through the jar wall have shown that milling reactions can proceed via short-lived intermediates and metastable polymorphs invisible in post-reaction analysis. Mechanoredox chemistry uses piezoelectric BaTiO_3 particles, polarised by impacts, to drive radical reactions in place of photocatalysts. Ball milling has been used to generate organometallic reagents such as Grignard and organolithium species in air without dry solvents, and twin-screw extrusion now offers continuous mechanochemical production at kilogram-per-hour scale. Polymer mechanochemistry, in which mechanophores in a chain respond to force by changing colour or releasing a molecule, links the field to materials science.