Topics in Current Chemistry (2019) 377:2
1 3
operation, but the process could be modified in flow to use toluene owing to the
low amount of oxygen present within the flow system at any one time [99].
Photochemical reactions pose an additional challenge for scale‑up, because the
light penetration depth has a critical influence on the performance of photooxy‑
genations [100]. Noël and co‑workers presented an interesting numbering‑up
approach to facilitate the scale‑up of a photochemical aerobic oxidation of thiols to
disulfides by placing eight capillaries in parallel that are irradiated with white LEDs
(Scheme 26b) [101]. A further challenge in parallelization of gas liquid reactions is
that efficient and uniform gas liquid distribution can be difficult to achieve within
parallelized reactor configurations. The lack of uniform mixing in flow can cause
stoichiometry imbalance and poor control of residence in the channels. In the study
by Noël and co‑workers, the calculated standard deviation for yield was less than
10% across the different channels.
Noël and co‑workers reported a mild and selective direct oxidation of acti‑
vated and unactivated C(sp
3
)–H bonds enabled by decatungstate photocatalysis
(Scheme 26c) [102]. Hydrogen atom transfer (HAT) can be utilized for the produc‑
tion of highly reactive radical species, which can be trapped to give synthetically
useful products. Decatungstate is a versatile and inexpensive HAT catalyst that read‑
ily performs hydrogen abstraction on C(sp
3
)–H upon photochemical activation. Ini‑
tial optimization studies using tetrabutylammonium decatungstate (TBADT) dem‑
onstrated that full conversion could not be achieved in batch probably caused by
the slow diffusion of oxygen into the liquid reaction mixture and the limited light
penetration. Nonetheless, significantly improved results were observed within a
continuous flow environment. In particular, the flow approach was successful for
the oxidation of natural scaffolds such as (−)‑ambroxide, pregnenolone acetate,
(+)‑sclareolide and artemisinin.
9 Electrochemistry
A re‑emerging area is electroorganic synthesis [103, 104]. The limitations of con‑
ventional batch electrosynthesis can be overcome by using electrochemical flow
cells [105–107]. Flow electrochemical reactors can be designed to have short dis‑
tances between electrodes, so no, or only low, concentrations of added supporting
electrolyte are required, and a large ratio of electrode area to reactor volume exists.
Mo and Jensen reported N‑hydroxyphthalimide (NHPI)‑mediated electrochemi‑
cal aerobic oxidation of benzylic C–H bonds to form the corresponding ketones
(Scheme 27) [108]. A tube‑in‑tube reactor was used for the safe introduction of
O 2 as a co‑oxidant into the system. The cation‑exchange membrane prevented the
reductive decomposition of NHPI at the cathode, because it minimized the crossover
of the NHPI anion from anolyte to catholyte. Relatively inexpensive RVC electrodes
could be used instead of a platinum electrode. The system described is not inher‑
ently a continuous flow process, because the liquid feeds were recirculated to obtain
high conversions to accommodate the slow reaction kinetics. In a recent perspective
article, Maes and co‑workers proposed that many of the challenges associated with
96
Reprinted from the journal
1 3
operation, but the process could be modified in flow to use toluene owing to the
low amount of oxygen present within the flow system at any one time [99].
Photochemical reactions pose an additional challenge for scale‑up, because the
light penetration depth has a critical influence on the performance of photooxy‑
genations [100]. Noël and co‑workers presented an interesting numbering‑up
approach to facilitate the scale‑up of a photochemical aerobic oxidation of thiols to
disulfides by placing eight capillaries in parallel that are irradiated with white LEDs
(Scheme 26b) [101]. A further challenge in parallelization of gas liquid reactions is
that efficient and uniform gas liquid distribution can be difficult to achieve within
parallelized reactor configurations. The lack of uniform mixing in flow can cause
stoichiometry imbalance and poor control of residence in the channels. In the study
by Noël and co‑workers, the calculated standard deviation for yield was less than
10% across the different channels.
Noël and co‑workers reported a mild and selective direct oxidation of acti‑
vated and unactivated C(sp
3
)–H bonds enabled by decatungstate photocatalysis
(Scheme 26c) [102]. Hydrogen atom transfer (HAT) can be utilized for the produc‑
tion of highly reactive radical species, which can be trapped to give synthetically
useful products. Decatungstate is a versatile and inexpensive HAT catalyst that read‑
ily performs hydrogen abstraction on C(sp
3
)–H upon photochemical activation. Ini‑
tial optimization studies using tetrabutylammonium decatungstate (TBADT) dem‑
onstrated that full conversion could not be achieved in batch probably caused by
the slow diffusion of oxygen into the liquid reaction mixture and the limited light
penetration. Nonetheless, significantly improved results were observed within a
continuous flow environment. In particular, the flow approach was successful for
the oxidation of natural scaffolds such as (−)‑ambroxide, pregnenolone acetate,
(+)‑sclareolide and artemisinin.
9 Electrochemistry
A re‑emerging area is electroorganic synthesis [103, 104]. The limitations of con‑
ventional batch electrosynthesis can be overcome by using electrochemical flow
cells [105–107]. Flow electrochemical reactors can be designed to have short dis‑
tances between electrodes, so no, or only low, concentrations of added supporting
electrolyte are required, and a large ratio of electrode area to reactor volume exists.
Mo and Jensen reported N‑hydroxyphthalimide (NHPI)‑mediated electrochemi‑
cal aerobic oxidation of benzylic C–H bonds to form the corresponding ketones
(Scheme 27) [108]. A tube‑in‑tube reactor was used for the safe introduction of
O 2 as a co‑oxidant into the system. The cation‑exchange membrane prevented the
reductive decomposition of NHPI at the cathode, because it minimized the crossover
of the NHPI anion from anolyte to catholyte. Relatively inexpensive RVC electrodes
could be used instead of a platinum electrode. The system described is not inher‑
ently a continuous flow process, because the liquid feeds were recirculated to obtain
high conversions to accommodate the slow reaction kinetics. In a recent perspective
article, Maes and co‑workers proposed that many of the challenges associated with
96
Reprinted from the journal