THE EVOLUTION OF IMMOBILIZED REAGENTS AND THEIR APPLICATION IN FLOW CHEMISTRY FOR THE SYNTHESIS OF NATURAL PRODUCTS AND PHARMACEUTICAL COMPOUNDS - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 366

manufactured microfluidic reactor chips into flow systems, controlled mixing and
exact temperature regulation of reaction sequences can be achieved (Figure 11.1c).
This essentially translates conventional batch reaction sequences into a continuous
flowing, dynamic cascade by passing flow streams of the starting materials
through various immobilized reagents or combining intermediates and reagents
in appropriately designed/combined reactor blocks. In this way, material gener-
ated in situ can be involved in a series of consecutive reactions and scavenging
purification protocols before exiting the reactor into a chemically inactive
environment ready to be collected as a pure product. Throughout this processing,
the reactors and packed cartridges can be heated or cooled. In addition, the
application of oscillation, ultrasound, electrical currents, or microwave irradiation
can be used. Furthermore, catalysts have been deposited on reactor surfaces or
tethered onto their surfaces, opening up new opportunities for flow synthesis
development; for example, a new polymer tubing reactor that has palladium
tethered to the inner wall has been developed that enables Pd-catalyzed reactions
to be conducted in flow [22].
Systems to conduct flow chemistry can be assembled from individual
components such as HPLC or syringe-driven pumps with appropriate connective
tubing, glass microreactor chips, tubular heating coils, fritted columns and other
units, for example, microwave machines, and hydrogen or ozone gas generators.
Commercial flow systems are available for micro- and mesoscale reactions that can
be reconfigured quite readily to suit the specific needs of the reaction. Micro-
systems (e.g., Advion NanoTek LF

) have multiple syringe pumps and micro-
fluidic heating blocks and can be used to quickly screen reaction conditions on a
small scale (Figure 11.2a). Mesosystems, such as the Uniqsis FlowSyn and
Vapourtec

R4 system, consist of at least two HPLC pumps, internal
pressure monitors, and coil and column heating facilities (Figure 11.2b and c).
These systems have various onboard automation features and mechanical safety
features, for example, pressure sensors that trigger automatic shutdown when a
blockage or leak is detected.
For the heating and cooling of flow streams, tubular coils are often used as these
can operate across a wide temperature range of

R2 þ

78 to 250 C (Figure 11.3a).
Furthermore, they can be connected in parallel (Figure 11.3b) to scale-up reaction
productivity or set in series (Figure 3c) to increase the reaction residence time or
create sequential but different temperature zones. Microscale reactions can be scaled
up by increasing throughput using stacks of coils of microcapillary tubing that can be
heated using a specialized heating unit [23,24].
Microwave reactors can be used to heat reaction streams as they pass through
columns containing an immobilized reagent. Reactions with metal-tethered cata-
lysts, for example, polyurea microencapsulated palladium species (Pd EnCat), are a
good example, whereby microwave heating activates the active palladium spe-
cies [25]; a number of reaction types using Pd EnCat have been explored, for
example, transfer hydrogenations [26], hydrogenations of epoxides [27], and
Suzuki reactions [28]. Being able to perform microwave reactions in flow readily
facilitates the transition from batch to continuous flow processing. Gas generators